CBX3

Summary

CBX3 (chromobox 3, HGNC:1553) is a protein-coding gene on chromosome 7p15.2, encoding Chromobox protein homolog 3 (Q13185). Component of heterochromatin, which recognizes and binds histone H3 tails methylated at ‘Lys-9’, leading to epigenetic repression.

At the nuclear envelope, the nuclear lamina and heterochromatin are adjacent to the inner nuclear membrane. The protein encoded by this gene binds DNA and is a component of heterochromatin. This protein also can bind lamin B receptor, an integral membrane protein found in the inner nuclear membrane. The dual binding functions of the encoded protein may explain the association of heterochromatin with the inner nuclear membrane. This protein binds histone H3 tails methylated at Lys-9 sites. This protein is also recruited to sites of ultraviolet-induced DNA damage and double-strand breaks. Two transcript variants encoding the same protein but differing in the 5’ UTR, have been found for this gene.

Source: NCBI Gene 11335 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 35 total — 3 pathogenic, 2 likely-pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_016587

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1553
Approved symbol	CBX3
Name	chromobox 3
Location	7p15.2
Locus type	gene with protein product
Status	Approved
Aliases	HP1Hs-gamma, HP1gamma
Ensembl gene	ENSG00000122565
Ensembl biotype	protein_coding
OMIM	604477
Entrez	11335

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 24 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000337620, ENST00000396386, ENST00000409747, ENST00000456948, ENST00000462165, ENST00000481057, ENST00000481300, ENST00000497498, ENST00000923370, ENST00000923371, ENST00000923372, ENST00000923373, ENST00000923374, ENST00000923375, ENST00000923376, ENST00000923377, ENST00000923378, ENST00000923379, ENST00000923380, ENST00000923381, ENST00000923382, ENST00000923383, ENST00000923384, ENST00000923385, ENST00000923386, ENST00000963183, ENST00000963184

RefSeq mRNA: 3 — MANE Select: NM_016587 NM_001410866, NM_007276, NM_016587

CCDS: CCDS5398, CCDS94069

Canonical transcript exons

ENST00000396386 — 6 exons

Exon	Start	End
ENSE00001433792	26202971	26203022
ENSE00001524790	26201745	26201826
ENSE00001553667	26212082	26213607
ENSE00003468049	26208393	26208555
ENSE00003596257	26206368	26206510
ENSE00003684959	26211662	26211756

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.40.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 206.4745 / max 4764.3561, expressed in 1828 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
77752	146.2909	1827
77753	44.9124	1809
77747	7.8670	1701
77751	2.1413	1221
77749	1.6616	921
77748	1.3897	734
77746	0.9070	600
77754	0.7172	390
77750	0.5873	304

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.40	gold quality
ganglionic eminence	UBERON:0004023	99.36	gold quality
visceral pleura	UBERON:0002401	99.32	gold quality
cortical plate	UBERON:0005343	99.25	gold quality
ventricular zone	UBERON:0003053	99.23	gold quality
pleura	UBERON:0000977	99.21	gold quality
embryo	UBERON:0000922	99.20	gold quality
parietal pleura	UBERON:0002400	99.20	gold quality
tibia	UBERON:0000979	99.10	gold quality
germinal epithelium of ovary	UBERON:0001304	99.10	gold quality
epithelium of nasopharynx	UBERON:0001951	98.86	gold quality
trabecular bone tissue	UBERON:0002483	98.74	gold quality
endometrium	UBERON:0001295	98.72	gold quality
endometrium epithelium	UBERON:0004811	98.64	gold quality
palpebral conjunctiva	UBERON:0001812	98.57	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.43	gold quality
epithelial cell of pancreas	CL:0000083	98.33	gold quality
monocyte	CL:0000576	98.28	gold quality
mononuclear cell	CL:0000842	98.25	gold quality
vermiform appendix	UBERON:0001154	98.25	gold quality
gingival epithelium	UBERON:0001949	98.25	gold quality
lymph node	UBERON:0000029	98.24	gold quality
tonsil	UBERON:0002372	98.24	gold quality
adrenal tissue	UBERON:0018303	98.21	gold quality
amniotic fluid	UBERON:0000173	98.18	gold quality
leukocyte	CL:0000738	98.15	gold quality
pigmented layer of retina	UBERON:0001782	98.14	gold quality
bone marrow	UBERON:0002371	98.08	gold quality
caecum	UBERON:0001153	98.01	gold quality
esophagus squamous epithelium	UBERON:0006920	98.00	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	27.92
E-CURD-122	yes	22.30
E-HCAD-1	yes	18.11
E-GEOD-125970	yes	17.84
E-MTAB-8410	yes	16.67
E-ANND-3	yes	11.82
E-MTAB-10042	yes	9.64
E-CURD-114	yes	7.53

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
FOXP3

Upstream regulators (CollecTRI, top): MYC, NFATC2

miRNA regulators (miRDB)

141 targeting CBX3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-186-5P	99.99	70.83	3707
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 40)

• Isoform-specific interaction of HP1 with human TAFII130. (PMID:11959914)
• Gene regulation by human orthologs of Drosophila heterochromatin protein 1. (PMID:12054505)
• the chromodomain and the chromoshadow domain of HP1 are both required for binding to native chromatin in vivo, but they contribute differentially to binding in euchromatin and heterochromatin (PMID:12560555)
• Pax3 represses transcription through a novel mechanism involving competition between corepressor KAP1 and the heterochromatin-binding protein HP1gamma (PMID:16945326)
• KAP1 functions to coordinate activities that dynamically regulate changes in histone modifications and deposition of HP1 to establish a de novo microenvironment of heterochromatin, which is required for repression of gene transcription by KRAB-zfps. (PMID:16954381)
• Suv39H1, HP1gamma and histone H3Lys9 trimethylation play a major role in chromatin-mediated repression of integrated HIV-1 gene expression. (PMID:17245432)
• In non-differentiated cells, transcriptional intermediary factor TIF1beta/heterochromatin protein HP1 interaction occurs only within euchromatin and involves selectively HP1beta and HP1gamma, but not HP1alpha. (PMID:17381543)
• Overexpression of HP1-GAMMA in wing imaginal discs caused abnormal wings. (PMID:17575412)
• present an investigation of DNA methylation and histone modification marks across the HNRPA2B1-CBX3 locus in primary peripheral blood mononuclear cells (PBMCs) to characterise the chromatin structure that underlies UCOE activity (PMID:18032920)
• Heterochromatin protein gamma coordinately regulates CCN2/CTGF transcription by interacting with nuclear MMP3. (PMID:18172013)
• HP1 recruitment-release is a sequential mechanism that is precisely regulated and highly dependent on transcription. (PMID:18239689)
• the spatial proximities among a constellation of functionally related sites that are found within euchromatic regions of the cell nucleus including: HP1gamma, RNA polymerase II, matrin 3, and SAF-A sites (PMID:18618731)
• Under oxidative conditions, HP1gamma dimerized and held TIF1beta in a chromatin component and inhibited its repression ability. (PMID:20675861)
• we show distinct cell-type- and cancer-stage-associated patterns of key heterochromatin marks: heterochromatic adaptor proteins HP1alpha and HP1gamma, compared with the gammaH2AX marker of endogenously activated DNA damage response. (PMID:20695923)
• The Ca2+ channel beta4c subunit interacts with heterochromatin protein 1 gama via a PXVXL binding motif. (PMID:21220418)
• HP1 gamma binds CD44 pre-mRNA inside the variant region of CD44. (PMID:21358630)
• this study reveals that human NIPBL is a novel protein recruited to DSB sites, and the recruitment is controlled by MDC1, RNF168 and HP1gamma. (PMID:21784059)
• HP1gamma localizes to telomeres in S phase, where it is required to establish/maintain cohesion (PMID:21865325)
• HIV-1 Vpr displaces heterochromatin protein 1-alpha and heterochromatin protein 1-gamma from chromatin, resulting in premature chromatid separation. (PMID:21875947)
• The Cbx3 chromodomain binds with comparable affinities to all of the methylated H3K9, H1K26 and G9aK185 peptides. (PMID:22514736)
• Loss of CBX3 results in global RNA processing defect. (PMID:22684280)
• Identification of CBX3 and ABCA5 as putative biomarkers for tumor stem cells in osteosarcoma. (PMID:22870217)
• study finds that while HP1apha and beta stimulate homologous recombination and single-strand annealing, HP1gamma has an inhibitory role (PMID:23287531)
• HP1gamma affects the spontaneous differentiation potential of P19 cells, and might play major roles in the decision of cell fates in pluripotent stem cells. (PMID:23313480)
• compartmentalized and total HP1gamma protein expression is increased in PCa and that expression correlates with clinical outcomes better than Gleason score. (PMID:23522301)
• CBX3 and CRABP2 expression was markedly increased in lung cancer tissues (PMID:24751108)
• our data suggested that HP1gamma plays an important role in promoting non-small cell lung cancer (PMID:24981246)
• BARD1 interacts with H3K9me2 through HP1 and plays a critical role in retention of a BRCA1/BARD1 complex at the site of DNA damage. (PMID:25634209)
• In contrast to HP1alpha, HP1gamma could not recognize H3K9me3 in extended nucleosomes. (PMID:26319017)
• this study identified miR-30a as a tumor-suppressive microRNA that targets HP1gamma in vitro and in vivo to specifically suppress the growth of colorectal cancer in mouse xenograft models. (PMID:26333808)
• these data underscore the importance of IDRs 1, 2, and 3 in defining the structural and dynamic properties of HP1gamma, discoveries that have both mechanistic and potentially biomedical relevance. (PMID:26680990)
• These data indicate that HP1-gamma is a novel epigenetic repressor of epsilon-globin gene expression. (PMID:28154185)
• The deletion of CBX3 directly enforces the expression of CDK6 and p21. (PMID:28193906)
• c-Myc was capable of upregulating HP1gamma by directly binding to the E-box element in the first intron of HP1gamma gene, and the upregulated HP1gamma, in turn, repressed the expression of miR-451a by enhancing H3K9 methylation at the promoter region of miR-451a. (PMID:28967902)
• We report a significant upregulation of CBX3/HP1-gamma in non-small cell lung cancer patients (PMID:29124886)
• HP1gamma is present in the nucleus and the cytoplasm interacting with actin, a protein complex that may exert different functions depending on its subcellular localization. (PMID:29208528)
• CBX3 has a role in promoting tumor proliferation by regulating G1/S phase via p21 downregulation and associates with poor prognosis in tongue squamous cell carcinoma (PMID:29462646)
• CBX3 serves as a positive regulator of aerobic glycolysis via suppressing of the FBP1 in pancreatic cancer cells. (PMID:29678579)
• Direct epigenetic repression of the transcription-repressive regulators NCOR2 and ZBTB7A by the histone reader protein HP1gamma leads to activation of protumorigenic genes in lung adenocarcinoma. (PMID:29764865)
• CBX3 was overexpressed in pancreatic adenocarcinoma, which was associated with poor prognosis. CDK1 knockdown attenuated the cell cycle transition, proliferation and invasion of CBX3-overexpressing PAAD cells. (PMID:29903985)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	cbx3a	ENSDARG00000003860
mus_musculus	Cbx3	ENSMUSG00000029836
rattus_norvegicus	Cbx3	ENSRNOG00000011814
drosophila_melanogaster	HP1b	FBGN0030082
drosophila_melanogaster	HP1c	FBGN0039019
caenorhabditis_elegans		WBGENE00001995
caenorhabditis_elegans		WBGENE00007615

Paralogs (8): CBX5 (ENSG00000094916), CBX7 (ENSG00000100307), CBX1 (ENSG00000108468), CBX8 (ENSG00000141570), CBX4 (ENSG00000141582), CBX2 (ENSG00000173894), CBX6 (ENSG00000183741), NPTXR (ENSG00000221890)

Protein

Protein identifiers

Chromobox protein homolog 3 — Q13185 (reviewed: Q13185)

Alternative names: HECH, Heterochromatin protein 1 homolog gamma, Modifier 2 protein

All UniProt accessions (5): A4D177, B8ZZ43, C9JMM0, Q13185, S4R2Y4

UniProt curated annotations — full annotation on UniProt →

Function. Component of heterochromatin, which recognizes and binds histone H3 tails methylated at ‘Lys-9’, leading to epigenetic repression. Also recognizes and binds histone H1.4 methylated at ‘Lys-26’ (H1.4K26me). Excluded from chromatin when histone H1.4 is Simultaneously methylated at Lys-26 (H1.4K26me) and phosphorylated at Ser-27 (H1.4S27Ph). Involved in the formation of functional kinetochore through interaction with MIS12 complex proteins. Contributes to the conversion of local chromatin to a heterochromatin-like repressive state through H3 ‘Lys-9’ trimethylation, mediates the recruitment of the methyltransferases SUV39H1 and/or SUV39H2 by the PER complex to the E-box elements of the circadian target genes such as PER2 itself or PER1. Mediates the recruitment of NIPBL to sites of DNA damage at double-strand breaks (DSBs).

Subunit / interactions. Binds directly to CHAF1A. Interacts with histone H3 methylated at ‘Lys-9’. Part of the E2F6.com-1 complex in G0 phase composed of E2F6, MGA, MAX, TFDP1, CBX3, BAT8, EUHMTASE1, RING1, RNF2, MBLR, L3MBTL2 and YAF2. Interacts with INCENP, TRIM28/TIF1B, KMT5B, KMT5C and SP100. Interacts with TIF1A. Interacts with MIS12 and DSN1. Can interact directly with CBX5 via the chromoshadow domain. Interacts with POGZ. Interacts with CHAMP1. The large PER complex involved in the histone methylation is composed of at least PER2, CBX3, TRIM28, SUV39H1 and/or SUV39H2; CBX3 mediates the formation of the complex. Interacts with INCENP. Interacts with NIPBL (via PxVxL motif). Interacts with LRIF1 (via PxVxL motif). Interacts with TTLL12. Interacts with ZNF263; recruited to the SIX3 promoter along with other proteins involved in chromatin modification and transcriptional corepression where it contributes to transcriptional repression. Interacts with CHD3. Interacts with CHD4.

Subcellular location. Nucleus.

Post-translational modifications. Phosphorylated by PIM1. Phosphorylated during interphase and possibly hyper-phosphorylated during mitosis.

RefSeq proteins (3): NP_001397795, NP_009207, NP_057671* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000953	Chromo/chromo_shadow_dom	Domain
IPR008251	Chromo_shadow_dom	Domain
IPR016197	Chromo-like_dom_sf	Homologous_superfamily
IPR017984	Chromo_dom_subgr	Domain
IPR023779	Chromodomain_CS	Conserved_site
IPR023780	Chromo_domain	Domain
IPR038033	CBX3_chromo_domain	Domain
IPR051219	Heterochromatin_chromo-domain	Family

Pfam: PF00385, PF01393

UniProt features (38 total): modified residue 10, strand 7, helix 6, cross-link 5, sequence conflict 3, domain 2, region of interest 2, initiator methionine 1, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
5T1I	X-RAY DIFFRACTION	1.6
3KUP	X-RAY DIFFRACTION	1.77
9OSC	X-RAY DIFFRACTION	1.77
8JZW	X-RAY DIFFRACTION	1.8
3TZD	X-RAY DIFFRACTION	1.81
6HW2	X-RAY DIFFRACTION	1.94
3DM1	X-RAY DIFFRACTION	2.4
2L11	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13185-F1	75.94	0.25

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (15): 44, 50, 93, 95, 97, 99, 176, 5, 10, 21, 103, 154, 2, 5, 10

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-427389	ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression
R-HSA-73772	RNA Polymerase I Promoter Escape
R-HSA-8953750	Transcriptional Regulation by E2F6
R-HSA-9940465	ChAHP complex assembly
R-HSA-212165	Epigenetic regulation of gene expression
R-HSA-212436	Generic Transcription Pathway
R-HSA-5250913	Positive epigenetic regulation of rRNA expression
R-HSA-73854	RNA Polymerase I Promoter Clearance
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-73864	RNA Polymerase I Transcription
R-HSA-74160	Gene expression (Transcription)

MSigDB gene sets: 0 (showing top):

GO Biological Process (7): chromatin remodeling (GO:0006338), DNA damage response (GO:0006974), heterochromatin formation (GO:0031507), negative regulation of DNA-templated transcription (GO:0045892), rhythmic process (GO:0048511), cellular response to dexamethasone stimulus (GO:0071549), chromatin organization (GO:0006325)

GO Molecular Function (10): transcription coregulator binding (GO:0001221), chromatin binding (GO:0003682), enzyme binding (GO:0019899), protein domain specific binding (GO:0019904), identical protein binding (GO:0042802), histone H3K9me2/3 reader activity (GO:0062072), histone H1K26me1 reader activity (GO:0160267), histone H1K26me2 reader activity (GO:0160268), histone methyltransferase binding (GO:1990226), protein binding (GO:0005515)

GO Cellular Component (16): chromosome, centromeric region (GO:0000775), condensed chromosome, centromeric region (GO:0000779), chromosome, telomeric region (GO:0000781), chromatin (GO:0000785), euchromatin (GO:0000791), heterochromatin (GO:0000792), nucleus (GO:0005634), nuclear envelope (GO:0005635), nuclear inner membrane (GO:0005637), nucleoplasm (GO:0005654), pericentric heterochromatin (GO:0005721), spindle (GO:0005819), senescence-associated heterochromatin focus (GO:0035985), chromatin lock complex (GO:0061793), RNA polymerase II transcription regulator complex (GO:0090575), site of DNA damage (GO:0090734)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Gene expression (Transcription)	3
Positive epigenetic regulation of rRNA expression	1
RNA Polymerase I Promoter Clearance	1
Generic Transcription Pathway	1
CHD3, CHD4, CHD5 subfamily	1
RNA Polymerase II Transcription	1
Epigenetic regulation of gene expression	1
RNA Polymerase I Transcription	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	3
cellular anatomical structure	3
binding	2
histone H1 reader activity	2
chromosomal region	2
chromosome, centromeric region	2
chromosome	2
chromatin	2
heterochromatin	2
chromatin organization	1
cellular response to stress	1
cellular component assembly	1
heterochromatin boundary formation	1
negative regulation of gene expression, epigenetic	1
heterochromatin organization	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
biological_process	1
cellular response to glucocorticoid stimulus	1
response to dexamethasone	1
cellular response to ketone	1
cellular component organization	1
transcription factor binding	1
histone H3 reader activity	1
enzyme binding	1
condensed chromosome	1
intracellular membrane-bounded organelle	1
nucleus	1
endomembrane system	1
organelle envelope	1
organelle inner membrane	1
nuclear membrane	1
nuclear lumen	1
microtubule cytoskeleton	1
intracellular membraneless organelle	1
chromatin silencing complex	1
transcription regulator complex	1
nuclear protein-containing complex	1

Protein interactions and networks

STRING

3062 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CBX3	H3-3A	P06351	991
CBX3	H3C14	Q71DI3	991
CBX3	H3C1	P02295	991
CBX3	H3-4	Q16695	991
CBX3	H3-7	Q5TEC6	991
CBX3	H3-5	Q6NXT2	991
CBX3	SUV39H1	O43463	990
CBX3	KDM1A	O60341	971
CBX3	EHMT2	Q96KQ7	966
CBX3	E2F6	O75461	956
CBX3	L3MBTL1	Q9Y468	939
CBX3	LBR	Q14739	934
CBX3	TRIM66	O15016	921
CBX3	HDAC1	Q13547	918
CBX3	TINF2	Q9BSI4	917

IntAct

286 interactions, top by confidence:

A	B	Type	Score
SUV39H1	CBX5	psi-mi:“MI:0914”(association)	0.950
DSN1	ZWINT	psi-mi:“MI:0914”(association)	0.900
RYBP	CSNK2A2	psi-mi:“MI:0914”(association)	0.900
CBX3	LRIF1	psi-mi:“MI:0915”(physical association)	0.880
CDK8	MED19	psi-mi:“MI:0914”(association)	0.850
ADNP	CBX3	psi-mi:“MI:0915”(physical association)	0.850
CBX3	ADNP2	psi-mi:“MI:0915”(physical association)	0.810
SUV39H1	CBX3	psi-mi:“MI:0915”(physical association)	0.800
CHD4	CBX1	psi-mi:“MI:0914”(association)	0.790
POGZ	CBX5	psi-mi:“MI:0914”(association)	0.780
CBX3	ZNF280C	psi-mi:“MI:0915”(physical association)	0.740
CBX3	PRR14	psi-mi:“MI:0915”(physical association)	0.740
EHMT2	WIZ	psi-mi:“MI:0914”(association)	0.730
RING1	CBX4	psi-mi:“MI:0914”(association)	0.730
RNF2	E2F6	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
LRIF1	SMCHD1	psi-mi:“MI:0914”(association)	0.680
PCGF6	CBX4	psi-mi:“MI:0914”(association)	0.640
CBX3	E2F6	psi-mi:“MI:0914”(association)	0.640
CBX3	CBX3	psi-mi:“MI:0915”(physical association)	0.640
CBX3	LBR	psi-mi:“MI:0915”(physical association)	0.620
LBR	CBX3	psi-mi:“MI:0407”(direct interaction)	0.620
LBR	CBX5	psi-mi:“MI:0914”(association)	0.610
L3MBTL1	H1-4	psi-mi:“MI:0914”(association)	0.590
STK16	CBX3	psi-mi:“MI:0915”(physical association)	0.560
CBX3	ZNF280D	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (983): HIST1H3A (Co-crystal Structure), HIST1H3A (Protein-peptide), CBX3 (Affinity Capture-MS), CBX3 (Protein-peptide), ADNP (Affinity Capture-MS), POGZ (Affinity Capture-MS), CBX5 (Affinity Capture-MS), CHAF1A (Affinity Capture-MS), MGA (Affinity Capture-MS), TRIM28 (Affinity Capture-MS), CHAF1B (Affinity Capture-MS), NIPBL (Affinity Capture-MS), CBX3 (Affinity Capture-MS), CBX3 (Affinity Capture-MS), CBX3 (Affinity Capture-MS)

ESM2 similar proteins: A0A286Y9D1, C8VBH4, F4IV99, G5EDE2, G5EET5, J9VQZ0, J9VW97, O13736, O14026, O94880, O97159, P05205, P0CP02, P0CP03, P23198, P29227, P40381, P45968, P45973, P83916, P83917, Q01491, Q10175, Q10251, Q10267, Q13185, Q19972, Q1DU03, Q1MTR4, Q2H988, Q2UTN6, Q4IB50, Q4P3S3, Q4WTT2, Q5ASA5, Q5R6X7, Q61686, Q6C5G5, Q6C9M9, Q6CND0

Diamond homologs: A0A0P0VUY4, B1Q3J6, C0SQ89, D4ZX35, G5EDE2, G5EET5, J9VQZ0, O23273, O33481, O49139, P13864, P23198, P23737, P25265, P26358, P31033, P45973, P50196, P94147, Q13185, Q24K09, Q27746, Q57983, Q5KQL9, Q5R6X7, Q61686, Q7JXA8, Q7Y1I7, Q8LPU5, Q92072, Q94F87, Q94F88, Q99549, Q9ARI6, Q9AXT8, Q9M0S8, G3V8T1, O60016, O95931, P05205

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
PRKACA	up-regulates	CBX3	phosphorylation
CBX3	“up-regulates activity”	H3-3A	binding
CBX3	“up-regulates activity”	H3-4	binding
CBX3	“up-regulates activity”	H3C1	binding
CBX3	“up-regulates activity”	NIPBL	binding
CBX3	“up-regulates activity”	“Histone H3”	binding
AURKA	“up-regulates activity”	CBX3	phosphorylation
CBX3	“form complex”	ChAHP	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 191 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Transcriptional Regulation by E2F6	10	20.6×	1e-08
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	8	16.9×	4e-06
SUMOylation of transcription cofactors	7	12.0×	2e-04
Regulation of PTEN gene transcription	8	10.1×	1e-04
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	9	9.3×	8e-05
Regulation of endogenous retroelements by KRAB-ZFP proteins	9	6.8×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
heterochromatin formation	6	8.9×	9e-03
chromatin remodeling	14	5.9×	3e-05
chromatin organization	9	5.2×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

35 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	2
Uncertain significance	13
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
3062983	GRCh37/hg19 7p21.1-14.3(chr7:17736012-30663423)x1	Pathogenic
3245865	NC_000007.13:g.(?26232136)(28172587_?)del	Pathogenic
443815	GRCh37/hg19 7p15.3-14.3(chr7:24344104-28879357)x1	Pathogenic
151979	GRCh38/hg38 7p15.2(chr7:25903388-27022498)x1	Likely pathogenic
395288	GRCh37/hg19 7p15.3-15.2(chr7:25448425-27578387)x3	Likely pathogenic

SpliceAI

953 predictions. Top by Δscore:

Variant	Effect	Δscore
7:26201558:AACGG:A	donor_loss	1.0000
7:26201559:ACGG:A	donor_loss	1.0000
7:26201560:CGGT:C	donor_loss	1.0000
7:26201561:GGT:G	donor_loss	1.0000
7:26201562:GT:G	donor_loss	1.0000
7:26206355:T:TA	acceptor_gain	1.0000
7:26206361:A:AG	acceptor_gain	1.0000
7:26206362:T:G	acceptor_gain	1.0000
7:26206366:A:AG	acceptor_gain	1.0000
7:26206366:AGC:A	acceptor_loss	1.0000
7:26206367:G:GA	acceptor_gain	1.0000
7:26206367:GC:G	acceptor_gain	1.0000
7:26206367:GCA:G	acceptor_gain	1.0000
7:26206367:GCAA:G	acceptor_gain	1.0000
7:26206367:GCAAA:G	acceptor_gain	1.0000
7:26206473:A:T	donor_gain	1.0000
7:26206507:CAGA:C	donor_gain	1.0000
7:26206507:CAGAG:C	donor_loss	1.0000
7:26206508:AGA:A	donor_gain	1.0000
7:26206509:GA:G	donor_gain	1.0000
7:26206509:GAG:G	donor_gain	1.0000
7:26206509:GAGT:G	donor_loss	1.0000
7:26206510:AGTA:A	donor_loss	1.0000
7:26206511:G:GG	donor_gain	1.0000
7:26206512:T:G	donor_loss	1.0000
7:26208377:A:AG	acceptor_gain	1.0000
7:26208378:A:G	acceptor_gain	1.0000
7:26208379:T:G	acceptor_gain	1.0000
7:26208380:A:AG	acceptor_gain	1.0000
7:26208381:A:AG	acceptor_gain	1.0000

AlphaMissense

1223 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:26206431:T:A	F30I	1.000
7:26206431:T:C	F30L	1.000
7:26206432:T:C	F30S	1.000
7:26206432:T:G	F30C	1.000
7:26206433:T:A	F30L	1.000
7:26206433:T:G	F30L	1.000
7:26206437:G:A	V32M	1.000
7:26206437:G:C	V32L	1.000
7:26206437:G:T	V32L	1.000
7:26206447:T:A	V35E	1.000
7:26206450:T:C	L36P	1.000
7:26206456:G:C	R38P	1.000
7:26206458:C:A	R39S	1.000
7:26206459:G:C	R39P	1.000
7:26206482:T:C	Y47H	1.000
7:26206489:T:A	L49Q	1.000
7:26206489:T:C	L49P	1.000
7:26206489:T:G	L49R	1.000
7:26206493:G:C	K50N	1.000
7:26206493:G:T	K50N	1.000
7:26206494:T:A	W51R	1.000
7:26206494:T:C	W51R	1.000
7:26206495:G:C	W51S	1.000
7:26206495:G:T	W51L	1.000
7:26206496:G:C	W51C	1.000
7:26206496:G:T	W51C	1.000
7:26206500:G:A	G53R	1.000
7:26206500:G:C	G53R	1.000
7:26206501:G:A	G53E	1.000
7:26206501:G:T	G53V	1.000

dbSNP variants (sampled 300 via entrez): RS1000172555 (7:26207056 A>G), RS1000259971 (7:26200774 C>A,G), RS1000317211 (7:26210055 C>T), RS1000607386 (7:26210708 A>G), RS1000770172 (7:26206271 T>C,G), RS1000836148 (7:26207247 C>A), RS1001244284 (7:26202145 A>T), RS1001282371 (7:26213582 T>C), RS1001284901 (7:26204060 T>C), RS1001298676 (7:26206007 T>C), RS1001313421 (7:26213410 C>T), RS1001408289 (7:26205718 C>T), RS1001442328 (7:26208263 G>A), RS1001580733 (7:26208114 C>G), RS1001824650 (7:26210363 G>A,C)

Disease associations

OMIM: gene MIM:604477 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST005956_35	Waist-to-hip ratio adjusted for BMI	8.000000e-14
GCST005958_8	Waist-to-hip ratio adjusted for BMI (age >50)	5.000000e-07
GCST005962_19	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	8.000000e-14
GCST009391_248	Metabolite levels	9.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0010494	guanosine diphosphate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3826866 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.84	Kd	142.8	nM	CHEMBL5653589
6.84	ED50	143.9	nM	CHEMBL5653589
5.22	IC50	6030	nM	MOLIBRESIB

PubChem BioAssay actives

2 with measured affinity, of 10 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148005: Binding affinity to human CBX3 incubated for 45 mins by Kinobead based pull down assay	kd	0.1428	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178991: Inhibition of CBX3 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	6.0300	uM

CTD chemical–gene interactions

54 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation	4
Tretinoin	decreases expression	3
bisphenol S	decreases methylation, increases expression	2
Vorinostat	increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
9-hydroxyoctadecadienoic acid	decreases expression	1
TAK-243	affects sumoylation	1
dicrotophos	decreases expression	1
4-oxoretinoic acid	decreases expression	1
bisphenol A	affects expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
ochratoxin A	decreases expression	1
quinoline	decreases expression	1
pinosylvin	decreases expression	1
tamibarotene	affects expression	1
CGP 52608	increases reaction, affects binding	1
K 7174	decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
quinocetone	decreases expression, increases expression	1
bromovanin	increases expression	1
jinfukang	decreases expression	1
bisphenol AF	increases expression	1
Bortezomib	increases expression	1
Alitretinoin	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Demecolcine	decreases expression	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3829393	Binding	Binding affinity to 15N-labeled CBX3ChD (29 to 86 residues) (unknown origin) expressed in RIPL-BL21 (DE3)-CodonPlus competent cells at 200 uM by 1H-15N HSQC NMR spectroscopy	Structure-Guided Discovery of Selective Antagonists for the Chromodomain of Polycomb Repressive Protein CBX7. — ACS Med Chem Lett

Cellosaurus cell lines

7 cell lines: 4 cancer cell line, 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A0L3	SEES3-1V human CBX3, clone1	Embryonic stem cell	Male
CVCL_A0L4	SEES3-1V human CBX3, clone2	Embryonic stem cell	Male
CVCL_A0L5	SEES3-1V human CBX3, clone3	Embryonic stem cell	Male
CVCL_B1ME	Abcam HeLa CBX3 KO	Cancer cell line	Female
CVCL_SH09	HAP1 CBX3 (-) 1	Cancer cell line	Male
CVCL_SH10	HAP1 CBX3 (-) 2	Cancer cell line	Male
CVCL_SH11	HAP1 CBX3 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.