8i60 | pdb_00008i60
Crystal structure of GAS41 YEATS domain in complex with histone H3K27cr
Structural highlights
FunctionYETS4_HUMAN Component of the NuA4 histone acetyltransferase (HAT) complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. NuA4 may also play a direct role in DNA repair when recruited to sites of DNA damage.[1] Publication Abstract from PubMedHistone lysine acylation, including acetylation and crotonylation, plays a pivotal role in gene transcription in health and diseases. However, our understanding of histone lysine acylation has been limited to gene transcriptional activation. Here, we report that histone H3 lysine 27 crotonylation (H3K27cr) directs gene transcriptional repression rather than activation. Specifically, H3K27cr in chromatin is selectively recognized by the YEATS domain of GAS41 in complex with SIN3A-HDAC1 co-repressors. Proto-oncogenic transcription factor MYC recruits GAS41/SIN3A-HDAC1 complex to repress genes in chromatin, including cell-cycle inhibitor p21. GAS41 knockout or H3K27cr-binding depletion results in p21 de-repression, cell-cycle arrest, and tumor growth inhibition in mice, explaining a causal relationship between GAS41 and MYC gene amplification and p21 downregulation in colorectal cancer. Our study suggests that H3K27 crotonylation signifies a previously unrecognized, distinct chromatin state for gene transcriptional repression in contrast to H3K27 trimethylation for transcriptional silencing and H3K27 acetylation for transcriptional activation. Histone H3 lysine 27 crotonylation mediates gene transcriptional repression in chromatin.,Liu N, Konuma T, Sharma R, Wang D, Zhao N, Cao L, Ju Y, Liu D, Wang S, Bosch A, Sun Y, Zhang S, Ji D, Nagatoishi S, Suzuki N, Kikuchi M, Wakamori M, Zhao C, Ren C, Zhou TJ, Xu Y, Meslamani J, Fu S, Umehara T, Tsumoto K, Akashi S, Zeng L, Roeder RG, Walsh MJ, Zhang Q, Zhou MM Mol Cell. 2023 Jul 6;83(13):2206-2221.e11. doi: 10.1016/j.molcel.2023.05.022. , Epub 2023 Jun 12. PMID:37311463[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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