Histone H3K23-specific acetylation by MORF is coupled to H3K14 acylation

Brianna J. Klein, Suk Min Jang, Catherine Lachance, Wenyi Mi, Jie Lyu, Shun Sakuraba, Krzysztof Krajewski, Wesley W. Wang, Simone Sidoli, Jiuyang Liu, Yi Zhang, Xiaolu Wang, Becka M. Warfield, Andrew J. Kueh, Anne K. Voss, Tim Thomas, Benjamin A. Garcia, Wenshe R. Liu, Brian D. Strahl, Hidetoshi Kono, Wei Li, Xiaobing Shi, Jacques Côté () and Tatiana G. Kutateladze ()
Additional contact information
Brianna J. Klein: University of Colorado School of Medicine
Suk Min Jang: CHU de Québec-UL Research Center-Oncology Division
Catherine Lachance: CHU de Québec-UL Research Center-Oncology Division
Wenyi Mi: Van Andel Research Institute
Jie Lyu: University of California, Irvine
Shun Sakuraba: National Institutes for Quantum and Radiological Science and Technology
Krzysztof Krajewski: The University of North Carolina School of Medicine
Wesley W. Wang: Texas A&M University
Simone Sidoli: University of Pennsylvania
Jiuyang Liu: University of Colorado School of Medicine
Yi Zhang: University of Colorado School of Medicine
Xiaolu Wang: Van Andel Research Institute
Becka M. Warfield: University of Colorado School of Medicine
Andrew J. Kueh: The Walter and Eliza Hall Institute of Medical Research
Anne K. Voss: The Walter and Eliza Hall Institute of Medical Research
Tim Thomas: The Walter and Eliza Hall Institute of Medical Research
Benjamin A. Garcia: University of Pennsylvania
Wenshe R. Liu: Texas A&M University
Brian D. Strahl: The University of North Carolina School of Medicine
Hidetoshi Kono: National Institutes for Quantum and Radiological Science and Technology
Wei Li: University of California, Irvine
Xiaobing Shi: Van Andel Research Institute
Jacques Côté: CHU de Québec-UL Research Center-Oncology Division
Tatiana G. Kutateladze: University of Colorado School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract Acetylation of histone H3K23 has emerged as an essential posttranslational modification associated with cancer and learning and memory impairment, yet our understanding of this epigenetic mark remains insufficient. Here, we identify the native MORF complex as a histone H3K23-specific acetyltransferase and elucidate its mechanism of action. The acetyltransferase function of the catalytic MORF subunit is positively regulated by the DPF domain of MORF (MORFDPF). The crystal structure of MORFDPF in complex with crotonylated H3K14 peptide provides mechanistic insight into selectivity of this epigenetic reader and its ability to recognize both histone and DNA. ChIP data reveal the role of MORFDPF in MORF-dependent H3K23 acetylation of target genes. Mass spectrometry, biochemical and genomic analyses show co-existence of the H3K23ac and H3K14ac modifications in vitro and co-occupancy of the MORF complex, H3K23ac, and H3K14ac at specific loci in vivo. Our findings suggest a model in which interaction of MORFDPF with acylated H3K14 promotes acetylation of H3K23 by the native MORF complex to activate transcription.

Date: 2019
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DOI: 10.1038/s41467-019-12551-5

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