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Nat Commun. 2019 Oct 17;10(1):4724. doi: 10.1038/s41467-019-12551-5.

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

Author information

1
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
2
Laval University Cancer Research Center, CHU de Québec-UL Research Center-Oncology Division, Quebec City, QC, G1R 3S3, Canada.
3
Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI, 49503, USA.
4
Department of Biological Chemistry, University of California, Irvine, Irvine, CA, 92697, USA.
5
Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
6
Molecular Modeling and Simulation Group, National Institute for Quantum Life Science, National Institutes for Quantum and Radiological Science and Technology, Kizugawa, Kyoto, 619 0215, Japan.
7
Department of Biochemistry & Biophysics, The University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA.
8
Department of Chemistry, Texas A&M University, College Station, TX, 77843, USA.
9
Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
10
Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, 10461, USA.
11
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3050, Australia.
12
Laval University Cancer Research Center, CHU de Québec-UL Research Center-Oncology Division, Quebec City, QC, G1R 3S3, Canada. jacques.cote@crhdq.ulaval.ca.
13
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA. tatiana.kutateladze@cuanschutz.edu.

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.

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