Combinatorial omics analysis reveals perturbed lysosomal homeostasis in collagen VII-deficient keratinocytes

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Combinatorial omics analysis reveals perturbed lysosomal homeostasis in collagen VII-deficient keratinocytes

Kerstin Thriene, Björn Andreas Grüning, Olivier Bornert, Anika Erxleben, Juna Leppert, Ioannis Athanasiou, Ekkehard Weber, Dimitra Kiritsi, Alexander Nyström, Thomas Reinheckel, Rolf Backofen, Cristina Has, Leena Bruckner-Tuderman, Jörn Dengjel

Supplemental Experimental Procedures

Cell culture and stable isotope labelling by amino acids in cell culture

Keratinocytes were isolated from skin samples of the eight patients and, as controls, from the skin of seven healthy, age-matched controls. Cells were subcultured and passaged in keratinocyte growth medium (Keratinocyte-SFM) (Invitrogen, Karlsruhe, Germany), supplemented with keratinocytes supplements (Bovine Pituitary Extract (BPE); EGF, human recombinant).

Normal human keratinocytes where seeded on 6-well-plate culture dishes. Medium was exchanged the following day and 10 ng/mL TGF-β 1 (Peprotech, Hamburg, Germany) was added. RDEB keratinocytes were incubated with 4.4 µg/mL TGF-β receptor type I and type II dual inhibitor LY2109761 (Adooq BioScience LLC, Irvine, CA, USA). Cells were harvested after 48 h by incubation with lysis buffer (25 mM Tris-HCL pH 7.5, 0.1 M NaCl, 1% NP-40, EDTA, Pefablock, Phosphatase inhibitor 3 cocktail, PHJ2) on a shaker for 20 min on ice. Cells were then scraped off, transferred into 1.5 mL tubes, vortexed and centrifuged at 13`000 rpm for 10 min. Supernatants were incubated for 5 min at 95°C in SDSbuffer and directly used for WB analysis or stored at -80°C until use.

For MS analysis, cells were cultured in keratinocyte growth medium (KGM2) (Promocell, Heidelberg, Germany) without arginine and lysine, but with “SupplementMix” (0.004 mL/mL bovine pituitary gland extract, 0.125 ng/mL recombinant human epidermal growth factor, 5 μg/mL

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recombinant human insulin, 0.33 μg/mL hydrocortisone, 0.39 μg/mL epinephrine, 10 μg/mL human holo transferrin) and 0.06 mM CaCl2 , 210 mg/L L-arginine and 63 mg/L L-lysine for the unlabeled condition. Cells were “heavy” labeled for 2 weeks with 210 mg/L L-arginine-13_C

6-15N4 (Arg10) and 63 mg/L L-lysine-13C6-15N2 (Lys8) or “medium” labeled with 210 mg/L L-arginine-13C6 (Arg6) and 63 mg/L L-lysine-2H4 (Lys4). Biological replicates were obtained by swapping labels.

RNA isolation from primary human keratinocytes and RNAseq

Total RNA from 80-90% confluent keratinocytes was isolated using the RNeasy Mini Kit according to the manufacturer’s instructions. Libraries were constructed with the stranded TruSeq GOLD protocol (RS-122-2301) followed by rRNA depletion (Illumina Ribo-Zero rRNA removal kit human, mouse, rat). Sequencing was performed on a HiSeq2500 (50 bp, Illumina, San Diego, USA). RNAseq raw data is available as a NCBI BioProject, ID PRJNA373827 (http://www.ncbi.nlm.nih.gov/bioproject/373827).

Functional annotation was done with a gene ontology analysis based on Cytoscape and ClueGO (2.2.4) (Bindea et al., 2009). Overrepresented GO terms from the categories “biological process”, “cellular component” and “molecular function” were corrected by Benjamini–Hochberg procedure for multiple testing-controlled p-values. Significantly enriched terms were functionally grouped and visualized and the most significant term of each group was displayed.

Data analysis

Transcriptomics. RNAseq data were analyzed using the Freiburg instance of Galaxy (Afgan et al., 2016; Blankenberg et al., 2011). Therefore, a workflow was created including steps from quality-control of raw reads to calculation of differentially expressed genes. Quality control was performed using FastQC. After manual quality inspection, reads were trimmed with Trim Galore! accordingly. RNAseq data were mapped to the human (hg19) reference genome, using TopHat2 and the human gene annotation model (GRCh37.75) (Kim et al., 2013). After read mapping,

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htseq-3

count was applied to count aligned reads per gene in a BAM file which overlap features in the gtf file (Anders et al., 2015). These count data then were used as input files for DESeq2 to calculate differentially expressed transcripts of RDEB patients compared to controls (Love et al., 2014). The results were filtered first by the adjusted p value 0.1 (FDR controlled with Benjamini-Hochberg procedure) and second by the log2 fold change. The workflow is publicly available on github https://github.com/galaxyproject/training-material/tree/master/RNA-Seq.

To show altered gene expression in RDEB keratinocytes compared to controls, cluster analysis was performed of 301 differentially regulated genes in RDEB keratinocytes (Benjamini–Hochberg corrected q-value 0.1) as determined by high-throughput sequencing of the transcripts. TPM values were log2-transformed and z-score normalized. Columns containing data from the different samples were hierarchically clustered and rows containing gene entries were clustered by k-means.

Functional annotation was done with a Gene Ontology (GO) analysis based on Cytoscape and ClueGO (2.2.4) (Bindea et al., 2009; Shannon et al., 2003). Over represented GO terms from the categories ‘biological process’, ‘cellular component’ and ‘molecular function’ were corrected by Benjamini–Hochberg procedure for multiple testing-controlled p-values. Significantly enriched terms were functionally grouped and visualized and the most significant term of each group was displayed.

Proteomics. To generate a list of extracellular proteins, the data were filtered using the freely available Perseus software to extract proteins that belong to the “matrisome” and/or are annotated as “extracellular” (extracellular region, extracellular region part, extracellular space, extracellular matrix, extracellular matrix part, proteinaceous extracellular matrix, extracellular organelle, extracellular membrane-bounded organelle, extracellular vesicular exosome) and “cell adhesion” (Tyanova et al., 2016). Data were readjusted to a median of 1 and log2 transformed and z-score normalized. SOTA clustering was performed of proteins quantified in intra- (11 clusters) and

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extracellular (7 clusters) compartments of RDEB cells compared to controls. Proteins in each cluster were tested by DAVID for enriched GO terms (biological process (BP), cellular compartment (CC) and molecular function (MF)) applying the default settings with a minimum significance of p<0.01 (Huang da et al., 2009). Network analysis of significantly regulated ECM proteins (Welch's t-test, permutation-based FDR 0.05) was created by STRING DB (confidence score 0.4) and Cytoscape (Szklarczyk et al., 2015).

Immunofluorescence staining of frozen skin biopsy specimens

Immunofluorescence staining of RDEB and site-matched control skin was performed on 5 µm cryosections, which were air dried and incubated with primary antibodies at 4°C overnight. Primary antibodies to the following proteins were used: anti-collagen VII (LH7.2, Abcam), anti-S100A9 (AF2065, R&D Systems, Minneapolis, MN, USA) and anti-cathepsin B (clone 6D5 and 3E4) (Weber et al., 2015). After four washing steps of 5 minutes each, secondary antibodies were applied for 1 h. Secondary antibodies were: Alexa-488 anti-mouse IgG or Alexa-488 anti-rabbit IgG (Invitrogen, Darmstadt, Germany). Nuclei were stained with 4′,6-diamidino-2-phenylindole (DAPI; Millipore, Temecula, CA, USA). Stained sections were observed with an Axiophot fluorescence microscope (Carl Zeiss, Jena, Germany). Images were captured using Zeiss internal software.

Active site labeling for cysteine cathepsins

Keratinocytes (10 cm2_{petri dishes, 80-90% confluent) were washed 3 times with ice-cold DPBS.} Cells were lysed by adding 200 µL ice-cold sodium acetate buffer directly onto the petri dish. Cells were scraped off, incubated on ice for 30 min and centrifuged (10,000xg, 10 min, 4°C). Cell lysates (without protease inhibitors) were then used directly for activity assays to avoid degradation of proteins. Cysteine cathepsins were labelled by incubating cell lysates with DCG-04 (final concentration 10 µM) for 1 h on ice (Greenbaum et al., 2000). In order to distinguish western blot

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signals, prior to DCG-04 treatment cell lysates were incubated for 15 min on ice with the cysteine protease inhibitor E-64 (final concentration 10 µM) or the specific cathepsin B inhibitor Ca074 (final concentration 5 µM). In order to reveal unspecific binding of the substrate, proteases were inactivated in a control sample through incubation for 10 min at 95°C prior to DCG-04 treatment. Afterwards, samples were directly boiled at 95°C for 10 min and then used for WB analysis or stored at -20°C.

Western blot

Cell lysate or ECM samples corresponding to 1/10 of confluent 10 cm2_{cell culture dishes were} separated by SDS–PAGE using self-casted SDS gels and transferred onto nitrocellulose membrane. Membranes were blocked with 5% milk powder in 1x TBS-T for a minimum of 1 h at room temperature and incubated with primary antibodies diluted with the same buffer for 1 h or overnight at 4°C. HRP-conjugated secondary antibodies and a chemiluminescent detection assay (Immobilon Western, Millipore, Schwalbach, Germany) were used for visualization according to manufacturer’s instructions.

For the active site labeling for cysteine cathepsins, fluorescently labeled streptavidin (LI-COR, Lincoln, NE, USA) was used to detect the biotin tag of the DCG-04 substrate. Detection was carried out on a Li-Cor Odyssey Infrared scanning system. ß-actin was used as loading control, using respective fluorescently labeled secondary antibodies.

To quantify changes of cathepsin B amount due to the treatment with TGF-1 bands corresponding to the single-chain enzyme of four different controls were quantified using image J. To investigate changes of cathepsin B after treatment with LY2109761 bands corresponding to the single-chain enzyme of four different RDEB keratinocytes were quantified. Intensities (AU) were normalized to the -tubulin signals from the same blots. Antibodies used for WB analysis: Anti-cathepsin B (3E4, Weber et al 2015) 1:1000; Anti-Phospho-Smad3 (phospho S423 + S425;

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EP823Y; ab52903, Abcam, Cambridge, UK) 1:1000; Anti-Phospho-Smad2 (Ser465/467 (138D4) Cell Signalling).

Autophagy assay

10 cm cell culture dishes (approximately 50 % confluent) were washed with PBS once and then incubated with fresh medium including 20 nM concanamycin A for 2 h in order to block degradation of autopahgosomes. Cells were then harvested, lysed and used for western blot analysis (anti-LC3 (clone5F10, Nanotools, Teningen, Germany)).

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Combinatorial omics analysis reveals perturbed lysosomal homeostasis in collagen VII-deficient keratinocytes

Kerstin Thriene, Björn Andreas Grüning, Olivier Bornert, Anika Erxleben, Juna Leppert, Ioannis Athanasiou, Ekkehard Weber, Dimitra Kiritsi, Alexander Nyström, Thomas Reinheckel, Rolf Backofen, Cristina Has, Leena Bruckner-Tuderman, Jörn Dengjel

Supplemental Figures

 Supplemental Figure S1: Correlation of replicates of ECM isolated from primary human keratinocytes.

 Supplemental Figure S2: PCA replicates ECM

 Supplemental Figure S3: Relative mRNA and protein abundances of laminin beta 1 and gamma 1

 Supplemental Figure S4: Gene expression analysis of keratin-encoding genes.  Supplemental Figure S5: Network analysis of significantly regulated intracellular

proteins.

 Supplemental Figure S6: Spontaneous restoration of COL7A1 expression in skin of a DEB patient

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Supplemental Figure S1: Correlation of replicates of ECM isolated from primary human keratinocytes.

Correlation of biological replicates of the ECM proteome isolated of primary human DEB keratinocytes (A, B) or healthy controls (C, D), r = Pearson correlation coefficient.

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Principle component analysis (PCA) of combined SILAC ratios for each patient and the respective controls.

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Supplemental Figure S3: Relative mRNA and protein abundances of laminin beta 1 and gamma 1

Relative values compared to the respective control 1 (Ctrl 1) are shown. Protein levels were significantly reduced (Welch's t-test, Permutation-based FDR 0.05) in ECM isolated of DEB cells compared to controls while mRNA levels did not change significantly.

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Supplemental Figure S4: Gene expression analysis of keratin-encoding genes.

Gene expression analysis of keratin encoding genes. Bar graphs show transcript abundances (TPM values). *: BH-corrected q-value < 0.1.

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Supplemental Figure S5: Network analysis of significantly regulated intracellular proteins.

STRING DB was used to identify protein-protein interactions of significantly regulated proteins (confidence score 0.4; Welch's t-test, Permutation-based FDR 0.05, minimal fold change > +/- 2). Color scale indicates log2 transformed SILAC ratios of respective proteins.

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Supplemental Figure S6: Spontaneous restoration of COL7A1 expression in skin of a DEB patient

Immunofluorescence staining of DEB skin reveals spontaneously restored C7 levels (green signal). Blue = DAPI staining.

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Annotation Cluster 1 Enrichment Score: 4.785469752865533 Category Term Count % PValue Genes List Total Pop Hits Pop Total Fold Enrichment Bonferroni Benjamini FDR

GOTERM_BP_FAT GO:0007155~cell adhesion 13 1.419213974 1.88E-07 "CD9, COL17A1, LGALS3BP, LY6D, ITGA6, PKP2, ITGB4, DSC3, CTNND1, LAMC1, CD151, CTNNB1, PNN" 38 700 13528 6.611428571 1.17E-04 1.17E-04 2.79E-04

GOTERM_BP_FAT GO:0022610~biological adhesion 13 1.419213974 1.91E-07 "CD9, COL17A1, LGALS3BP, LY6D, ITGA6, PKP2, ITGB4, DSC3, CTNND1, LAMC1, CD151, CTNNB1, PNN" 38 701 13528 6.601997147 1.19E-04 5.97E-05 2.84E-04

GOTERM_CC_FAT GO:0005911~cell-cell junction 6 0.655021834 2.32E-04 "COL17A1, ITGA6, PKP2, DSC3, CTNNB1, PNN" 39 190 12782 10.34979757 0.041357115 0.020896898 0.285969015

GOTERM_CC_FAT GO:0044459~plasma membrane part 14 1.528384279 0.008662785 "MYO1C, ITGB4, SDC4, CD151, EPHA2, PNN, CTNNB1, CD9, CDC42, COL17A1, ITGA6, PKP2, RAB35, DSC3" 39 2203 12782 2.082800843 0.794743634 0.088940249 10.18033999

GOTERM_BP_FAT GO:0031589~cell-substrate adhesion 5 0.545851528 1.42E-04 "COL17A1, ITGA6, ITGB4, LAMC1, CTNNB1" 38 98 13528 18.16326531 0.085139901 0.029225793 0.211227656

GOTERM_CC_FAT GO:0016323~basolateral plasma membrane 6 0.655021834 3.15E-04 "COL17A1, MYO1C, ITGA6, ITGB4, SDC4, CTNNB1" 39 203 12782 9.687002653 0.055762015 0.014241872 0.388279809

GOTERM_BP_FAT GO:0007160~cell-matrix adhesion 4 0.436681223 0.001819412 "COL17A1, ITGA6, ITGB4, CTNNB1" 38 89 13528 16 0.679594593 0.090488238 2.668357659

GOTERM_CC_FAT GO:0016323~basolateral plasma membrane 6 0.655021834 3.15E-04 "COL17A1, MYO1C, ITGA6, ITGB4, SDC4, CTNNB1" 39 203 12782 9.687002653 0.055762015 0.014241872 0.388279809

GOTERM_CC_FAT GO:0009925~basal plasma membrane 3 0.327510917 0.002673947 "COL17A1, MYO1C, ITGB4" 39 26 12782 37.81656805 0.385723565 0.059095638 3.250136712

GOTERM_CC_FAT GO:0045178~basal part of cell 3 0.327510917 0.003552289 "COL17A1, MYO1C, ITGB4" 39 30 12782 32.77435897 0.476735161 0.057179033 4.296377095

GOTERM_CC_FAT GO:0070161~anchoring junction 6 0.655021834 1.46E-04 "ITGA6, PKP2, DSC3, SDC4, CTNNB1, PNN" 39 172 12782 11.43291592 0.026194503 0.026194503 0.179813258

GOTERM_CC_FAT GO:0005911~cell-cell junction 6 0.655021834 2.32E-04 "COL17A1, ITGA6, PKP2, DSC3, CTNNB1, PNN" 39 190 12782 10.34979757 0.041357115 0.020896898 0.285969015

GOTERM_CC_FAT GO:0030057~desmosome 3 0.327510917 0.001580896 "PKP2, DSC3, PNN" 39 20 12782 49.16153846 0.250201457 0.046858384 1.933466446

GOTERM_CC_FAT GO:0043296~apical junction complex 4 0.436681223 0.003123645 "PKP2, DSC3, CTNNB1, PNN" 39 99 12782 13.24216524 0.434131284 0.061306166 3.787102337

GOTERM_CC_FAT GO:0016327~apicolateral plasma membrane 4 0.436681223 0.003398536 "PKP2, DSC3, CTNNB1, PNN" 39 102 12782 12.85268979 0.461833302 0.060078288 4.113987507

GOTERM_CC_FAT GO:0030054~cell junction 7 0.76419214 0.003936286 "COL17A1, ITGA6, PKP2, DSC3, SDC4, CTNNB1, PNN" 39 518 12782 4.428967429 0.512184381 0.058064189 4.75050283 GOTERM_CC_FAT GO:0005912~adherens junction 4 0.436681223 0.01081591 "ITGA6, PKP2, SDC4,

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CTNNB1" 39 155 12782 8.45789909 0.861822831 0.104126974 12.55827846

GOTERM_BP_FAT GO:0016337~cell-cell adhesion 4 0.436681223 0.039203969 "PKP2, DSC3, CTNND1, CTNNB1" 38 276 13528 5.15942029 1 0.590453163 44.78677783

GOTERM_BP_FAT GO:0046847~filopodium assembly 3 0.327510917 7.47E-04 "CDC42, ITGA6, ITGB4" 38 15 13528 71.2 0.373285399 0.056734986 1.104207818

GOTERM_BP_FAT GO:0030035~microspike assembly 3 0.327510917 8.53E-04 "CDC42, ITGA6, ITGB4" 38 16 13528 66.75 0.413231449 0.05751577 1.258862253

GOTERM_BP_FAT GO:0030031~cell projection assembly 4 0.436681223 0.001488693 "CDC42, ITGA6, RAC3, ITGB4" 38 83 13528 17.15662651 0.605890419 0.08890912 2.188316562

GOTERM_BP_FAT GO:0030030~cell projection organization 4 0.436681223 0.078680759 "CDC42, ITGA6, RAC3, ITGB4" 38 368 13528 3.869565217 1 0.768544874 70.39066531

GOTERM_BP_FAT GO:0030036~actin cytoskeleton organization 6 0.655021834 3.51E-04 "ACTG1, ALDOA, CDC42, RAC3, CAPZA2, CAPZA1" 38 226 13528 9.451327434 0.196962535 0.042922379 0.519889846

GOTERM_BP_FAT GO:0030029~actin filament-based process 6 0.655021834 4.71E-04 "ACTG1,

ALDOA, CDC42, RAC3, CAPZA2, CAPZA1" 38 241 13528 8.863070539 0.25508262 0.047895354 0.697328464

GOTERM_CC_FAT GO:0015629~actin cytoskeleton 6 0.655021834 0.001130915 "ACTG1, ALDOA, MYO1C, RAC3, CAPZA2, CAPZA1" 39 269 12782 7.310265942 0.18612048 0.040351864 1.386658198

GOTERM_BP_FAT GO:0033043~regulation of organelle organization 5 0.545851528 0.002809085

"CDC42, CAPZA2, NPM1, CAPZA1, CTNNB1" 38 217 13528 8.202764977 0.827636308 0.118016595 4.091781158

GOTERM_BP_FAT GO:0031333~negative regulation of protein complex assembly 3 0.327510917 0.003864537 "CDC42, CAPZA2, CAPZA1" 38 34 13528 31.41176471 0.911079701 0.148992487 5.588404976

GOTERM_BP_FAT GO:0051129~negative regulation of cellular component organization 4 0.436681223 0.006777739 "CDC42, CAPZA2, NPM1, CAPZA1" 38 142 13528 10.02816901 0.985743006

0.210329346 9.607049147

GOTERM_MF_FAT GO:0008092~cytoskeletal protein binding 6 0.655021834 0.008344925 "ALDOA, MYO1C, FYN, CAPZA2, CAPZA1, SDC4" 34 504 12983 4.545868347 0.657893149 0.657893149 9.273346327

GOTERM_BP_FAT GO:0043254~regulation of protein complex assembly 3 0.327510917 0.025070197 "CDC42, CAPZA2, CAPZA1" 38 90 13528 11.86666667 0.999999872 0.483764849 31.41407383 GOTERM_MF_FAT GO:0003779~actin binding 4 0.436681223 0.049154323 "ALDOA, MYO1C, CAPZA2, CAPZA1" 34 326 12983 4.685312162 0.998422081 0.960276975 44.30905395

GOTERM_BP_FAT GO:0044087~regulation of cellular component biogenesis 3 0.327510917 0.057383128 "CDC42, CAPZA2, CAPZA1" 38 142 13528 7.521126761 1 0.673469005 58.42491151

GOTERM_BP_FAT GO:0007010~cytoskeleton organization 8 0.873362445 1.53E-04 "ACTG1, ALDOA, CDC42, RAC3, CAPZA2, NPM1, CAPZA1, CTNNB1" 38 436 13528 6.532110092 0.091355036 0.02366568 0.22739055

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MYO1C, RAC3, CAPZA2, CAPZA1" 39 269 12782 7.310265942 0.18612048 0.040351864 1.386658198

GOTERM_CC_FAT GO:0005856~cytoskeleton 11 1.200873362 0.005839232 "ACTG1, ALDOA, MYO1C, PKP2, RAC3, CAPZA2, NPM1, CAPZA1, KRT13, CTNNB1, PNN" 39 1381 12782 2.610557196

0.655566827 0.064445567 6.971896884

GOTERM_CC_FAT GO:0044430~cytoskeletal part 8 0.873362445 0.020506066 "MYO1C, RAC3, CAPZA2, NPM1, CAPZA1, KRT13, CTNNB1, PNN" 39 952 12782 2.754147813 0.97696869 0.164367787 22.56100381

GOTERM_CC_FAT GO:0043232~intracellular non-membrane-bounded organelle 14 1.528384279

0.032111202 "ALDOA, MYO1C, CAPZA2, CAPZA1, KRT13, PNN, CTNNB1, ACTG1, RPS18, HIST1H4A, PKP2, RAC3, NPM1, H3F3B" 39 2596 12782 1.767492395 0.997368312 0.236625014 33.15279671 GOTERM_CC_FAT GO:0043228~non-membrane-bounded organelle 14 1.528384279 0.032111202 "ALDOA, MYO1C, CAPZA2, CAPZA1, KRT13, PNN, CTNNB1, ACTG1, RPS18, HIST1H4A, PKP2, RAC3, NPM1, H3F3B" 39 2596 12782 1.767492395 0.997368312 0.236625014 33.15279671

GOTERM_CC_FAT GO:0030016~myofibril 4 0.436681223 0.004310635 "ALDOA, SDC4, CTNNB1, ENO1" 39 111 12782 11.81057981 0.544441629 0.058686784 5.191311091

GOTERM_CC_FAT GO:0044449~contractile fiber part 4 0.436681223 0.004531563 "ALDOA, SDC4, CTNNB1, ENO1" 39 113 12782 11.601543 0.562473867 0.0573349 5.450580271

GOTERM_CC_FAT GO:0043292~contractile fiber 4 0.436681223 0.005483566 "ALDOA, SDC4, CTNNB1, ENO1" 39 121 12782 10.83449883 0.632398369 0.064540129 6.560365074

GOTERM_CC_FAT GO:0030017~sarcomere 3 0.327510917 0.034205465 "ALDOA, CTNNB1, ENO1" 39 98 12782 10.03296703 0.998225715 0.240736855 34.9159512

GOTERM_BP_FAT GO:0007010~cytoskeleton organization 8 0.873362445 1.53E-04 "ACTG1, ALDOA, CDC42, RAC3, CAPZA2, NPM1, CAPZA1, CTNNB1" 38 436 13528 6.532110092 0.091355036 0.02366568 0.22739055

GOTERM_BP_FAT GO:0043933~macromolecular complex subunit organization 8 0.873362445 0.002759053 "HIST1H4A, CAPZA2, NPM1, CAPZA1, LIPG, H3F3B, LAMC1, CTNNB1" 38 710 13528 4.011267606 0.822145825 0.124386154 4.020289927

"CDC42, CAPZA2, NPM1, CAPZA1, CTNNB1" 38 217 13528 8.202764977 0.827636308 0.118016595 4.091781158

GOTERM_BP_FAT GO:0051493~regulation of cytoskeleton organization 4 0.436681223 0.006015836 "CAPZA2, NPM1, CAPZA1, CTNNB1" 38 136 13528 10.47058824 0.976976799 0.198955199 8.571731276

GOTERM_BP_FAT GO:0051129~negative regulation of cellular component organization 4 0.436681223 0.006777739 "CDC42, CAPZA2, NPM1, CAPZA1" 38 142 13528 10.02816901 0.985743006

0.210329346 9.607049147

GOTERM_BP_FAT GO:0065003~macromolecular complex assembly 7 0.76419214 0.008713534 "HIST1H4A, CAPZA2, NPM1, CAPZA1, H3F3B, LAMC1, CTNNB1" 38 665 13528 3.747368421 0.995788029 0.250152558 12.18854827

GOTERM_CC_FAT GO:0044430~cytoskeletal part 8 0.873362445 0.020506066 "MYO1C, RAC3, CAPZA2, NPM1, CAPZA1, KRT13, CTNNB1, PNN" 39 952 12782 2.754147813 0.97696869 0.164367787 22.56100381

GOTERM_BP_FAT GO:0010639~negative regulation of organelle organization 3 0.327510917

0.021073646 "CAPZA2, NPM1, CAPZA1" 38 82 13528 13.02439024 0.999998345 0.48602957 27.11776178

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GOTERM_BP_FAT GO:0032535~regulation of cellular component size 4 0.436681223 0.03744848 "CAPZA2, NPM1, CAPZA1, ENO1" 38 271 13528 5.254612546 1 0.586670955 43.26940861 GOTERM_BP_FAT GO:0006461~protein complex assembly 5 0.545851528 0.04797944 "CAPZA2, NPM1, CAPZA1, LAMC1, CTNNB1" 38 505 13528 3.524752475 1 0.6289073 51.82066535 GOTERM_BP_FAT GO:0070271~protein complex biogenesis 5 0.545851528 0.04797944 "CAPZA2, NPM1, CAPZA1, LAMC1, CTNNB1" 38 505 13528 3.524752475 1 0.6289073 51.82066535

GOTERM_CC_FAT GO:0044421~extracellular region part 10 1.091703057 0.001636367 "ALDOA, COL17A1, LGALS3BP, LGALS3, HTRA1, RAB35, LIPG, CD109, LAMC1, FGFBP1" 39 960 12782 3.413995726 0.257745191 0.04168657 2.000680301

GOTERM_CC_FAT GO:0005578~proteinaceous extracellular matrix 4 0.436681223 0.06895066

"COL17A1, LGALS3BP, LGALS3, LAMC1" 39 320 12782 4.096794872 0.999997746 0.382192764 58.58891996

GOTERM_CC_FAT GO:0031012~extracellular matrix 4 0.436681223 0.082260021 "COL17A1,

LGALS3BP, LGALS3, LAMC1" 39 345 12782 3.799925678 0.999999836 0.405936936 65.3300938

GOTERM_CC_FAT GO:0044421~extracellular region part 10 1.091703057 0.001636367 "ALDOA, COL17A1, LGALS3BP, LGALS3, HTRA1, RAB35, LIPG, CD109, LAMC1, FGFBP1" 39 960 12782 3.413995726 0.257745191 0.04168657 2.000680301

GOTERM_CC_FAT GO:0005576~extracellular region 11 1.200873362 0.064488427 "ALDOA, DCD, COL17A1, LGALS3BP, LGALS3, HTRA1, RAB35, LIPG, CD109, LAMC1, FGFBP1" 39 2010 12782 1.793621635 0.999994618 0.372889386 56.07208302

GOTERM_CC_FAT GO:0005615~extracellular space 5 0.545851528 0.144246117 "LGALS3BP, HTRA1, LIPG, CD109, FGFBP1" 39 685 12782 2.392288976 1 0.54502661 85.37247153

GOTERM_CC_FAT GO:0030027~lamellipodium 3 0.327510917 0.018304679 "RAC3, CTNND1, CTNNB1" 39 70 12782 14.04615385 0.965345211 0.154744193 20.38570478

GOTERM_CC_FAT GO:0042995~cell projection 6 0.655021834 0.053887008 "CDC42, MYO1C, RAC3, RAB35, CTNND1, CTNNB1" 39 697 12782 2.82132215 0.999958157 0.342996327 49.51857042 GOTERM_CC_FAT GO:0031252~cell leading edge 3 0.327510917 0.063203635 "RAC3, CTNND1, CTNNB1" 39 138 12782 7.124860647 0.999993091 0.378305487 55.32178889

GOTERM_BP_FAT GO:0006928~cell motion 7 0.76419214 0.00167234 "ACTG1, CD9, ITGA6, FYN, CAPZA2, CAPZA1, LAMC1" 38 475 13528 5.246315789 0.648690392 0.090716954 2.455153445

GOTERM_BP_FAT GO:0016477~cell migration 3 0.327510917 0.174040255 "ITGA6, FYN, LAMC1" 38 276 13528 3.869565217 1 0.941887566 94.15620658

GOTERM_BP_FAT GO:0051674~localization of cell 3 0.327510917 0.204749191 "ITGA6, FYN, LAMC1" 38 307 13528 3.478827362 1 0.958493819 96.67100607

GOTERM_BP_FAT GO:0048870~cell motility 3 0.327510917 0.204749191 "ITGA6, FYN, LAMC1" 38 307 13528 3.478827362 1 0.958493819 96.67100607

(64)

Category Term Count % PValue Genes List Total Pop Hits Pop Total Fold Enrichment Bonferroni Benjamini FDR

GOTERM_BP_FAT GO:0065003~macromolecular complex assembly 7 0.76419214 0.008713534 "HIST1H4A, CAPZA2, NPM1, CAPZA1, H3F3B, LAMC1, CTNNB1" 38 665 13528 3.747368421 0.995788029 0.250152558 12.18854827

GOTERM_BP_FAT GO:0006334~nucleosome assembly 3 0.327510917 0.022045428 "HIST1H4A, NPM1, H3F3B" 38 84 13528 12.71428571 0.99999911 0.48493087 28.18493298

GOTERM_BP_FAT GO:0031497~chromatin assembly 3 0.327510917 0.023537499 "HIST1H4A, NPM1, H3F3B" 38 87 13528 12.27586207 0.999999657 0.476518483 29.79513536

GOTERM_BP_FAT GO:0065004~protein-DNA complex assembly 3 0.327510917 0.025589998 "HIST1H4A, NPM1, H3F3B" 38 91 13528 11.73626374 0.999999908 0.476949857 31.95516894 GOTERM_BP_FAT GO:0034728~nucleosome organization 3 0.327510917 0.026642795 "HIST1H4A, NPM1, H3F3B" 38 93 13528 11.48387097 0.999999953 0.4775041 33.03891656

GOTERM_BP_FAT GO:0006323~DNA packaging 3 0.327510917 0.040575609 "HIST1H4A, NPM1, H3F3B" 38 117 13528 9.128205128 1 0.590455819 45.94592934

GOTERM_BP_FAT GO:0006333~chromatin assembly or disassembly 3 0.327510917 0.047037883 "HIST1H4A, NPM1, H3F3B" 38 127 13528 8.409448819 1 0.633498496 51.10811478

GOTERM_BP_FAT GO:0034622~cellular macromolecular complex assembly 3 0.327510917 0.215804386 "HIST1H4A, NPM1, H3F3B" 38 318 13528 3.358490566 1 0.963225309 97.2959251

GOTERM_BP_FAT GO:0034621~cellular macromolecular complex subunit organization 3 0.327510917 0.255402121 "HIST1H4A, NPM1, H3F3B" 38 357 13528 2.991596639 1 0.976753936 98.74739041 GOTERM_BP_FAT GO:0006325~chromatin organization 3 0.327510917 0.276850243 "HIST1H4A, NPM1, H3F3B" 38 378 13528 2.825396825 1 0.976520044 99.18848898

GOTERM_BP_FAT GO:0051276~chromosome organization 3 0.327510917 0.384767364 "HIST1H4A, NPM1, H3F3B" 38 485 13528 2.202061856 1 0.993654098 99.92640177

GOTERM_CC_FAT GO:0016323~basolateral plasma membrane 6 0.655021834 3.15E-04 "COL17A1,

MYO1C, ITGA6, ITGB4, SDC4, CTNNB1" 39 203 12782 9.687002653 0.055762015 0.014241872

0.388279809

GOTERM_CC_FAT GO:0044459~plasma membrane part 14 1.528384279 0.008662785 "MYO1C, ITGB4,

SDC4, CD151, EPHA2, PNN, CTNNB1, CD9, CDC42, COL17A1, ITGA6, PKP2, RAB35, DSC3" 39 2203

12782 2.082800843 0.794743634 0.088940249 10.18033999

GOTERM_CC_FAT GO:0005887~integral to plasma membrane 7 0.76419214 0.136450796 "CD9,

COL17A1, ITGA6, ITGB4, SDC4, CD151, EPHA2" 39 1188 12782 1.931149098 1 0.544017127

83.64052788

GOTERM_CC_FAT GO:0031226~intrinsic to plasma membrane 7 0.76419214 0.147360477 "CD9,

COL17A1, ITGA6, ITGB4, SDC4, CD151, EPHA2" 39 1215 12782 1.888234673 1 0.543499866

86.01600591

GOTERM_CC_FAT GO:0031224~intrinsic to membrane 14 1.528384279 0.895358303 "GLG1, CD9,

COL17A1, LY6D, MYO1C, ITGA6, PKP2, ITGB4, DSC3, CD109, CD151, SDC4, NT5E, EPHA2" 39 5485

12782 0.836537877 1 0.999682538 100

GOTERM_CC_FAT GO:0016021~integral to membrane 11 1.200873362 0.982569733 "GLG1, CD9,

COL17A1, MYO1C, ITGA6, PKP2, ITGB4, DSC3, SDC4, CD151, EPHA2" 39 5297 12782 0.680607794

1 0.999999301 100

Annotation Cluster 16 Enrichment Score: 1.1351396044413542

Category Term Count % PValue Genes List Total Pop Hits Pop Total Fold Enrichment Bonferroni

Benjamini FDR

GOTERM_CC_FAT GO:0031253~cell projection membrane 3 0.327510917 0.015912627 "MYO1C, RAB35,

CTNNB1" 39 65 12782 15.12662722 0.946033286 0.142429589 17.95844345

(65)

RAB35, CTNND1, CTNNB1" 39 697 12782 2.82132215 0.999958157 0.342996327 49.51857042

GOTERM_CC_FAT GO:0044463~cell projection part 3 0.327510917 0.153137715 "MYO1C, RAB35,

CTNNB1" 39 234 12782 4.201840894 1 0.548912006 87.14137014

GOTERM_BP_FAT GO:0008104~protein localization 5 0.545851528 0.21934789 "CDC42, MYO1C,

RAB35, NPM1, CTNNB1" 38 882 13528 2.01814059 1 0.962853828 97.47182425

Benjamini FDR

GOTERM_BP_FAT GO:0016337~cell-cell adhesion 4 0.436681223 0.039203969 "PKP2, DSC3,

CTNND1, CTNNB1" 38 276 13528 5.15942029 1 0.590453163 44.78677783

GOTERM_CC_FAT GO:0005624~membrane fraction 6 0.655021834 0.089556808 "LY6D, DSC3,

CTNND1, CD151, NT5E, CTNNB1" 39 809 12782 2.430731197 0.999999962 0.423532521 68.58249857

GOTERM_CC_FAT GO:0000267~cell fraction 7 0.76419214 0.098121578 "ACTG1, LY6D, DSC3,

CTNND1, CD151, NT5E, CTNNB1" 39 1083 12782 2.11837962 0.999999993 0.444218319

72.04130779

GOTERM_CC_FAT GO:0005626~insoluble fraction 6 0.655021834 0.100836449 "LY6D, DSC3,

CTNND1, CD151, NT5E, CTNNB1" 39 839 12782 2.343815898 0.999999996 0.443566328 73.06234486

Benjamini FDR

"CDC42, CAPZA2, NPM1, CAPZA1, CTNNB1" 38 217 13528 8.202764977 0.827636308 0.118016595

4.091781158

RAB35, NPM1, CTNNB1" 38 882 13528 2.01814059 1 0.962853828 97.47182425

GOTERM_BP_FAT GO:0034613~cellular protein localization 3 0.327510917 0.310515793 "CDC42,

NPM1, CTNNB1" 38 411 13528 2.598540146 1 0.985376574 99.60023465

GOTERM_BP_FAT GO:0070727~cellular macromolecule localization 3 0.327510917 0.31356684

"CDC42, NPM1, CTNNB1" 38 414 13528 2.579710145 1 0.984992104 99.62571736

Benjamini FDR

GOTERM_CC_FAT GO:0042995~cell projection 6 0.655021834 0.053887008 "CDC42, MYO1C, RAC3,

RAB35, CTNND1, CTNNB1" 39 697 12782 2.82132215 0.999958157 0.342996327 49.51857042

GOTERM_MF_FAT GO:0003924~GTPase activity 3 0.327510917 0.100009777 "CDC42, RAC3,

RAB35" 34 211 12983 5.429188737 0.999998612 0.894381608 70.58639153

GOTERM_BP_FAT GO:0007264~small GTPase mediated signal transduction 3 0.327510917 0.20274672

"CDC42, RAC3, RAB35" 38 305 13528 3.501639344 1 0.959985225 96.54431619

GOTERM_MF_FAT GO:0005525~GTP binding 3 0.327510917 0.243858227 "CDC42, RAC3, RAB35"

34 372 12983 3.079459203 1 0.981229831 96.10794384

GOTERM_MF_FAT GO:0032561~guanyl ribonucleotide binding 3 0.327510917 0.253343392 "CDC42,

RAC3, RAB35" 34 382 12983 2.998845088 1 0.97623446 96.63867025

GOTERM_MF_FAT GO:0019001~guanyl nucleotide binding 3 0.327510917 0.253343392 "CDC42,

RAC3, RAB35" 34 382 12983 2.998845088 1 0.97623446 96.63867025

GOTERM_BP_FAT GO:0007242~intracellular signaling cascade 6 0.655021834 0.256773945 "CDC42,

HIST1H4A, RAC3, FYN, RAB35, CTNNB1" 38 1256 13528 1.700636943 1 0.975508715

98.78123089

GOTERM_MF_FAT GO:0032553~ribonucleotide binding 7 0.76419214 0.320729425 "ACTG1, CDC42,

MYO1C, RAC3, FYN, RAB35, EPHA2" 34 1836 12983 1.455866333 1 0.9888932 98.87938249

GOTERM_MF_FAT GO:0032555~purine ribonucleotide binding 7 0.76419214 0.320729425 "ACTG1,

(66)

98.87938249

GOTERM_BP_FAT GO:0030182~neuron differentiation 3 0.327510917 0.337878169 "CDC42, RAC3,

EPHA2" 38 438 13528 2.438356164 1 0.988238801 99.78091317

GOTERM_MF_FAT GO:0017076~purine nucleotide binding 7 0.76419214 0.359873034 "ACTG1,

CDC42, MYO1C, RAC3, FYN, RAB35, EPHA2" 34 1918 12983 1.393623873 1 0.991419644

99.43752363

Benjamini FDR

GOTERM_BP_FAT GO:0033674~positive regulation of kinase activity 3 0.327510917 0.131219235

"CDC42, NPM1, SDC4" 38 231 13528 4.623376623 1 0.901091526 87.62030068

GOTERM_BP_FAT GO:0051347~positive regulation of transferase activity 3 0.327510917 0.139570517

"CDC42, NPM1, SDC4" 38 240 13528 4.45 1 0.910097749 89.27472766

GOTERM_BP_FAT GO:0043549~regulation of kinase activity 3 0.327510917 0.255402121 "CDC42,

NPM1, SDC4" 38 357 13528 2.991596639 1 0.976753936 98.74739041

GOTERM_BP_FAT GO:0051338~regulation of transferase activity 3 0.327510917 0.270719874 "CDC42,

NPM1, SDC4" 38 372 13528 2.870967742 1 0.97583491 99.0800952

GOTERM_BP_FAT GO:0042325~regulation of phosphorylation 3 0.327510917 0.365949853 "CDC42,

NPM1, SDC4" 38 466 13528 2.291845494 1 0.991985955 99.88486929

GOTERM_BP_FAT GO:0051174~regulation of phosphorus metabolic process 3 0.327510917 0.384767364

"CDC42, NPM1, SDC4" 38 485 13528 2.202061856 1 0.993654098 99.92640177

GOTERM_BP_FAT GO:0019220~regulation of phosphate metabolic process 3 0.327510917 0.384767364

"CDC42, NPM1, SDC4" 38 485 13528 2.202061856 1 0.993654098 99.92640177

GOTERM_BP_FAT GO:0043085~positive regulation of catalytic activity 3 0.327510917 0.418832906

"CDC42, NPM1, SDC4" 38 520 13528 2.053846154 1 0.995411017 99.96841653

GOTERM_BP_FAT GO:0044093~positive regulation of molecular function 3 0.327510917 0.480515569

"CDC42, NPM1, SDC4" 38 586 13528 1.822525597 1 0.998331262 99.99403299

Benjamini FDR

RAB35, NPM1, CTNNB1" 38 882 13528 2.01814059 1 0.962853828 97.47182425

GOTERM_BP_FAT GO:0015031~protein transport 3 0.327510917 0.624804891 "MYO1C, RAB35,

NPM1" 38 762 13528 1.401574803 1 0.999893213 99.99995247

GOTERM_BP_FAT GO:0045184~establishment of protein localization 3 0.327510917 0.629885439

"MYO1C, RAB35, NPM1" 38 769 13528 1.388816645 1 0.999892229 99.99996118

Benjamini FDR

GOTERM_CC_FAT GO:0005829~cytosol 7 0.76419214 0.198179322 "ACTG1, CDC42, RPS18, FYN,

NPM1, CTNNB1, ENO1" 39 1330 12782 1.724966262 1 0.633940656 93.44921801

GOTERM_MF_FAT GO:0003712~transcription cofactor activity 3 0.327510917 0.235340081 "NPM1,

CTNNB1, ENO1" 34 363 12983 3.155809431 1 0.986338662 95.56719058

GOTERM_BP_FAT GO:0051253~negative regulation of RNA metabolic process 3 0.327510917

0.260505702 "NPM1, CTNNB1, ENO1" 38 362 13528 2.950276243 1 0.973411278 98.86902216

GOTERM_MF_FAT GO:0008134~transcription factor binding 3 0.327510917 0.376843293 "NPM1,

CTNNB1, ENO1" 34 513 12983 2.233058136 1 0.99050329 99.58829127

GOTERM_BP_FAT "GO:0045934~negative regulation of nucleobase, nucleoside, nucleotide and nucleic acid

metabolic process" 3 0.327510917 0.411121091 "NPM1, CTNNB1, ENO1" 38 512 13528 2.0859375 1 0.995597402 99.96158633

(67)

0.327510917 0.417871483 "NPM1, CTNNB1, ENO1" 38 519 13528 2.057803468 1 0.995722021 99.96763159

GOTERM_BP_FAT GO:0010605~negative regulation of macromolecule metabolic process 3 0.327510917

0.603970694 "NPM1, CTNNB1, ENO1" 38 734 13528 1.455040872 1 0.999844904 99.99989394

GOTERM_MF_FAT GO:0030528~transcription regulator activity 3 0.327510917 0.910369989 "NPM1,

CTNNB1, ENO1" 34 1512 12983 0.757644725 1 0.999999196 100

GOTERM_BP_FAT GO:0045449~regulation of transcription 5 0.545851528 0.943782365 "NPM1,

CTNND1, CTNNB1, ENO1, PNN" 38 2601 13528 0.684352172 1 1 100

GOTERM_BP_FAT GO:0051252~regulation of RNA metabolic process 3 0.327510917 0.967385811

"NPM1, CTNNB1, ENO1" 38 1813 13528 0.589078875 1 1 100

Benjamini FDR

GOTERM_MF_FAT GO:0000166~nucleotide binding 9 0.982532751 0.199383113 "ACTG1, CDC42,

MYO1C, RAC3, FYN, RAB35, NT5E, RBMX, EPHA2" 34 2245 12983 1.530813573 1 0.982858355

92.44143109

GOTERM_MF_FAT GO:0032553~ribonucleotide binding 7 0.76419214 0.320729425 "ACTG1, CDC42,

MYO1C, RAC3, FYN, RAB35, EPHA2" 34 1836 12983 1.455866333 1 0.9888932 98.87938249

GOTERM_MF_FAT GO:0032555~purine ribonucleotide binding 7 0.76419214 0.320729425 "ACTG1,

98.87938249

GOTERM_MF_FAT GO:0017076~purine nucleotide binding 7 0.76419214 0.359873034 "ACTG1,

99.43752363

GOTERM_MF_FAT GO:0005524~ATP binding 4 0.436681223 0.74136561 "ACTG1, MYO1C, FYN,

EPHA2" 34 1477 12983 1.034131188 1 0.999979979 99.99998489

GOTERM_MF_FAT GO:0032559~adenyl ribonucleotide binding 4 0.436681223 0.74997068 "ACTG1,

MYO1C, FYN, EPHA2" 34 1497 12983 1.02031514 1 0.999970676 99.9999898

GOTERM_MF_FAT GO:0030554~adenyl nucleotide binding 4 0.436681223 0.782238425 "ACTG1,

MYO1C, FYN, EPHA2" 34 1577 12983 0.968555336 1 0.999980398 99.99999795

GOTERM_MF_FAT GO:0001883~purine nucleoside binding 4 0.436681223 0.791261115 "ACTG1,

MYO1C, FYN, EPHA2" 34 1601 12983 0.95403608 1 0.999973922 99.99999875

GOTERM_MF_FAT GO:0001882~nucleoside binding 4 0.436681223 0.795297358 "ACTG1, MYO1C,

FYN, EPHA2" 34 1612 12983 0.947525909 1 0.999960989 99.999999

Benjamini FDR

GOTERM_CC_FAT GO:0005654~nucleoplasm 5 0.545851528 0.265561815 "MYO1C, HIST1H4A,

NPM1, CTNNB1, PNN" 39 882 12782 1.857956858 1 0.737493894 97.78252049

GOTERM_CC_FAT GO:0044451~nucleoplasm part 3 0.327510917 0.495925197 "NPM1, CTNNB1,

PNN" 39 555 12782 1.771586972 1 0.94494551 99.97868302

GOTERM_CC_FAT GO:0005730~nucleolus 3 0.327510917 0.622208805 "MYO1C, NPM1, PNN" 39 698

12782 1.408640071 1 0.978748593 99.99939299

GOTERM_CC_FAT GO:0031981~nuclear lumen 5 0.545851528 0.639317293 "MYO1C, HIST1H4A,

NPM1, CTNNB1, PNN" 39 1450 12782 1.130150309 1 0.980723043 99.99965736

GOTERM_CC_FAT GO:0070013~intracellular organelle lumen 5 0.545851528 0.794699441 "MYO1C,

HIST1H4A, NPM1, CTNNB1, PNN" 39 1779 12782 0.921145559 1 0.997529342 99.99999967

GOTERM_CC_FAT GO:0043233~organelle lumen 5 0.545851528 0.809887361 "MYO1C, HIST1H4A,

NPM1, CTNNB1, PNN" 39 1820 12782 0.900394477 1 0.997900863 99.99999987

GOTERM_CC_FAT GO:0031974~membrane-enclosed lumen 5 0.545851528 0.822496456 "MYO1C,

HIST1H4A, NPM1, CTNNB1, PNN" 39 1856 12782 0.882929929 1 0.998150248 99.99999995

(68)

CTNNB1, ENO1, PNN" 34 2331 12983 0.819075378 1 0.999995654 99.99999999

GOTERM_BP_FAT GO:0006350~transcription 4 0.436681223 0.941418036 "CTNND1, CTNNB1, ENO1,

PNN" 38 2101 13528 0.677772489 1 1 100

GOTERM_BP_FAT GO:0045449~regulation of transcription 5 0.545851528 0.943782365 "NPM1,

CTNND1, CTNNB1, ENO1, PNN" 38 2601 13528 0.684352172 1 1 100

Benjamini FDR

GOTERM_MF_FAT GO:0005509~calcium ion binding 4 0.436681223 0.416758421 "S100A16, ITGA6,

DSC3, S100A14" 34 919 12983 1.662036741 1 0.992769205 99.80913743

GOTERM_MF_FAT GO:0046872~metal ion binding 8 0.873362445 0.938583224 "DCD, S100A16,

ITGA6, FYN, DSC3, NT5E, S100A14, ENO1" 34 4140 12983 0.73788008 1 0.999999819 100

GOTERM_MF_FAT GO:0043169~cation binding 8 0.873362445 0.942805235 "DCD, S100A16, ITGA6,

FYN, DSC3, NT5E, S100A14, ENO1" 34 4179 12983 0.730993905 1 0.999999764 100

GOTERM_MF_FAT GO:0043167~ion binding 8 0.873362445 0.949020813 "DCD, S100A16, ITGA6,

(69)

GOTERM_CC_FAT GO:0070013~intracellular organelle lumen 199 40.44715447 3.06E-64 "XRCC5, XRCC6, SRP68, SYNCRIP, INTS3, SART3, XRCC1, U2AF1, PQBP1, RPP30, MRPL39, DHX30, SUPT5H,

LUC7L3, EMG1, PTBP1, LIG3, NOP2, RFC2, MYBBP1A, MRPL43, MRE11A, HNRNPA3, VRK1, NAT10, NUP54, PRPF40A, DHX9, MKI67, TP53BP1, DLAT, DDX5, RPS6, RPF2, HNRNPA1, FXR1, CCT5, POP1, SUPT16H, PCNA, PARP1, COPS2, UTP18, TCOF1, UTP15, RRP1B, QKI, MRPL1, SYMPK, PRPF31, RBBP4, EXOSC9, EXOSC6, EXOSC7, SF1, EXOSC2, ADNP, NDUFA10, RBBP7, EIF4A3, NOL11, RBM39, PMPCB, POLR2A, PRPF19, SRRT, SF3B1, SUMO1, MRPL13, NUMA1, TOE1, MORC3, GATAD2A, GATAD2B, ACTL6A, TCEA1, RBM27, RBM28, BUB3, RBM25, TRIM28, KIAA1967, POLR3A, ILF3, SF3A1, SF3A3, ILF2, UBTF, MRPL28, SFPQ, NOP58, NOP56, RBM14, PES1, TEX10, NCBP1, RNMT, SNRPD3, SRP19, CTNNBL1, SMNDC1, PNN, CBX5, EBNA1BP2, CSNK2A1, SRRM2, TARDBP, DDX24, SRRM1, ACIN1, GNL2, GNL3, PABPN1, MTA2, HNRNPA2B1, RRP8, HNRNPR, RSL1D1, MRPS18A, SMARCA5, SNRPB, LRPPRC, XRN2, HMGB1, HMGB2, MRPS15, DAZAP1, HNRNPL, HNRNPM, DDX46, HNRNPK, HIST1H4A, ZNF326, NPM1, RPL3, DNAJA3, DDX42, XPOT, CSTF2, TSR1, MRPS22, SSB, HEATR1, RNPS1, PSMC5, HDAC2, HDAC1, SMARCC1, SMARCC2, GTF2F2, PSMC1, HSPD1, HNRNPH1, DAP3, FOXK1, SKIV2L2, TIMM50, MKI67IP, ZNF207,

FUBP1, MCM7, DKC1, GRWD1, TPR, PSMD8, FTSJ3, TBL1XR1, MCM2, CDC5L, MCM3, PRPF4, NCL, MCM4, MCM5, CDK2, MCM6, C1QBP, CPSF6, MATR3, NUP98, HCFC1, PRKDC, WBP11, EXOSC10, RPA1, TFAM, PRPF8, SAFB, NUDT21, GTF3C5, APEX1, CHD4, HSPA9, NUP153, NDUFA9, FBL, SMC3, DIS3, SON" 415 1779 12782 3.445306352 1.19E-61 5.93E-62 4.25E-61

GOTERM_CC_FAT GO:0031981~nuclear lumen 179 36.38211382 6.37E-63 "XRCC5, NCBP1,

RNMT, SNRPD3, XRCC6, SRP68, SYNCRIP, INTS3, SRP19, SART3, XRCC1, CBX5, SMNDC1, PNN, CTNNBL1, EBNA1BP2, CSNK2A1, SRRM2, TARDBP, DDX24, U2AF1, PQBP1, RPP30, SRRM1, ACIN1, GNL2, SUPT5H, LUC7L3, GNL3, PABPN1, EMG1, MTA2, HNRNPA2B1, PTBP1, LIG3, RRP8, HNRNPR, RSL1D1, NOP2, RFC2, SNRPB, SMARCA5, MYBBP1A, LRPPRC, XRN2, HMGB1, HMGB2, MRE11A, DAZAP1, HNRNPA3, HNRNPL, HNRNPM, VRK1, HNRNPK, DDX46, HIST1H4A, ZNF326, NPM1, RPL3, NAT10, NUP54, DDX42, PRPF40A, XPOT, DHX9, CSTF2, TSR1, MKI67, TP53BP1, SSB, HEATR1, RNPS1, DDX5, RPS6, RPF2, HNRNPA1, FXR1, CCT5, PSMC5, HDAC2, HDAC1, SMARCC1, SMARCC2, GTF2F2, PSMC1, PCNA, SUPT16H, POP1, PARP1, HNRNPH1, COPS2, FOXK1, UTP18, TCOF1, UTP15, SKIV2L2, MKI67IP, TIMM50, ZNF207, FUBP1, MCM7, DKC1, RRP1B, GRWD1, QKI, TPR, FTSJ3, PSMD8, PRPF31, SYMPK, TBL1XR1, RBBP4, EXOSC9, EXOSC6, EXOSC7, SF1, EXOSC2, ADNP, CDC5L, MCM2, RBBP7, MCM3, MCM4, NCL, PRPF4, CDK2, MCM5, MCM6, EIF4A3, NOL11, CPSF6, RBM39, MATR3, NUP98, PRKDC, HCFC1, WBP11, POLR2A, PRPF19, EXOSC10, RPA1, SF3B1, SRRT, NUMA1, SUMO1, TOE1, MORC3, SAFB, PRPF8, NUDT21, GATAD2A, GATAD2B, GTF3C5, ACTL6A, TCEA1, RBM27, APEX1, RBM28, CHD4, BUB3, RBM25, NUP153, TRIM28, POLR3A, ILF3, SF3A1, SMC3, FBL, SF3A3, DIS3, SON, UBTF, ILF2, SFPQ, NOP58, NOP56, PES1, RBM14, TEX10" 415 1450 12782 3.802206897 2.47E-60 8.24E-61 8.85E-60

GOTERM_CC_FAT GO:0043233~organelle lumen 199 40.44715447 1.61E-62 "XRCC5, XRCC6, SRP68, SYNCRIP, INTS3, SART3, XRCC1, U2AF1, PQBP1, RPP30, MRPL39, DHX30, SUPT5H, LUC7L3, EMG1, PTBP1, LIG3, NOP2, RFC2, MYBBP1A, MRPL43, MRE11A, HNRNPA3, VRK1, NAT10, NUP54, PRPF40A, DHX9, MKI67, TP53BP1, DLAT, DDX5, RPS6, RPF2, HNRNPA1, FXR1, CCT5, POP1, SUPT16H, PCNA, PARP1, COPS2, UTP18, TCOF1, UTP15, RRP1B, QKI, MRPL1, SYMPK, PRPF31, RBBP4, EXOSC9, EXOSC6, EXOSC7, SF1, EXOSC2, ADNP, NDUFA10, RBBP7, EIF4A3, NOL11, RBM39, PMPCB, POLR2A, PRPF19, SRRT, SF3B1, SUMO1, MRPL13, NUMA1, TOE1, MORC3, GATAD2A, GATAD2B, ACTL6A, TCEA1, RBM27, RBM28, BUB3, RBM25, TRIM28, KIAA1967, POLR3A, ILF3, SF3A1, SF3A3, ILF2, UBTF, MRPL28, SFPQ, NOP58, NOP56, RBM14, PES1, TEX10, NCBP1, RNMT, SNRPD3, SRP19, CTNNBL1, SMNDC1, PNN, CBX5, EBNA1BP2, CSNK2A1, SRRM2, TARDBP, DDX24, SRRM1, ACIN1, GNL2, GNL3, PABPN1, MTA2, HNRNPA2B1, RRP8, HNRNPR, RSL1D1, MRPS18A, SMARCA5, SNRPB, LRPPRC, XRN2, HMGB1, HMGB2, MRPS15, DAZAP1, HNRNPL, HNRNPM, DDX46, HNRNPK, HIST1H4A, ZNF326, NPM1, RPL3, DNAJA3, DDX42, XPOT, CSTF2, TSR1, MRPS22, SSB, HEATR1, RNPS1, PSMC5, HDAC2, HDAC1, SMARCC1, SMARCC2, GTF2F2, PSMC1, HSPD1, HNRNPH1, DAP3, FOXK1, SKIV2L2, TIMM50, MKI67IP, ZNF207, FUBP1, MCM7, DKC1, GRWD1, TPR, PSMD8, FTSJ3, TBL1XR1, MCM2, CDC5L, MCM3, PRPF4, NCL, MCM4, MCM5, CDK2, MCM6, C1QBP, CPSF6, MATR3, NUP98, HCFC1, PRKDC, WBP11, EXOSC10, RPA1, TFAM, PRPF8, SAFB, NUDT21, GTF3C5,

(70)

APEX1, CHD4, HSPA9, NUP153, NDUFA9, FBL, SMC3, DIS3, SON" 415 1820 12782 3.367692308 6.25E-60 1.56E-60 2.24E-59

GOTERM_CC_FAT GO:0031974~membrane-enclosed lumen 200 40.6504065 7.99E-62 "XRCC5, XRCC6, SRP68, SYNCRIP, INTS3, SART3, XRCC1, U2AF1, PQBP1, RPP30, MRPL39, DHX30, SUPT5H, LUC7L3, EMG1, PTBP1, LIG3, NOP2, RFC2, MYBBP1A, MRPL43, MRE11A, HNRNPA3, VRK1, CACYBP, NAT10, NUP54, PRPF40A, DHX9, MKI67, TP53BP1, DLAT, DDX5, RPS6, RPF2, HNRNPA1, FXR1, CCT5, POP1, SUPT16H, PCNA, PARP1, COPS2, UTP18, TCOF1, UTP15, RRP1B, QKI, MRPL1, SYMPK, PRPF31, RBBP4, EXOSC9, EXOSC6, EXOSC7, SF1, EXOSC2, ADNP, NDUFA10, RBBP7, EIF4A3, NOL11, RBM39, PMPCB, POLR2A, PRPF19, SRRT, SF3B1, SUMO1, MRPL13, NUMA1, TOE1, MORC3, GATAD2A, GATAD2B, ACTL6A, TCEA1, RBM27, RBM28, BUB3, RBM25, TRIM28, KIAA1967, POLR3A, ILF3, SF3A1, SF3A3, ILF2, UBTF, MRPL28, SFPQ, NOP58, NOP56, RBM14, PES1, TEX10, NCBP1, RNMT, SNRPD3, SRP19, SMNDC1, CTNNBL1, PNN, CBX5, EBNA1BP2, CSNK2A1, SRRM2, TARDBP, DDX24, SRRM1, ACIN1, GNL2, GNL3, PABPN1, MTA2, HNRNPA2B1, RRP8, HNRNPR, RSL1D1, MRPS18A, SMARCA5, SNRPB, LRPPRC, XRN2, HMGB1, HMGB2, MRPS15, DAZAP1, HNRNPL, HNRNPM, DDX46, HNRNPK, HIST1H4A, ZNF326, NPM1, RPL3, DNAJA3, DDX42, XPOT, CSTF2, TSR1, MRPS22, SSB, HEATR1, RNPS1, PSMC5, HDAC2, HDAC1, SMARCC1, SMARCC2, GTF2F2, PSMC1, HSPD1, HNRNPH1, DAP3, FOXK1, SKIV2L2, TIMM50, MKI67IP, ZNF207,

FUBP1, MCM7, DKC1, GRWD1, TPR, PSMD8, FTSJ3, TBL1XR1, MCM2, CDC5L, MCM3, PRPF4, NCL, MCM4, MCM5, CDK2, MCM6, C1QBP, CPSF6, MATR3, NUP98, HCFC1, PRKDC, WBP11, EXOSC10, RPA1, TFAM, PRPF8, SAFB, NUDT21, GTF3C5, APEX1, CHD4, HSPA9, NUP153, NDUFA9, SMC3, FBL, DIS3, SON" 415 1856 12782 3.318965517 3.10E-59 6.20E-60 1.11E-58

GOTERM_CC_FAT GO:0005730~nucleolus 99 20.12195122 4.28E-37 "SNRPD3, SRP68, SRP19, PNN, CTNNBL1, CBX5, EBNA1BP2, TARDBP, DDX24, PQBP1, RPP30, ACIN1, GNL2, GNL3, PABPN1, EMG1, MTA2, HNRNPA2B1, PTBP1, RRP8, RSL1D1, NOP2, SMARCA5, MYBBP1A, XRN2, HMGB1, HMGB2, MRE11A, DAZAP1, HNRNPA3, HNRNPM, VRK1, HNRNPK, NPM1, RPL3, NAT10, DHX9, CSTF2, TSR1, MKI67, HEATR1, SSB, RPS6, DDX5, HNRNPA1, RPF2, FXR1, CCT5, PSMC5, PSMC1, SMARCC2, POP1, HNRNPH1, PARP1, COPS2, FOXK1, UTP18, TCOF1, UTP15, SKIV2L2, MKI67IP, ZNF207, FUBP1, DKC1, RRP1B, GRWD1, QKI, PSMD8, FTSJ3, EXOSC9, EXOSC6, EXOSC7, ADNP, EXOSC2, SF1, CDC5L, MCM3, NCL, MCM4, NOL11, POLR2A, EXOSC10, TOE1, SAFB, GATAD2A, GATAD2B, RBM28, BUB3, ILF3, SF3A1, FBL, DIS3, ILF2, UBTF, NOP58, NOP56, RBM14, PES1, TEX10" 415 698 12782 4.368481375 1.66E-34 2.37E-35 5.94E-34

GOTERM_CC_FAT GO:0005654~nucleoplasm 106 21.54471545 2.18E-33 "XRCC5, NCBP1, RNMT, SNRPD3, XRCC6, SYNCRIP, INTS3, XRCC1, SART3, CBX5, PNN, SMNDC1, CSNK2A1, SRRM2, U2AF1, SRRM1, SUPT5H, LUC7L3, GNL3, PABPN1, MTA2, HNRNPA2B1, PTBP1, LIG3, HNRNPR, RFC2, SMARCA5, SNRPB, LRPPRC, HMGB1, HMGB2, MRE11A, HNRNPL, DDX46, HNRNPK, HIST1H4A, NPM1, NUP54, PRPF40A, DDX42, XPOT, TP53BP1, RNPS1, HNRNPA1, HDAC2, HDAC1, SMARCC1, GTF2F2, SMARCC2, SUPT16H, PCNA, PARP1, HNRNPH1, TIMM50, MKI67IP, MCM7, DKC1, TPR, TBL1XR1, SYMPK, PRPF31, RBBP4, MCM2, CDC5L, MCM3, RBBP7, MCM4, NCL, PRPF4, MCM5, CDK2, MCM6, EIF4A3, CPSF6, RBM39, NUP98, HCFC1, PRKDC, WBP11, POLR2A, RPA1, PRPF19, SRRT, SF3B1, NUMA1, SUMO1, TOE1, MORC3, PRPF8, NUDT21, GATAD2A, GTF3C5, TCEA1, ACTL6A, RBM27, APEX1, RBM25, CHD4, NUP153, TRIM28, POLR3A, SF3A3, SON, UBTF, RBM14, PES1" 415 882 12782 3.701587302 8.47E-31 9.41E-32 3.03E-30

GOTERM_BP_FAT GO:0006396~RNA processing 123 25 2.71E-71 "RALY, NCBP1, RNMT, CHERP, PRPF4B, RPL14, U2AF2, SNRPD3, RBM3, SYNCRIP, INTS3, SART3, PNN, SMNDC1, NONO, DDX17, DDX23, DHX38, SRRM2, TARDBP, DNAJC8, U2AF1, SRRM1, RPP30, LUC7L3, CCAR1, PABPN1, SNRPA1, EMG1, EFTUD2, HNRNPA2B1, PTBP1, RRP8, HNRNPR, HNRNPU, RSL1D1, NOP2, SNRPB, SNRPA, XRN2, MRPL44, FIP1L1, PABPC4, PUS7, HNRNPA3, HNRNPL, HNRNPM, DDX46, HNRNPK, HNRNPD, HNRNPC, PABPC1, PRPF40A, DHX9, CSTF3, CSTF2, SSB, RNPS1, HEATR1, RPS6, DDX5, HNRNPA1, RBMX, HNRNPA0, HNRNPH3, GTF2F2, POP1, SMC1A, HNRNPH1, PUF60, UTP18, UTP15, SKIV2L2, YBX1, DKC1, RRP1B,

TRMT6, QKI, FTSJ3, KHDRBS1, MRPL1, PRPF31, EXOSC9, EXOSC6, EXOSC7, EXOSC2, SF1, CDC5L, PRPF4, PRPF6, HNRPDL, EIF4A3, SNRNP200, CPSF7, CPSF6, RBM39, TRA2B, TRA2A, WBP11, SF3B4, SF3B2,

(71)

POLR2A, EXOSC10, PRPF19, SF3B1, SRRT, PRPF8, USP39, NUDT21, DHX15, SNRNP70, RBM28, RBM25, SF3A2, SF3A1, FBL, SF3A3, DIS3, SFPQ, NOP58, NOP56, PES1, RBM14" 430 547 13528 7.074291059 4.27E-68 4.27E-68 4.53E-68

GOTERM_BP_FAT GO:0006397~mRNA processing 86 17.4796748 2.77E-55 "RALY, NCBP1, PRPF4B, RNMT, SNRPD3, U2AF2, SYNCRIP, SKIV2L2, YBX1, SMNDC1, PNN, NONO, DHX38, DDX23, SRRM2, TARDBP, DNAJC8, U2AF1, SRRM1, QKI, LUC7L3, CCAR1, PABPN1, KHDRBS1, PRPF31, SNRPA1, EFTUD2, PTBP1, HNRNPA2B1, SF1, CDC5L, PRPF4, HNRNPR, HNRNPU, PRPF6, EIF4A3, SNRNP200, SNRPB, CPSF7, SNRPA, CPSF6, RBM39, XRN2, FIP1L1, TRA2B, TRA2A, WBP11, SF3B4, POLR2A, SF3B2, HNRNPA3, PRPF19, HNRNPL, SF3B1, HNRNPM, HNRNPK, DDX46, PRPF8, USP39, NUDT21, HNRNPD, DHX15, HNRNPC, PABPC1, SNRNP70, RBM28, RBM25, PRPF40A, DHX9, CSTF3, CSTF2, RNPS1, SF3A2, DDX5, HNRNPA1,

RBMX, SF3A1, HNRNPA0, SF3A3, HNRNPH3, SFPQ, GTF2F2, HNRNPH1, RBM14, SMC1A, PUF60" 430 321 13528 8.428660436 4.37E-52 2.19E-52 4.64E-52

GOTERM_BP_FAT GO:0008380~RNA splicing 81 16.46341463 3.06E-54 "RALY, NCBP1, PRPF4B, SNRPD3, U2AF2, SYNCRIP, SKIV2L2, YBX1, SMNDC1, PNN, NONO, DHX38, DDX23, SRRM2, TARDBP, DNAJC8, U2AF1, QKI, SRRM1, LUC7L3, CCAR1, PABPN1, PRPF31, SNRPA1, EFTUD2, PTBP1, HNRNPA2B1, SF1, CDC5L, PRPF4, HNRNPR, HNRNPU, PRPF6, EIF4A3, SNRNP200, CPSF7, SNRPB, SNRPA, RBM39,

TRA2B, TRA2A, WBP11, SF3B4, POLR2A, SF3B2, HNRNPA3, PRPF19, HNRNPL, SF3B1, HNRNPM, HNRNPK, DDX46, PRPF8, USP39, NUDT21, HNRNPD, DHX15, HNRNPC, PABPC1, SNRNP70, RBM28, RBM25, PRPF40A, DHX9, CSTF3, CSTF2, RNPS1, SF3A2, DDX5, HNRNPA1, RBMX, SF3A1, HNRNPA0, SF3A3, HNRNPH3, SFPQ, GTF2F2, HNRNPH1, RBM14, SMC1A, PUF60" 430 284 13528 8.972879135 4.83E-51 1.61E-51 5.12E-51

GOTERM_BP_FAT GO:0016071~mRNA metabolic process 89 18.08943089 5.22E-53 "RALY, NCBP1, PRPF4B, RNMT, SNRPD3, U2AF2, SYNCRIP, SKIV2L2, YBX1, SMNDC1, PNN, NONO, DHX38, DDX23, SRRM2, TARDBP, DNAJC8, U2AF1, SRRM1, QKI, LUC7L3, CCAR1, PABPN1, KHDRBS1, PRPF31, SNRPA1, EFTUD2, PTBP1, HNRNPA2B1, SF1, CDC5L, HNRNPR, PRPF4, HNRNPU, PRPF6, EIF4A3,

SNRNP200, SNRPB, CPSF7, SNRPA, CPSF6, RBM39, XRN2, FIP1L1, TRA2B, TRA2A, WBP11, SF3B4, POLR2A, SF3B2, HNRNPA3, HNRNPL, EXOSC10, PRPF19, SF3B1, HNRNPM, HNRNPK, DDX46, PRPF8, USP39,

NUDT21, HNRNPD, DHX15, HNRNPC, PABPC1, SNRNP70, RBM28, RBM25, PRPF40A, DHX9, CSTF3, CSTF2, ELAVL1, SSB, RNPS1, SF3A2, DDX5, HNRNPA1, RBMX, SF3A1, HNRNPA0, SF3A3, HNRNPH3, SFPQ,

GTF2F2, HNRNPH1, RBM14, SMC1A, PUF60" 430 370 13528 7.567517285 8.23E-50 2.06E-50 8.72E-50

GOTERM_BP_FAT "GO:0000375~RNA splicing, via transesterification reactions" 57 11.58536585 5.85E-45 "NCBP1, SNRPD3, U2AF2, YBX1, SMNDC1, DDX23, DHX38, DNAJC8, U2AF1, SRRM1, CCAR1, PABPN1,

PRPF31, SNRPA1, EFTUD2, PTBP1, HNRNPA2B1, SF1, PRPF4, HNRNPR, HNRNPU, PRPF6, SNRNP200, CPSF7, SNRPB, SNRPA, TRA2B, TRA2A, SF3B4, SF3B2, POLR2A, HNRNPL, HNRNPA3, HNRNPM, SF3B1, HNRNPK, PRPF8, USP39, NUDT21, HNRNPD, SNRNP70, HNRNPC, RBM25, DHX9, CSTF3, CSTF2, RNPS1, SF3A2, SF3A1, RBMX, HNRNPA1, HNRNPA0, SF3A3, HNRNPH3, GTF2F2, HNRNPH1, SMC1A" 430 153 13528 11.72056544 9.23E-42 1.85E-42 9.78E-42

GOTERM_BP_FAT "GO:0000377~RNA splicing, via transesterification reactions with bulged adenosine as

nucleophile" 57 11.58536585 5.85E-45 "NCBP1, SNRPD3, U2AF2, YBX1, SMNDC1, DDX23, DHX38, DNAJC8, U2AF1, SRRM1, CCAR1, PABPN1, PRPF31, SNRPA1, EFTUD2, PTBP1, HNRNPA2B1, SF1, PRPF4, HNRNPR, HNRNPU, PRPF6, SNRNP200, CPSF7, SNRPB, SNRPA, TRA2B, TRA2A, SF3B4, SF3B2, POLR2A, HNRNPL, HNRNPA3, HNRNPM, SF3B1, HNRNPK, PRPF8, USP39, NUDT21, HNRNPD, SNRNP70, HNRNPC, RBM25, DHX9, CSTF3, CSTF2, RNPS1, SF3A2, SF3A1, RBMX, HNRNPA1, HNRNPA0, SF3A3, HNRNPH3, GTF2F2, HNRNPH1, SMC1A" 430 153 13528 11.72056544 9.23E-42 1.85E-42 9.78E-42

GOTERM_BP_FAT "GO:0000398~nuclear mRNA splicing, via spliceosome" 57 11.58536585 5.85E-45 "NCBP1, SNRPD3, U2AF2, YBX1, SMNDC1, DDX23, DHX38, DNAJC8, U2AF1, SRRM1, CCAR1, PABPN1, PRPF31, SNRPA1, EFTUD2, PTBP1, HNRNPA2B1, SF1, PRPF4, HNRNPR, HNRNPU, PRPF6, SNRNP200, CPSF7, SNRPB, SNRPA, TRA2B, TRA2A, SF3B4, SF3B2, POLR2A, HNRNPL, HNRNPA3, HNRNPM, SF3B1, HNRNPK, PRPF8, USP39, NUDT21, HNRNPD, SNRNP70, HNRNPC, RBM25, DHX9, CSTF3, CSTF2, RNPS1, SF3A2, SF3A1, RBMX, HNRNPA1, HNRNPA0, SF3A3, HNRNPH3, GTF2F2, HNRNPH1, SMC1A" 430 153 13528 11.72056544 9.23E-42 1.85E-42 9.78E-42

GOTERM_CC_FAT GO:0005681~spliceosome 48 9.756097561 8.90E-37 "RALY, PRPF4B, U2AF2, SNRPD3, SYNCRIP, SKIV2L2, SF3B4, SF3B2, PNN, SMNDC1, PRPF19, HNRNPA3, HNRNPM, SF3B1,

(72)

HNRNPK, DHX38, DDX23, PRPF8, SRRM2, DHX15, U2AF1, SRRM1, SNRNP70, HNRNPC, PABPC1, RBM28, API5, PRPF31, SNRPA1, EFTUD2, HNRNPA2B1, SF1, CDC5L, DDX5, SF3A2, SF3A1, HNRNPA1, RBMX, HNRNPR, PRPF4, HNRNPU, PRPF6, SF3A3, EIF4A3, SNRNP200, SNRPB, SNRPA, HNRNPH1" 415 132 12782 11.2 3.46E-34 4.32E-35 1.24E-33

GOTERM_CC_FAT GO:0043232~intracellular non-membrane-bounded organelle 213 43.29268293 5.04E-46 "XRCC5, HIST2H2AA3, RPL19, RPL14, RPL13, XRCC6, SRP68, H1FX, HIST1H2BM, RPLP0, RPLP1, PQBP1, RPP30, MRPL39, DHX30, STAG2, H1F0, EMG1, PTBP1, KRT13, NCAPD2, JUP, NOP2, KRT16, RFC2, RPS10, MYBBP1A, MRPL46, NUP43, MRPL43, MRPL44, MRE11A, IGF2BP2, RCC1, HNRNPA3, VRK1, NAT10, DHX9, MKI67, TP53BP1, DDX5, FXR2, RPS6, HNRNPA1, RPF2, RPS8, FXR1, SYNE1, CCT5, POP1, SUPT16H, PCNA, PARP1, COPS2, UTP18, TCOF1, UTP15, RRP1B, QKI, MRPL1, SYMPK, MRPL4, HIST1H1D, EXOSC9, RBBP4, EXOSC6, HIST1H1C, HIST1H1B, EXOSC7, SF1, EXOSC2, ADNP, RAD50, NOL11, RBM39, NUP107, KLC2, POLR2A, NCAPH, MRPL13, NUMA1, TOE1, MRPL15, RPL34, GATAD2A, MRPL19, GATAD2B, TRIP10,

RBM28, BUB3, PDS5A, TRIM28, ILF3, SF3A1, RPL29, MRPL22, ILF2, UBTF, MRPL28, RPL7L1, NOP58, NOP56, RBM14, PES1, TEX10, PRPF4B, SNRPD3, CBX3, SRP19, MRPS31, CBX5, CTNNBL1, PNN, EBNA1BP2, RAD21, CSNK2A1, TARDBP, DDX24, TUBG1, ACIN1, GNL2, GNL3, PABPN1, NUP133, MTA2, HNRNPA2B1, RRP8, RSL1D1, MRPS18A, PSMA3, SMARCA5, MAP7D1, LRPPRC, XRN2, SMARCA4, HMGB1, HMGB2, MRPS15, ANLN, C14ORF166, DAZAP1, HNRNPM, HNRNPK, HIST1H4A, RPL6, NPM1, HNRNPD, RPL3, DNAJA3, HIST2H3A, CSTF2, TSR1, MRPS22, CKAP5, HEATR1, SSB, RPL23A, SMEK1, SUGT1, MPRIP, PSMC5, HDAC2, HDAC1, SMARCC1, SMARCC2, GTF2F2, PSMC1, SPTBN2, TMPO, HNRNPH1, SMC1A, DAP3, MYH10,

FOXK1, HP1BP3, SKIV2L2, MKI67IP, ZNF207, FUBP1, MCM7, DKC1, GRWD1, GOPC, TPR, PSMD8, FTSJ3, ZW10, TBL1XR1, HMBS, NUP85, MCM2, CDC5L, MCM3, MCM4, NCL, CDK2, KRT6A, NUP98, NUP160, EXOSC10, RPA1, TFAM, SAFB, NUDT21, TGM1, APEX1, CHD4, HSPA9, TCP1, SMC3, FBL, DIS3, KRT79" 415 2596 12782 2.527118644 1.95E-43 3.26E-44 7.00E-43

GOTERM_CC_FAT GO:0043228~non-membrane-bounded organelle 213 43.29268293 5.04E-46 "XRCC5, HIST2H2AA3, RPL19, RPL14, RPL13, XRCC6, SRP68, H1FX, HIST1H2BM, RPLP0, RPLP1, PQBP1, RPP30, MRPL39, DHX30, STAG2, H1F0, EMG1, PTBP1, KRT13, NCAPD2, JUP, NOP2, KRT16, RFC2, RPS10, MYBBP1A, MRPL46, NUP43, MRPL43, MRPL44, MRE11A, IGF2BP2, RCC1, HNRNPA3, VRK1, NAT10, DHX9, MKI67, TP53BP1, DDX5, FXR2, RPS6, HNRNPA1, RPF2, RPS8, FXR1, SYNE1, CCT5, POP1, SUPT16H, PCNA, PARP1, COPS2, UTP18, TCOF1, UTP15, RRP1B, QKI, MRPL1, SYMPK, MRPL4, HIST1H1D, EXOSC9, RBBP4, EXOSC6, HIST1H1C, HIST1H1B, EXOSC7, SF1, EXOSC2, ADNP, RAD50, NOL11, RBM39, NUP107, KLC2, POLR2A, NCAPH, MRPL13, NUMA1, TOE1, MRPL15, RPL34, GATAD2A, MRPL19, GATAD2B, TRIP10,

RBM28, BUB3, PDS5A, TRIM28, ILF3, SF3A1, RPL29, MRPL22, ILF2, UBTF, MRPL28, RPL7L1, NOP58, NOP56, RBM14, PES1, TEX10, PRPF4B, SNRPD3, CBX3, SRP19, MRPS31, CBX5, CTNNBL1, PNN, EBNA1BP2, RAD21, CSNK2A1, TARDBP, DDX24, TUBG1, ACIN1, GNL2, GNL3, PABPN1, NUP133, MTA2, HNRNPA2B1, RRP8, RSL1D1, MRPS18A, PSMA3, SMARCA5, MAP7D1, LRPPRC, XRN2, SMARCA4, HMGB1, HMGB2, MRPS15, ANLN, C14ORF166, DAZAP1, HNRNPM, HNRNPK, HIST1H4A, RPL6, NPM1, HNRNPD, RPL3, DNAJA3, HIST2H3A, CSTF2, TSR1, MRPS22, CKAP5, HEATR1, SSB, RPL23A, SMEK1, SUGT1, MPRIP, PSMC5, HDAC2, HDAC1, SMARCC1, SMARCC2, GTF2F2, PSMC1, SPTBN2, TMPO, HNRNPH1, SMC1A, DAP3, MYH10,

FOXK1, HP1BP3, SKIV2L2, MKI67IP, ZNF207, FUBP1, MCM7, DKC1, GRWD1, GOPC, TPR, PSMD8, FTSJ3, ZW10, TBL1XR1, HMBS, NUP85, MCM2, CDC5L, MCM3, MCM4, NCL, CDK2, KRT6A, NUP98, NUP160, EXOSC10, RPA1, TFAM, SAFB, NUDT21, TGM1, APEX1, CHD4, HSPA9, TCP1, SMC3, FBL, DIS3, KRT79"

415 2596 12782 2.527118644 1.95E-43 3.26E-44 7.00E-43

GOTERM_CC_FAT GO:0005730~nucleolus 99 20.12195122 4.28E-37 "SNRPD3, SRP68, SRP19, PNN,

CTNNBL1, CBX5, EBNA1BP2, TARDBP, DDX24, PQBP1, RPP30, ACIN1, GNL2, GNL3, PABPN1, EMG1, MTA2, HNRNPA2B1, PTBP1, RRP8, RSL1D1, NOP2, SMARCA5, MYBBP1A, XRN2, HMGB1, HMGB2, MRE11A, DAZAP1, HNRNPA3, HNRNPM, VRK1, HNRNPK, NPM1, RPL3, NAT10, DHX9, CSTF2, TSR1, MKI67, HEATR1, SSB, RPS6, DDX5, HNRNPA1, RPF2, FXR1, CCT5, PSMC5, PSMC1, SMARCC2, POP1, HNRNPH1, PARP1, COPS2, FOXK1, UTP18, TCOF1, UTP15, SKIV2L2, MKI67IP, ZNF207, FUBP1, DKC1, RRP1B, GRWD1, QKI, PSMD8, FTSJ3, EXOSC9, EXOSC6, EXOSC7, ADNP, EXOSC2, SF1, CDC5L, MCM3, NCL, MCM4, NOL11, POLR2A, EXOSC10, TOE1, SAFB, GATAD2A, GATAD2B, RBM28, BUB3, ILF3, SF3A1,