Abstract
BackgroundEP300 is a conserved protein in vertebrates, which serves as a key mediator of cellular homeostasis. Mutations and dysregulation of EP300 give rise to severe human developmental disorders and malignancy. Danio rerio is a promising model organism to study EP300 related diseases and drugs; however, the effect of EP300 duplicates derived from teleost-specific whole genome duplication should not just be neglected.ResultsIn this study, we obtained EP300 protein sequences of representative teleosts, mammals and sauropsids, with which we inferred a highly supported maximum likelihood tree. We observed that Ep300 duplicates (Ep300a and Ep300b) were widely retained in teleosts and universally expressed in a variety of tissues. Consensus sequences of Ep300a and Ep300b had exactly the same distribution of conserved domains, suggesting that their functions should still be largely overlapped. We analyzed the molecular evolution of Ep300 duplicates in teleosts, using branch-site models, clade models and site models. The results showed that both duplicates were subject to strong positive selection; however, for an extant species, generally at most one copy was under positive selection. At the clade level, there were evident positive correlations between evolutionary rates, the number of positively selected sites and gene expression levels. In Ostariophysi, Ep300a were under stronger positive selection than Ep300b; in Neoteleostei, another species-rich teleost clade, the contrary was the case. We also modeled 3D structures of zf-TAZ domain and its flanking regions of Ep300a and Ep300b of D. rerio and Oryzias latipes and found that in either species the faster evolving copy had more short helixes.ConclusionsCollectively, the two copies of Ep300 have undoubtedly experienced directional divergence in main teleost clades. The divergence of EP300 between teleosts and mammals should be greater than the divergence between different teleost clades. Further studies are needed to clarify to what extent the EP300 involved regulatory network has diverged between teleosts and mammals, which would also help explain the huge success of teleosts.
Highlights
E1A binding protein p300 (EP300) is a conserved protein in vertebrates, which serves as a key mediator of cellular homeostasis
EP300 and CREB binding protein (CREBBP) originated from a whole genome duplication (WGD) event that occurred in the common ancestor of vertebrates more than 450 million years ago (MYA) [5, 7]
Retention of Ep300 duplicates in teleosts Through blastp search against NCBI nr database, we obtained 114 EP300 protein sequences from 28 fishes, 30 mammals and 25 sauropsids
Summary
EP300 is a conserved protein in vertebrates, which serves as a key mediator of cellular homeostasis. Besides the KAT domain, they share other non-catalytic conserved regions: a nuclear receptor interacting domain (NRID) at the N-terminal side; three cysteine-histidine (CH)-rich domains (CH1, CH2 and CH3), of which the CH1 and CH3 contain transcriptional adaptor zinc fingers (TAZ1 and TAZ2) and the CH3 contains a ZZ zinc finger, while the CH2 is part of the catalytic KAT domain and contains a plant homeodomain (PHD) and an interleaved RING domain; a KIX domain and a bromodomain between the CH1 and CH2; a nuclear receptor coactivator binding domain (NCBD) at the C-terminal side [6, 8, 9] Based on these domains, both EP300 and CREBBP contain at least nine proteinbinding sites for a huge variety of proteins, including TFs, kinases, chromatin remodelers, structural proteins and others [10]. There is increasing evidence that they serve unique functions, which may be due to slight differences in substrate specificity or a subset of protein-protein binding interactions or both [11]
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