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Epigenetics of exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Daniel C. Turner, Robert A. Seaborne, Adam P. Sharples
By contrast, acetylation modifications that occur along histone tails are relatively more straightforward to understand. Indeed, the enzymes responsible for histone acetylation are commonly referred to as histone acetyltransferases (HATs; three main protein families, GNAT, MYST and P300/CREB families) and histone deacetylases (HDACs; for which there are sub-categories of class I, class II, class III and class IV HDACs). More comprehendible is that histone acetylation only exists on one level, unlike histone methylation that has three levels as described above. Of particular interest for molecular exercise physiologists is the class III HDACs, as this class of enzymes contains the sirtuins which are commonly implicated in processes such as ageing, stress resistance and low-calorie insults (25). The sirtuins are NAD+/NADH sensors that detect the signal from the alterations in mitochondrial reduction/oxidation (redox state) following the breakdown of nutrients required to fuel exercise, as discussed in general in Chapter 7 and in response to endurance exercise in Chapter 9. As a general rule, when a histone is acetylated, it creates a chromatin state that helps to activate and increase transcription of genes near those loci (site or location of a specific gene). This is due to the new acetyl group changing the electrical charge between histones and DNA, repelling their tightly bound association and creating a more accessible chromatin structure which allows the relevant machinery to perform the processes required for gene transcription (26).
Rubinstein−Taybi Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The EP300 gene on chromosome 22q13.2 consists of 31 exons in a stretch of 87.75 kb and encodes p300 that contains 3 cysteine- and histidine-rich regions, including the carboxyterminal region interacting specifically with E1A, and a centrally located bromodomain representing a hallmark of certain transcriptional coactivators. As a homolog to CREBBP, p300 shares >70% and 63% homology with CREBBP at nucleotide and amino acid levels, respectively, and demonstrates HAT activity. Strongly expressed in human cerebellum as well as in other brain regions, p300 functions as transcriptional coactivator in the regulation of gene expression via chromatin remodeling and plays an important role in the processes of cell proliferation and differentiation. CREBBP/p300 may also modulate with p53 pathway through P53 acetylation, and loss of CREBBP/p300 could disrupt p53 activation, stability, and transactivation of target genes. It has been shown that p300 knockdown by hammerhead ribozymes inhibits apoptosis, probably by disrupting the p53-mediated response to DNA damage [1].
Genetics
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Jane A. Hurst, Richard H. Scott
Children present with microcephaly with short stature and developmental delay. Learning difficulties are moderate to severe. The facial appearance is often recognisable with downslanting palpebral fissures, prominent columella and a grimacing smile (Fig. 15.33). Thumbs and great toes are often broad and medially deviated (Figs 15.34, 15.35). Structural cardiac and renal tract abnormalities are common and cryptorchidism is almost invariably present in males. The phenotype may be more subtle in individuals with EP300 mutations.
Rewiring of miRNA-mRNA bipartite co-expression network as a novel way to understand the prostate cancer related players
Published in Systems Biology in Reproductive Medicine, 2023
Mohammad Mehdi Naghizadeh, Behnaz Bakhshandeh, Farshid Noorbakhsh, Marjan Yaghmaie, Ali Masoudi-Nejad
Mediator complex subunit 12 (MED12), a prostate-related oncogene (Shaikhibrahim et al. 2014; Kampjarvi et al. 2016), was a common gene in two Beta-catenin and hormone receptor binding molecular functions of our gene rewiring set. Histone acetyltransferase P300 (EP300), another cancer-related oncogene (Ring et al. 2020), plays a critical role in the above function and also in the androgen receptor and SMAD binding molecular function as well. EP300 is known as a miRNA-regulated metastasis suppressor gene (Mees et al. 2010). Both EP300 and MED12 lost their connection with miR-4662a which is a high-degree centrality hub of our network. miR-361 was a microRNA that increased its connectivity with EP300 in our network. There were some reports that approved interaction between them in ischemic cardiomyopathy in which miR-361 and EP300 were up- and down-regulated respectively (Leger et al. 2013). Moreover, via text mining approaches the interaction between miR-361 and EP300 changed the regulation of other gene expressions (Anandaram 2018).
Near-Haploid B-Cell Acute Lymphoblastic Leukemia in a Patient with Rubinstein-Taybi Syndrome
Published in Pediatric Hematology and Oncology, 2022
Kristen J. Kurtz, Eran Tallis, Andrea N. Marcogliese, Rao H. Pulivarthi, Lorraine Potocki, Alexandra M. Stevens
Rubinstein-Taybi Syndrome (RSTS) is a rare autosomal dominant disorder associated with deletion or pathogenic variants in CREBBP or EP300. Approximately 50–70% of patients with RSTS carry a heterozygous pathogenic variant in CREBBP on chromosome 16p13.3.1,6,17 These variants are most often de novo, and most patients with RSTS represent simplex cases in a family. However, parental somatic or germline mosaicism can be observed.4,18CREBBP variants generally result in decreased function of the nuclear phosphoprotein CREBBP, which plays a major role in epigenetic regulation of gene expression.17,18 Of the 30–50% of patients who do not harbor pathogenic variants in CREBBP, up to 10% carry various variants in EP300 resulting in decreased function of the epigenetic regulator p300. The remaining patients with RSTS are diagnosed clinically with no identifiable molecular change.17
The therapeutic potential of PROTACs
Published in Expert Opinion on Therapeutic Patents, 2021
Andrew B. Benowitz, Katherine L. Jones, John D. Harling
E1A-associated protein p300 (EP300) has been identified as a multi-domain epigenetic protein that plays an important role in chromatin remodeling, and which can be harnessed by viral oncogenes and by cancer cells to initiate and maintain neoplastic phenotypes [154]. Tool inhibitors of the EP300 bromodomain, histone acetyltransferase domain, and other domains have been previously described in an effort to probe EP300 function as well as that of the closely related CREB-binding protein (CBP) [155], and EP300 inhibition remains the subject of active research focus. A single PCT patent filing claiming PROTAC degraders of EP300 has been published to date, from the Dana-Farber Cancer Institute [156]. This filing exemplified 23 compounds that employed cereblon and VHL binders as the E3 ligase-recruiting elements, combined with a modified oxazolidinedione-containing structure previously reported as a potent inhibitor of the EP300 and CBP histone acetyltransferase domains [157,158]. Exemplified compounds (e.g. compound 69, Figure 18) were reported to degrade EP300 in various cell types. This compound was also described as a selective degrader of EP300 over CBP in Kelly neuroblastoma cells over 36 h of compound treatment, although degradation of CBP was also observed after 48 h. Compound 69 was further characterized in CD1 mouse PK and tolerability studies, where it was described as well tolerated when dosed IP at 40 mg/kg/day over 21 days, and to cause tumor growth inhibition when dosed IP at 40 mg/kg/day in a mouse in vivo Kelly neuroblastoma xenograft study.