EP300
protein-codingE1A binding protein p300, the group of Bromodomain containing|Zinc fingers ZZ-type|Lysine acetyltransferases
Gene summary
This gene encodes the adenovirus E1A-associated cellular p300 transcriptional co-activator protein. It functions as histone acetyltransferase that regulates transcription via chromatin remodeling and is important in the processes of cell proliferation and differentiation. It mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein. This gene has also been identified as a co-activator of HIF1A (hypoxia-inducible factor 1 alpha), and thus plays a role in the stimulation of hypoxia-induced genes such as VEGF. Defects in this gene are a cause of Rubinstein-Taybi syndrome and may also play a role in epithelial cancer. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~87.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013364
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0019200
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0013364
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0019188
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0013364
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013364
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013364
Submitter: ClinGen
EP300 is located at 22q13.2 and encodes the E1A binding protein p300. It was first reported in relation to autosomal dominant Rubinstein-Taybi syndrome in 2005 (Roelfsema et al., PMID:15706485). Rubinstein-Taybi syndrome is characterized by distinctive facial features, broad and angulated thumbs and halluces, short stature, and intellectual disability. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, distinct molecular mechanisms and phenotypic variability have been described for Rubinstein-Taybi syndrome 2 (OMIM:613684), and Menke-Hennekam syndrome 2 (OMIM:618333). Individuals with Rubinstein-Taybi syndrome typically have characteristic facial features, broad and angulated thumbs and halluces, short stature, and intellectual disability. Menke-Hennekam syndrome presents with impaired intellectual development and dysmorphic facial features, but the patients do not have the distinctive features of those with Rubinstein-Taybi syndrome. Therefore, these disorders have been split into multiple disease entities for consideration. 6 nonsense or frameshift variants, and deletions that have been reported in 6 probands in 3 publications (Foley et al., 2009, PMID: 19353645; Fergelot et al., 2016, PMID: 27648933; PMID: 15706485) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by expression data and an animal model that recapitulates many features of the human disease phenotype (Yao et al., 1998, PMID: 9590171; Viosca et al., 2010, PMID: 19822209). In summary, EP300 is definitively associated with autosomal dominant Rubinstein-Taybi syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 09.01.2021 (SOP Version 8).
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Craniofacial; Musculoskeletal; Neurologic
Intervention: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic
Rationale: Rubinstein-Taybi syndrome can include a risk of frequent infections (especially respiratory infections), and prophylaxis and early and aggressive treatment of infections may be beneficial; Menke-Hennekam syndrome can include frequent infections, and prophylaxis and early and aggressive treatment of infections may be beneficial; Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development
Comments: The condition may include a risk of malignancy and frequent infections, as well as arrhythmia
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to EP300 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001429.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 13 | 508 | 65 | 586 | ||
| missense | 6 | 50 | 1041 | 340 | 28 | 1465 |
| nonsense | 52 | 19 | 2 | 73 | ||
| start loss | 0 | |||||
| frameshift | 91 | 53 | 14 | 158 | ||
| splice donor/acceptor (+/-2bp) | 7 | 17 | 20 | 1 | 45 | |
| Total | 156 | 139 | 1090 | 849 | 93 | 2327 |
Highest pathogenic variant AF is 0.0000034210632
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001420.2 | 31 | MANE Select | |
| Ensembl | ENSP00000263253.7 | 31 | MANE Select | |
| RefSeq | NP_001349772.1 | 30 | Standard | |
| Ensembl | ENSP00000489397.1 | 5 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| ep300a | Danio rerio | Structure: pharyngeal arch 3-7 Quality: decreased size abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
- TGF-beta signaling pathway - Homo sapiens (human)
- Renal cell carcinoma - Homo sapiens (human)
- Long-term potentiation - Homo sapiens (human)
- Adherens junction - Homo sapiens (human)
Biological Process
- negative regulation of transcription by RNA polymerase II
- response to hypoxia
- somitogenesis
- stimulatory C-type lectin receptor signaling pathway
- transcription-coupled nucleotide-excision repair
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- RNA polymerase II activating transcription factor binding
- DNA-binding transcription activator activity, RNA polymerase II-specific
- p53 binding
- DNA binding
Cellular Component
- histone acetyltransferase complex
- nucleus
- nucleoplasm
- transcription factor complex
- chromosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000263253
- Coding exons
- 31
- Length
- 88292
- Individuals with no LoFs
- 125737
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 11
- Defined
- 125748
- p
- 0.0000437
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.03 | 1119 | 1.33e+3 | 0.843 | 0.0000732 | 15941 |
| Missense (PolyPhen) | 177 | 337.96 | 0.52374 | 4133 | ||
| Synonymous | -7.05 | 659 | 465 | 1.42 | 0.0000258 | 4698 |
| Loss of Function | 9.65 | 6 | 120 | 0.0500 | 0.00000710 | 1222 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000062 | 0.000062 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Functions as histone acetyltransferase and regulates transcription via chromatin remodeling (PubMed:23415232, PubMed:23934153, PubMed:8945521). Acetylates all four core histones in nucleosomes. Histone acetylation gives an epigenetic tag for transcriptional activation (PubMed:23415232, PubMed:23934153, PubMed:8945521). Mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein. Mediates acetylation of histone H3 at 'Lys-122' (H3K122ac), a modification that localizes at the surface of the histone octamer and stimulates transcription, possibly by promoting nucleosome instability. Mediates acetylation of histone H3 at 'Lys-27' (H3K27ac) (PubMed:23911289). Also functions as acetyltransferase for nonhistone targets. Acetylates 'Lys-131' of ALX1 and acts as its coactivator (PubMed:12929931). Acetylates SIRT2 and is proposed to indirectly increase the transcriptional activity of TP53 through acetylation and subsequent attenuation of SIRT2 deacetylase function (PubMed:18722353). Acetylates HDAC1 leading to its inactivation and modulation of transcription (PubMed:16762839). Acts as a TFAP2A-mediated transcriptional coactivator in presence of CITED2 (PubMed:12586840). Plays a role as a coactivator of NEUROD1-dependent transcription of the secretin and p21 genes and controls terminal differentiation of cells in the intestinal epithelium. Promotes cardiac myocyte enlargement. Can also mediate transcriptional repression. Acetylates FOXO1 and enhances its transcriptional activity (PubMed:15890677). Acetylates BCL6 wich disrupts its ability to recruit histone deacetylases and hinders its transcriptional repressor activity (PubMed:12402037). Participates in CLOCK or NPAS2-regulated rhythmic gene transcription; exhibits a circadian association with CLOCK or NPAS2, correlating with increase in PER1/2 mRNA and histone H3 acetylation on the PER1/2 promoter (PubMed:14645221). Acetylates MTA1 at 'Lys-626' which is essential for its transcriptional coactivator activity (PubMed:16617102). Acetylates XBP1 isoform 2; acetylation increases protein stability of XBP1 isoform 2 and enhances its transcriptional activity (PubMed:20955178). Acetylates PCNA; acetylation promotes removal of chromatin-bound PCNA and its degradation during nucleotide excision repair (NER) (PubMed:24939902). Acetylates MEF2D (PubMed:21030595). Acetylates and stabilizes ZBTB7B protein by antagonizing ubiquitin conjugation and degragation, this mechanism may be involved in CD4/CD8 lineage differentiation (PubMed:20810990). In addition to protein acetyltransferase, can use different acyl-CoA substrates, such as (2E)-butenoyl-CoA (crotonyl-CoA), butanoyl-CoA (butyryl-CoA) or propanoyl-CoA (propionyl-CoA), and is able to mediate protein crotonylation, butyrylation or propionylation, respectively (PubMed:25818647, PubMed:17267393). Acts as a histone crotonyltransferase; crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors (PubMed:25818647). Histone crotonyltransferase activity is dependent on the concentration of (2E)-butenoyl-CoA (crotonyl-CoA) substrate and such activity is weak when (E)-but-2-enoyl-CoA (crotonyl-CoA) concentration is low (PubMed:25818647). Also acts as a histone butyryltransferase; butyrylation marks active promoters (PubMed:17267393). Functions as a transcriptional coactivator for SMAD4 in the TGF-beta signaling pathway (PubMed:25514493). {ECO:0000250|UniProtKB:B2RWS6, ECO:0000269|PubMed:10733570, ECO:0000269|PubMed:11430825, ECO:0000269|PubMed:11701890, ECO:0000269|PubMed:12402037, ECO:0000269|PubMed:12586840, ECO:0000269|PubMed:12929931, ECO:0000269|PubMed:14645221, ECO:0000269|PubMed:15186775, ECO:0000269|PubMed:15890677, ECO:0000269|PubMed:16617102, ECO:0000269|PubMed:16762839, ECO:0000269|PubMed:17267393, ECO:0000269|PubMed:18722353, ECO:0000269|PubMed:18995842, ECO:0000269|PubMed:20810990, ECO:0000269|PubMed:21030595, ECO:0000269|PubMed:23415232, ECO:0000269|PubMed:23911289, ECO:0000269|PubMed:23934153, ECO:0000269|PubMed:24939902, ECO:0000269|PubMed:25514493, ECO:0000269|PubMed:25818647, ECO:0000269|PubMed:8945521, ECO:0000305|PubMed:20955178}.;
- Disease
- DISEASE: Note=Defects in EP300 may play a role in epithelial cancer.; DISEASE: Note=Chromosomal aberrations involving EP300 may be a cause of acute myeloid leukemias. Translocation t(8;22)(p11;q13) with KAT6A.; DISEASE: Rubinstein-Taybi syndrome 2 (RSTS2) [MIM:613684]: A disorder characterized by craniofacial abnormalities, postnatal growth deficiency, broad thumbs, broad big toes, mental retardation and a propensity for development of malignancies. Some individuals with RSTS2 have less severe mental impairment, more severe microcephaly, and a greater degree of changes in facial bone structure than RSTS1 patients. {ECO:0000269|PubMed:15706485}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.910
Intolerance Scores
- LoFtool
- 0.000482
- RVIS EVS
- -3.68
- RVIS percentile EVS
- 0.26
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- S
- Essential (gene trap)
- K
- Indispensability pred.
- E
- Indispensability score
- 1.00
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |