Alternative titles; symbols
HGNC Approved Gene Symbol: EP300
Cytogenetic location: 22q13.2 Genomic coordinates (GRCh38) : 22:41,092,592-41,180,077 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q13.2 | Colorectal cancer, somatic | 114500 | 3 | |
| Menke-Hennekam syndrome 2 | 618333 | Autosomal dominant | 3 | |
| Rubinstein-Taybi syndrome 2 | 613684 | Autosomal dominant | 3 |
The EP300 gene encodes p300, a histone acetyltransferase that regulates transcription via chromatin remodeling and is important in the processes of cell proliferation and differentiation (Gayther et al., 2000).
The growth-controlling functions of the adenovirus E1A oncoprotein depend on its ability to interact with a set of cellular proteins. Among these are the retinoblastoma protein, p107, p130, and p300. Eckner et al. (1994) isolated a cDNA encoding full-length human p300. p300 contains 3 cysteine- and histidine-rich regions of which the most carboxy-terminal region interacts specifically with E1A. In its center, p300 contains a bromodomain, a hallmark of certain transcriptional coactivators. p300 and CREB-binding protein (CREBBP, or CBP; 600140) are highly related in primary structure (Arany et al., 1994). Several protein motifs such as a bromodomain, a KIX domain, and 3 regions rich in cys/his residues are well conserved between these 2 proteins.
Nibbeling et al. (2017) noted that EP300 is strongly expressed in human cerebellum as well as in other brain regions.
Lin et al. (2001) identified a compactly folded 46-residue domain in CBP and p300, the IRF3-binding domain (IBID), and determined its structure by nuclear magnetic resonance spectroscopy. IBID has a helical framework containing an apparently flexible polyglutamine loop that participates in ligand binding. Spectroscopic data indicated that induced folding accompanies association of IBID with its partners, which exhibit no evident sequence similarities. IBID is an important contributor to signal integration by CBP and p300.
Crystal Structure
Liu et al. (2008) described a high resolution x-ray crystal structure of a semisynthetic heterodimeric p300 HAT domain in complex with a bisubstrate inhibitor, Lys-CoA. This structure showed that p300/CBP is a distant cousin of other structurally characterized HATs, but revealed several novel features that explain the broad substrate specificity and preference for nearby basic residues. Based on this structure and accompanying biochemical data, Liu et al. (2008) proposed that p300/CBP uses an unusual hit-and-run (Theorell-Chance) catalytic mechanism that is distinct from other characterized HATs. Several disease-associated mutations could also be readily accounted for by the p300 HAT structure.
Ortega et al. (2018) described a crystal structure of p300 in which the autoinhibitory loop invades the active site of a neighboring HAT domain, revealing a snapshot of a trans-autoacetylation reaction intermediate. Substrate access to the active site involves the rearrangement of an autoinhibitory RING domain. Ortega et al. (2018) concluded that their data explained how cellular signaling and the activation and dimerization of transcription factors control the activation of p300, and therefore explained why gene transcription is associated with chromatin acetylation.
Eckner et al. (1994) examined the ability of p300 to overcome the repressive effect of E1A on the SV40 enhancer. They showed that p300 molecules lacking an intact E1A-binding site can bypass E1A repression and restore to a significant extent the activity of the SV40 enhancer, even in the presence of high levels of E1A protein. These results imply that p300 may function as a transcriptional adaptor protein for certain complex transcriptional regulatory elements.
Weaver et al. (1998) identified EP300/CREBBP and IRF3 (603734) as components of DRAF1 (double-stranded RNA-activated factor-1), a positive regulator of interferon-stimulated gene transcription that functions as a direct response to viral infection.
The cytokines LIF (159540) and BMP2 (112261) signal through different receptors and transcription factors, namely STATs and SMADs, respectively. Nakashima et al. (1999) found that LIF and BMP2 act in synergy on primary fetal neural progenitor cells to induce astrocytes. The transcriptional coactivator p300 interacted physically with STAT3 (102582) at its amino terminus in a cytokine stimulation-independent manner, and with SMAD1 (601595) at its carboxyl terminus in a cytokine stimulation-dependent manner. The formation of a complex between STAT3 and SMAD1, bridged by p300, is involved in the cooperative signaling of LIF and BMP2 and the subsequent induction of astrocytes from neuronal progenitors.
Hasan et al. (2001) demonstrated that p300 may have a role in DNA repair synthesis through its interaction with proliferating cell nuclear antigen (PCNA; 176740). Hasan et al. (2001) demonstrated that in vitro and in vivo p300 forms a complex with PCNA that does not depend on the S phase of the cell cycle. A large fraction of both p300 and PCNA colocalized to speckled structures in the nucleus. Furthermore, the endogenous p300-PCNA complex stimulates DNA synthesis in vitro. Chromatin immunoprecipitation experiments indicated that p300 is associated with freshly synthesized DNA after ultraviolet irradiation. Hasan et al. (2001) suggested the p300 may participate in chromatin remodeling at DNA lesion sites to facilitate PCNA function in DNA repair synthesis.
Hasan et al. (2001) found that p300 formed a complex with flap endonuclease-1 (FEN1; 600393) and acetylated FEN1 in vitro. Furthermore, FEN1 acetylation was observed in vivo and was enhanced upon ultraviolet treatment of human cells. Acetylation of the FEN1 C terminus by p300 significantly reduced DNA binding and nuclease activity of FEN1. PCNA was able to stimulate both acetylated and unacetylated FEN1 activity to the same extent. These results identified acetylation as a novel regulatory modification of FEN1 and suggested that p300 is not only a component of the chromatin remodeling machinery but might also play a critical role in regulating DNA metabolic events.
TDG (601423) initiates repair of G/T and G/U mismatches, commonly associated with CpG islands, by removing thymine and uracil moieties. Tini et al. (2002) reported that TDG associates with transcriptional coactivators CBP (600140) and p300 and that the resulting complexes are competent for both the excision step of repair and histone acetylation. TDG stimulated CBP transcriptional activity in transfected cells and reciprocally served as a substrate for CBP/p300 acetylation. This acetylation triggered release of CBP from DNA ternary complexes and also regulated recruitment of repair endonuclease APE (107748). These observations revealed a potential regulatory role for protein acetylation in base mismatch repair and a role for CBP/p300 in maintaining genomic stability.
Etchegaray et al. (2003) demonstrated that transcriptional regulation of the core clock mechanism in mouse liver is accompanied by rhythms in H3 histone (see 602810) acetylation, and that H3 acetylation is a potential target of the inhibitory action of Cry. The promoter regions of the Per1 (602260), Per2 (603426), and Cry1 (601933) genes exhibited circadian rhythms in H3 acetylation and RNA polymerase II (see 180660) binding that were synchronous with the corresponding steady-state mRNA rhythms. The histone acetyltransferase p300 precipitated with Clock (601851) in vivo in a time-dependent manner. Moreover, the Cry proteins inhibited a p300-induced increase in Clock/Bmal1 (602550)-mediated transcription. Etchegaray et al. (2003) concluded that the delayed timing of the Cry1 mRNA rhythm, relative to the Per rhythms, was due to the coordinated activities of Rev-Erb-alpha (602408) and Clock/Bmal1, and defined a novel mechanism for circadian phase control.
Rapid turnover of the tumor suppressor protein p53 (191170) requires the MDM2 (164785) ubiquitin ligase, and both interact with p300-CBP transcriptional coactivators. p53 is stabilized by the binding of p300 to the oncoprotein E1A, suggesting that p300 regulates p53 degradation. Grossman et al. (2003) observed that purified p300 exhibited intrinsic ubiquitin ligase activity but was inhibited by E1A. In vitro, p300 with MDM2 catalyzed p53 polyubiquitination, whereas MDM2 catalyzed p53 monoubiquitination. E1A expression caused a decrease in polyubiquitinated but not monoubiquitinated p53 in cells. Thus, Grossman et al. (2003) concluded that generation of the polyubiquitinated forms of p53 that are targeted for proteasome degradation requires the intrinsic ubiquitin ligase activities of MDM2 and p300.
Tsuda et al. (2003) found that SOX9 (608160) used CBP and p300 as transcriptional coactivators. SOX9 bound CBP and p300 in vitro and in vivo, and both coactivators enhanced SOX9-dependent COL2A1 (120140) promoter activity. Disruption of the CBP-SOX9 complex inhibited COL2A1 mRNA expression and differentiation of human mesenchymal stem cells into chondrocytes.
Using systems reconstituted with recombinant chromatin templates and coactivators, An et al. (2004) demonstrated the involvement of PRMT1 (602950) and CARM1 (603934) in p53 function; both independent and ordered cooperative functions of p300, PRMT1, and CARM1; and mechanisms involving direct interactions with p53 and obligatory modifications of corresponding histone substrates. Chromatin immunoprecipitation analyses confirmed the ordered accumulation of these (and other) coactivators and cognate histone modifications on a p53-responsive gene, GADD45 (126335), following ectopic p53 expression and/or ultraviolet irradiation.
Turnell et al. (2005) showed that 2 anaphase-promoting complex/cyclosome (APC/C) components, APC5 (606948) and APC7 (606949), interact directly with the coactivators CBP and p300 through protein-protein interaction domains that are evolutionarily conserved in adenovirus E1A. This interaction stimulates intrinsic CBP/p300 acetyltransferase activity and potentiates CBP/p300-dependent transcription. Turnell et al. (2005) also showed that APC5 and APC7 suppress E1A-mediated transformation in a CBP/p300-dependent manner, indicating that these components of the APC/C may be targeted during cellular transformation. Furthermore, Turnell et al. (2005) established that CBP is required for APC/C function; specifically, gene ablation of CBP by RNA-mediated interference markedly reduces the E3 ubiquitin ligase activity of the APC/C and the progression of cells through mitosis. Taken together, Turnell et al. (2005) concluded that their results define discrete roles for the APC/C-CBP/p300 complexes in growth regulation.
In vivo transcription by RNA polymerase II takes place in the context of chromatin. Guermah et al. (2006) found that a purified, reconstituted RNA polymerase II system that sufficed for activator-dependent transcription on DNA templates was incapable of transcribing chromatin templates, even in the presence of factors that effected transcription in less-purified assay systems. Using a complementation and HeLa cell nuclear extract fractionation scheme, Guermah et al. (2006) identified and purified an activity, designated CTEA (chromatin transcription-enabling activity), that allowed for transcription through chromatin templates in a manner that was both activator and p300/acetyl-CoA dependent. CTEA acted primarily at the elongation step and enabled RNA polymerase II machinery to transcribe efficiently through several contiguously positioned nucleosomes. Guermah et al. (2006) identified the major functional component of CTEA as transcription elongation factor SII (TCEA1; 601425). SII was essential for productive transcription elongation, and its function at this step was dependent on p300-dependent acetylation. These synergistic transcriptional elongation activities were potentiated by HMGB2 (163906).
Liu et al. (2008) demonstrated that a fasting-inducible switch, consisting of the histone acetyltransferase p300 and the nutrient-sensing deacetylase sirtuin-1 (SIRT1; 604479), maintains energy balance in mice through the sequential induction of CRTC2 (608972) and FOXO1 (136533). After glucagon induction, CRTC2 stimulated gluconeogenic gene expression by an association with p300, which Liu et al. (2008) showed is also activated by dephosphorylation at serine-89 during fasting. In turn, p300 increased hepatic CRTC2 activity by acetylating it at lysine-628, a site that also targets CRTC2 for degradation after its ubiquitination by the E3 ligase constitutive photomorphogenic protein (COP1; 608067). Glucagon effects were attenuated during late fasting, when CRTC2 was downregulated owing to SIRT1-mediated deacetylation and when FOXO1 supported expression of the gluconeogenic program. Disrupting SIRT1 activity, by liver-specific knockout of the SIRT1 gene or by administration of a SIRT1 antagonist, increased CRTC2 activity and glucose output, whereas exposure to SIRT1 agonists reduced them. In view of the reciprocal activation of FOXO1 and its coactivator Ppar-gamma coactivator 1-alpha (PGC1-alpha; 604517) by SIRT1 activators, Liu et al. (2008) concluded that their results illustrate how the exchange of 2 gluconeogenic regulators during fasting maintains energy balance.
Visel et al. (2009) presented the results of chromatin immunoprecipitation with the enhancer-associated protein p300 followed by massively parallel sequencing, and mapped several thousand in vivo binding sites of p300 in mouse embryonic forebrain, midbrain, and limb tissue. They tested 86 of these sequences in a transgenic mouse assay, which in nearly all cases demonstrated reproducible enhancer activity in the tissues that were predicted by p300 binding. Visel et al. (2009) concluded that in vivo mapping of p300 binding is a highly accurate means for identifying enhancers and their associated activities, and suggested that such datasets will be useful in the study of the role of tissue-specific enhancers in human biology and disease on a genomewide scale.
Das et al. (2009) demonstrated that the histone acetyltransferase CBP (600140) in flies, and CBP and p300 in humans, acetylate histone H3 (see 601128) on lys56 (H3K56), whereas Drosophila sir2 and human SIRT1 and SIRT2 (604480) deacetylate H3K56 acetylation. The histone chaperones ASF1A (609189) in humans and Asf1 in Drosophila are required for acetylation of H3K56 in vivo, whereas the histone chaperone CAF1 (see 601245) in humans and Caf1 in Drosophila are required for the incorporation of histones bearing this mark into chromatin. Das et al. (2009) showed that, in response to DNA damage, histones bearing acetylated K56 are assembled into chromatin in Drosophila and human cells, forming foci that colocalize with sites of DNA repair. Furthermore, acetylation of H3K56 is increased in multiple types of cancer, correlating with increased levels of ASF1A in these tumors. Das et al. (2009) concluded that their identification of multiple proteins regulating the levels of H3K56 acetylation in metazoans will allow future studies of this critical and unique histone modification that couples chromatin assembly to DNA synthesis, cell proliferation, and cancer.
Vilhais-Neto et al. (2010) found that RERE (605226) forms a complex with NR2F2 (107773), p300, and a retinoic acid receptor, which is recruited to the retinoic acid regulatory element of retinoic acid targets, such as the RARB (180220) promoter. Furthermore, the knockdown of NR2F2 and/or RERE decreases retinoic acid signaling, suggesting that this complex is required to promote transcriptional activation of retinoic acid targets. The symmetrical expression of NR2F2 in the presomitic mesoderm overlaps with the symmetry of the retinoic acid signaling response, supporting its implication in the control of somitic symmetry. Vilhais-Neto et al. (2010) suggested that misregulation of this mechanism could be involved in symmetry defects of the human spine, such as those observed in patients with scoliosis.
Xu et al. (2011) isolated mouse embryonic endoderm cells and assessed histone modifications at regulatory elements of silent genes that are activated upon liver or pancreas fate choices, and found that the liver and pancreas elements have distinct chromatin patterns. Furthermore, the histone acetyltransferase P300, recruited via bone morphogenetic protein (BMP; see 600799) signaling, and the histone methyltransferase Ezh2 (601573) have modulatory roles in the fate choice. Xu et al. (2011) concluded that their studies revealed a functional 'prepattern' of chromatin states within multipotent progenitors and potential targets to modulate cell fate induction.
Wang et al. (2011) found that AML1-ETO (see 151385), a fusion protein generated by the t(8;21) translocation found in acute myelogenous leukemia, is acetylated by the transcriptional coactivator p300 in leukemia cells isolated from t(8;21) AML patients, and that this acetylation is essential for its self-renewal-promoting effects in human cord blood CD34+ (142230) cells and its leukemogenicity in mouse models. Inhibition of p300 abrogates the acetylation of AML1-ETO and impairs its ability to promote leukemic transformation. Wang et al. (2011) concluded that lysine acetyltransferases represent a potential therapeutic target in AML.
To identify distant-acting enhancers active during craniofacial development, Attanasio et al. (2013) used chromatin immunoprecipitation on embryonic mouse face tissue followed by sequencing to identify noncoding genome regions bound by the enhancer-associated p300 protein. They identified more than 4,000 candidate enhancers, the majority of which were at least partially conserved between humans and mice. Attanasio et al. (2013) subsequently used LacZ reporter assays in transgenic mice and optical projection tomography to determine 3-dimensional expression patterns of a subset of these candidate enhancers. Further characterization of more than 200 candidate enhancer sequences in transgenic mice revealed a remarkable spatial complexity of in vivo expression patterns. Candidate enhancers were identified within the gene desert associated with cleft palate and facial morphology on chromosome 8q24, and at the ABCA4 (601691) locus. Targeted deletions of 3 craniofacial enhancers near genes with roles in craniofacial development (Snai2, 602150; Msx1, 142983; and Isl1, 600366) resulted in changes of expression of those genes as well as quantitatively subtle yet definable alterations of craniofacial shape.
Gao et al. (2014) investigated the role of AUTS2 (607270) as part of a previously identified Polycomb repressive complex (PRC1-AUTS2) and in the context of neurodevelopment. In contrast to the canonical role of PRC1 in gene repression, PRC1-AUTS2 activates transcription. Biochemical studies demonstrated that the casein kinase-2 (CK2; see 115440) component of PRC1-AUTS2 neutralizes PRC1 repressive activity, whereas AUTS2-mediated recruitment of p300 leads to gene activation. Chromatin immunoprecipitation followed by sequencing demonstrated that AUTS2 regulates neuronal gene expression through promoter association. Conditional targeting of Auts2 in the mouse central nervous system (CNS) leads to various developmental defects. Gao et al. (2014) concluded that their findings revealed a natural means of subverting PRC1 activity, linking key epigenetic modulators with neuronal functions and diseases.
Ortega et al. (2018) showed that the activation of p300 directly depends on the activation and oligomerization status of transcription factor ligands. Using 2 model transcription factors, IRF3 (603734) and STAT1 (600555), Ortega et al. (2018) demonstrated that transcription factor dimerization enables the trans-autoacetylation of p300 in a highly conserved and intrinsically disordered autoinhibitory lysine-rich loop, resulting in p300 activation.
By fluorescence in situ hybridization, Eckner et al. (1994) mapped the p300 gene, symbolized EP300, to chromosome 22q13.
Rubinstein-Taybi Syndrome 2
In 3 unrelated patients with Rubinstein-Taybi syndrome-2 (RSTS2; 613684), Roelfsema et al. (2005) identified 3 different heterozygous de novo mutations in the EP300 gene (602700.0003-602700.0005). CREBBP and EP300 function as transcriptional coactivators in the regulation of gene expression through various signal transduction pathways. Inactivation of CREBBP also results in Rubinstein-Taybi syndrome-1 (RSTS1; 180849), indicating that a certain level of the protein is essential for normal development. There is a direct link between loss of acetyltransferase activity and RSTS, which indicates the disorder is caused by aberrant chromatin regulation. Roelfsema et al. (2005) stated that these were the first mutations identified in EP300 underlying a congenital disorder.
In 1 (2.6%) of 38 patients with RSTS who did not have mutations in the CREBBP gene, Zimmermann et al. (2007) identified a mutation in the EP300 gene (602700.0006) predicted to result in mild protein truncation. The patient had a very mild form of the disorder. Zimmermann et al. (2007) concluded that mutations in the EP300 gene play only a minor role in the etiology of RSTS.
In a 7-year-old boy with suspected Rubinstein-Taybi syndrome in whom sequencing and MLPA analysis of the CREBBP gene was normal, Foley et al. (2009) identified a de novo deletion involving exons 3 to 8 in the EP300 gene (602700.0007).
Hamilton et al. (2016) reported heterozygous de novo mutations at highly conserved residues in the EP300 gene in 9 unrelated patients from the UK or Ireland with RSTS2. Six mutations were truncating mutations and 3 were missense (see, e.g., 602700.0010 and 602700.0011) mutations.
Menke-Hennekam Syndrome 2
In 2 patients with MKHK2, 1 of whom had been studied by Hamilton et al. (2016), Menke et al. (2018) identified 2 heterozygous de novo mutations in EP300 (602700.0012, 602700.0013).
Somatic Mutations
A role for EP300 in cancer had been implied by the fact that it is targeted by viral oncoproteins (Arany et al., 1995), it is fused to MLL (159555) in leukemia (Ida et al., 1997), and 2 missense sequence alterations in EP300 were identified in epithelial malignancies (Muraoka et al., 1996).
Gayther et al. (2000) described somatic EP300 mutations (see, e.g., 602700.0001; 602700.0002) that predicted a truncated protein in 6 (3%) of 193 epithelial cancers analyzed. Of these 6 mutations, 2 were in primary tumors (a colorectal cancer and a breast cancer) and 4 were in cancer cell lines (colorectal, breast, and pancreatic). In addition, they identified a somatic in-frame insertion in a primary breast cancer and missense alterations in a primary colorectal cancer and 2 cell lines (breast and pancreatic). Inactivation of the second allele was demonstrated in 5 of the 6 cases with truncating mutations and in 2 other cases. The data showed that EP300 is mutated in epithelial cancers and provided the first evidence that it behaves as a classic tumor suppressor gene.
Pasqualucci et al. (2011) reported that the 2 most common types of B cell non-Hodgkin lymphoma (605027), follicular lymphoma and diffuse large B-cell lymphoma, harbor frequent structural alterations inactivating CREBBP and, more rarely, EP300, 2 highly related histone and nonhistone acetyltransferases (HATs) that act as transcriptional coactivators in multiple signaling pathways. Overall, about 39% of diffuse large B-cell lymphoma and 41% of follicular lymphoma cases display genomic deletions and/or somatic mutations that remove or inactivate the HAT coding domain of these 2 genes. These lesions usually affect 1 allele, suggesting that reduction in HAT dosage is important for lymphomagenesis. Pasqualucci et al. (2011) demonstrated specific defects in acetylation-mediated inactivation of the BCL6 oncoprotein (109565) and activation of the p53 tumor suppressor (191170).
Le Gallo et al. (2012) used whole-exome sequencing to comprehensively search for somatic mutations in 13 primary serous endometrial tumors (see 608089), and subsequently resequenced 18 genes that were mutated in more than 1 tumor and/or were components of an enriched functional grouping from 40 additional serous tumors. Le Gallo et al. (2012) identified a high frequency of somatic mutation (8%) in the EP300 gene.
Associations Pending Confirmation
In a mother and daughter (family RF19) with autosomal dominant spinocerebellar ataxia (see, e.g., SCA1; 164400), Nibbeling et al. (2017) identified a heterozygous 1-bp insertion (c.6693_6694insC) in the EP300 gene, predicted to result in a frameshift and premature termination (Gln2232fs70Ter) leading to a loss of the C-terminal part of the second transactivation domain. The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The family was 1 of 20 unrelated families with autosomal dominant SCA who underwent whole-exome sequencing. A second heterozygous missense variant (c.6020A-G, gln2007 to arg, Q2007R) at a highly conserved residue in the linker preceding the second transactivation domain was subsequently identified in a man (case DNA008784) with apparently sporadic SCA. (The Q2007R mutation also appeared as Gln2232Arg in Table 1 of the report.) This patient was 1 of 96 individuals with SCA who were screened with a gene panel. Both variants were absent from the 1000 Genomes Project database. The truncating variant was not found in the ExAC database, whereas Q2007R was found at a very low frequency in the ExAC database (8.245 x 10(-6)). Functional studies of the variants and studies of patient cells were not performed. The mother and daughter had slowly progressive gait ataxia with an unclear age at onset. Brain imaging showed loss of parenchyma in the cerebellar vermis. The unrelated patient with sporadic disease had onset of slowly progressive cerebellar ataxia at age 20 years, cerebellar atrophy on brain imaging, and spasticity. Gene network analysis suggested that EP300 is linked with known SCA genes based on predicted functions.
The transcriptional coactivator and integrator p300 and its closely related family member CREBBP mediate multiple signal-dependent transcriptional events. Yao et al. (1998) generated mice lacking a functional p300 gene. Animals nullizygous for p300 died between days 9 and 11.5 of gestation, exhibiting defects in neurulation, cell proliferation, and heart development. Cells derived from p300-deficient embryos displayed specific transcriptional defects and proliferated poorly. p300 heterozygotes also manifested considerable embryonic lethality. Moreover, double heterozygosity for p300 and CREBBP was invariably associated with embryonic death. Thus, mouse development is exquisitely sensitive to the overall gene dosage of p300 and CREBBP. These results provide evidence that a coactivator endowed with histone acetyltransferase activity is essential for mammalian cell proliferation and development.
Kasper et al. (2002) demonstrated that the protein-binding KIX domains of CBP (600140) and p300 have nonredundant functions in mice. In mice homozygous for point mutations in the KIX domain of p300 designed to disrupt the binding surface for the transcription factors c-Myb (189990) and Creb (123810), multilineage defects occur in hematopoiesis, including anemia, B-cell deficiency, thymic hypoplasia, megakaryocytosis, and thrombocytosis. By contrast, age-matched mice homozygous for identical mutations in the KIX domain of CBP are essentially normal. There is a synergistic genetic interaction between mutations in c-MYB and mutations in the KIX domain of p300, which suggests that the binding of c-MYB to this domain of p300 is crucial for the development and function of megakaryocytes. Thus, Kasper et al. (2002) concluded that conserved domains in 2 highly related coactivators have contrasting roles in hematopoiesis.
Sandberg et al. (2005) created mice with a homozygous met303-to-val (M303V) mutation in the Myb gene, which disrupted the interaction between Myb and p300. The biologic consequences of the mutation included thrombocytosis, megakaryocytosis, anemia, lymphopenia, and absence of eosinophils. Detailed analysis of hematopoiesis in mutant mice revealed distinct blocks in T-cell, B-cell, and red blood cell development, as well as a 10-fold increase in the number of hematopoietic stem cells. Cell cycle analysis showed that twice as many mutant hematopoietic stem cells were actively cycling in mutant mice compared with wildtype mice. Sandberg et al. (2005) concluded that MYB, through its interaction with p300, controls the proliferation and differentiation of hematopoietic stem and progenitor cells.
Lin et al. (2012) reported that acetylation and deacetylation of the catalytic subunit of the adenosine monophosphate-activated protein kinase (AMPK), PRKAA1 (602739), a critical cellular energy-sensing protein kinase complex, is controlled by the opposing catalytic activities of HDAC1 (601241) and p300. Deacetylation of AMPK enhanced physical interaction with the upstream kinase LKB1 (602216), leading to AMPK phosphorylation and activation, and resulting in lipid breakdown in human liver cells. The authors later found that the Methods section of their article was inaccurate. Because they could not reproduce all of their results, they retracted the article.
In 1 of 20 primary colorectal cancers (114500), Gayther et al. (2000) found a somatic arg580-to-ter (R580X) nonsense mutation in the EP300 gene resulting from a C-to-T transition at nucleotide 2837. This was associated with loss of heterozygosity (LOH).
In a primary colorectal cancer (114500), Gayther et al. (2000) found a somatic 7861C-A transversion in exon 31 of the EP300 gene, resulting in a pro2221-to-gln amino acid substitution. This was associated with loss of heterozygosity of the other allele.
In a patient with Rubinstein-Taybi syndrome-2 (RSTS2; 613684), Roelfsema et al. (2005) found a de novo 1942C-T transition in exon 10 of the EP300 gene, resulting in an arg648-to-ter (R648X) mutation.
In a patient with Rubinstein-Taybi syndrome-2 (RSTS2; 613684), Roelfsema et al. (2005) found a de novo 8-bp deletion that removed nucleotides 2877-2884 from exon 15 of the EP300 gene. The 8-bp deletion resulted in a frameshift beginning at codon 959 and ending with a premature stop at codon 966.
In a patient with Rubinstein-Taybi syndrome-2 (RSTS2; 613684), Roelfsema et al. (2005) found a deletion of the first exon of the EP300 gene. It was considered probable that this deletion would lead to no expression from the affected allele.
In a patient with Rubinstein-Taybi syndrome-2 (RSTS2; 613684), Zimmermann et al. (2007) identified a 1-bp deletion (7100delC) in exon 31 of the EP300 gene, The patient had a 'mild' form of the disorder with higher intelligence than other reported patients (IQ estimated at 75) and mild facial dysmorphism. The mutation is located close to the 3-prime end of the protein, was predicted to be a mild truncation, and does not alter the HAT domain.
In a 7-year-old boy with global developmental delay, slightly broad halluces but normal thumbs, and facial dysmorphism reminiscent of Rubinstein-Taybi syndrome-2 (RSTS2; 613684), especially while smiling, Foley et al. (2009) identified heterozygosity for a de novo deletion of exon 4 of the EP300 gene; RNA sequencing revealed that exon 2 was spliced to exon 9, indicating deletion of exons 3 through 8. Neither parent carried the deletion.
In a 3-year-old boy with RSTS2 (RSTS2; 613684), Bartsch et al. (2010) identified an apparently de novo heterozygous 1-bp deletion (638delG) in exon 2 of the EP300 gene, predicted to result in a frameshift and premature termination. The child had severe microcephaly, retrognathia, broad thumbs and great toes, and delayed psychomotor development with marked speech delay. He also had posterior helical pits but normal palpebral fissures, nose, and mouth.
In a 5-year-old Caucasian boy with a phenotype overlapping Cornelia de Lange syndrome (122470), Woods et al. (2014) made the molecular diagnosis of RSTS2 (RSTS2; 613684) postmortem. Whole-exome sequencing identified a heterozygous c.104_107del mutation in exon 2 of the EP300 gene, resulting in a frameshift (Ser35fs). The mutation, which was confirmed by Sanger sequencing, was not found in either parent.
Hamilton et al. (2016) reported a 5-year-old girl (patient 5) with Rubinstein-Taybi syndrome (RSTS2; 613684) who was found by whole-exome sequencing as part of the Deciphering Developmental Disorders study (Firth et al., 2011) to have a de novo heterozygous c.4783T-G transversion (c.4783T-G, NM_001429.3) in the EP300 gene, resulting in a phe1595-to-val (F1595V) substitution at a highly conserved residue. Hamilton et al. (2016) confirmed the mutation by Sanger sequencing.
By direct sequencing of the EP300 gene in a 2-year-old boy (patient 9) with typical features of Rubinstein-Taybi syndrome-2 (RSTS2; 613684), Hamilton et al. (2016) identified a de novo heterozygous c.3857A-G transition (c.3857-A-G, NM_001429.3), resulting in an asn1286-to-ser (N1286S) substitution at a highly conserved residue.
In a 17-year-old girl from the UK (patient E1) with Menke-Hennekam syndrome-2 (MKHK2; 618333), Menke et al. (2018) identified a heterozygous A-to-C transversion at nucleotide 5471 (c.5471A-C, NM_001429.3) in exon 31 of the EP300 gene, resulting in a glutamine-to-proline substitution at codon 1824 (Q1824P). This patient had been reported by Hamilton et al. (2016) as patient 6. Menke et al. (2018) and Hamilton et al. (2016) demonstrated that this mutation occurred as a de novo event. The Q1824P mutation was not found in the ESP or gnomAD databases.
In a 14-year-old girl from the Netherlands (patient E2) with Menke-Hennekam syndrome-2 (MKHK2; 618333), Menke et al. (2018) identified a heterozygous 3-basepair deletion in exon 31 of the EP300 gene (c.5492_5494del, NM_001429.3) that resulted in deletion of arginine-1831 (arg1831del). Menke et al. (2018) demonstrated that this mutation occurred as a de novo event. The arg1831del mutation was not found in the ESP or gnomAD databases.
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