This article was accepted into the corpus but its outbound wikilinks were never NER-processed — typical at the deepest BFS hop or when the run's entity cap was reached. No expansion funnel to show.
| EP300 | |
|---|---|
| Name | EP300 protein |
| Uniprot | Q09472 |
| Organism | Homo sapiens |
| Length | 2414 aa |
EP300 is a human transcriptional co-activator and lysine acetyltransferase implicated in chromatin remodeling, transcriptional regulation, and cell growth control. It integrates signals from multiple pathways including those mediated by p53, NF-κB, HIF-1α, and MYC to modulate gene expression programs. EP300 functions as a scaffold for complexes containing factors such as CREB, BRD4, Mediator and chromatin remodelers like SWI/SNF.
EP300 catalyzes acetylation of histone and non-histone lysine residues, influencing chromatin accessibility at loci regulated by transcription factors including p53, AP-1, STAT3, ERα, and GR (glucocorticoid receptor). It acts as a co-activator for sequence-specific regulators such as CREB, HIF-1α, NF-κB, MYC, and β-catenin, promoting transcriptional activation at promoters and enhancers associated with genes like those controlled by TP53 and E2F1. EP300-dependent acetylation of targets such as p53, GATA1, FOXO1, and SMAD3 modifies protein stability, DNA binding, and protein–protein interactions, integrating signals from pathways exemplified by TGF-β, Wnt/β-catenin, MAPK/ERK, and PI3K/AKT.
The EP300 protein comprises multiple conserved domains: a bromodomain that recognizes acetyl-lysine marks seen in complexes with BRD4 and P-TEFb; a histone acetyltransferase (HAT) domain homologous to yeast Gcn5; cysteine/histidine-rich zinc-finger TAZ domains interacting with factors such as p53 and E1A from Adenovirus; and nuclear receptor interaction domains that bind ERα and RXRα. EP300's structural organization supports multivalent interactions with co-regulators like Mediator, chromatin remodelers including SWI/SNF components such as BRG1, and histone mark readers such as BRD4 and HP1.
EP300 is regulated by post-translational modifications (phosphorylation by CDK2 and MAPK1/ERK2; methylation by PRMT1; ubiquitination by ligases like MDM2), and by interactions with viral proteins E1A and HPV E6. It forms complexes with transcription factors CREB, HIF-1α, NF-κB, and p53 and with co-regulators such as CBP (CREBBP), Mediator, PCAF, and chromatin remodelers including SWI/SNF. EP300 activity is modulated by signaling cascades involving cAMP, TGF-β, Wnt, and Notch, and by metabolites that affect acetyl-CoA availability as in pathways involving ATP citrate lyase and ACLY.
EP300 contributes to lineage specification and organogenesis by co-activating transcriptional programs controlled by factors such as GATA1 in erythropoiesis, MYOD1 in myogenesis, HNF4α in hepatic differentiation, and NEUROD1 in neuronal development. It participates in angiogenesis via interaction with HIF-1α and vascular regulators like VEGF-A and modulates immune responses through NF-κB and STAT3 pathways. EP300 influences metabolic regulation by acetylating metabolic transcription factors such as PPARγ and interacts with circadian regulators including CLOCK and BMAL1.
Germline and somatic alterations affecting EP300 associate with syndromic and neoplastic conditions. Germline haploinsufficiency produces developmental syndromes with overlapping features of Rubinstein–Taybi syndrome phenotypes linked to mutations in CREBBP. Somatic mutations or translocations involving EP300 occur in cancers including diffuse large B-cell lymphoma, acute lymphoblastic leukemia, bladder cancer, lung adenocarcinoma, and colorectal cancer. EP300 dysregulation affects tumor suppressor pathways such as p53 and oncogenic programs driven by MYC and β-catenin, and influences responses to targeted therapies like inhibitors of BET bromodomain proteins and epigenetic drugs targeting HDACs.
Pathogenic variants include truncating, missense, and splice-site changes that disrupt the HAT, bromodomain, or TAZ domains, with recurrent lesions reported in cohorts sequenced by consortia such as The Cancer Genome Atlas and International Cancer Genome Consortium. Germline mutations in EP300 show genotype–phenotype correlations with neurodevelopmental outcomes reminiscent of alterations in CREBBP. Somatic hotspot mutations cluster in regions critical for acetyltransferase activity and protein–protein interactions, identified in sequencing studies of diffuse large B-cell lymphoma, small-cell lung carcinoma, and head and neck squamous cell carcinoma.
EP300 function has been probed using genetic models including knockout and conditional alleles in Mus musculus, RNAi and CRISPR screens in human cell lines like HeLa and HEK293T, and patient-derived xenografts used in studies with inhibitors such as A-485 and CBP/EP300 bromodomain inhibitors assessed alongside olaparib and trametinib. Biochemical assays employ recombinant HAT domains, bromodomain-binding probes, chromatin immunoprecipitation sequencing in cell lines and tissues, and proteomics platforms used by groups collaborating with initiatives like ENCODE and GTEx.
Category:Human proteins