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; Tatiana G. Kutateladze

doi:10.1038/s41467-019-12551-5

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 KonoWei Li, Xiaobing Shi, Jacques Côté, Tatiana G. Kutateladze

Research output: Contribution to journal › Article › peer-review

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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 (MORF_DPF). The crystal structure of MORF_DPF 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 MORF_DPF 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 MORF_DPF with acylated H3K14 promotes acetylation of H3K23 by the native MORF complex to activate transcription.

Original language	English (US)
Article number	4724
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12551-5
State	Published - Dec 1 2019

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Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Klein, B. J., Jang, S. M., Lachance, C., Mi, W., Lyu, J., Sakuraba, S., Krajewski, K., Wang, W. W., Sidoli, S., Liu, J., Zhang, Y., Wang, X., Warfield, B. M., Kueh, A. J., Voss, A. K., Thomas, T., Garcia, B. A., Liu, W. R., Strahl, B. D., ... Kutateladze, T. G. (2019). Histone H3K23-specific acetylation by MORF is coupled to H3K14 acylation. Nature communications, 10(1), Article 4724. https://doi.org/10.1038/s41467-019-12551-5

Klein, BJ, Jang, SM, Lachance, C, Mi, W, Lyu, J, Sakuraba, S, Krajewski, K, Wang, WW, Sidoli, S, Liu, J, Zhang, Y, Wang, X, Warfield, BM, Kueh, AJ, Voss, AK, Thomas, T, Garcia, BA, Liu, WR, Strahl, BD, Kono, H, Li, W, Shi, X, Côté, J & Kutateladze, TG 2019, 'Histone H3K23-specific acetylation by MORF is coupled to H3K14 acylation', Nature communications, vol. 10, no. 1, 4724. https://doi.org/10.1038/s41467-019-12551-5

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title = "Histone H3K23-specific acetylation by MORF is coupled to H3K14 acylation",

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.",

author = "Klein, {Brianna J.} and Jang, {Suk Min} and Catherine Lachance and Wenyi Mi and Jie Lyu and Shun Sakuraba and Krzysztof Krajewski and Wang, {Wesley W.} and Simone Sidoli and Jiuyang Liu and Yi Zhang and Xiaolu Wang and Warfield, {Becka M.} and Kueh, {Andrew J.} and Voss, {Anne K.} and Tim Thomas and Garcia, {Benjamin A.} and Liu, {Wenshe R.} and Strahl, {Brian D.} and Hidetoshi Kono and Wei Li and Xiaobing Shi and Jacques C{\^o}t{\'e} and Kutateladze, {Tatiana G.}",

note = "Funding Information: We thank X.J. Yang for kindly providing the cDNA of wild-type FLAG-MORFN and R.A. Dickins for kindly providing the Trp53 shRNA knockdown construct. This work was supported by NIH grants R01 GM100907, GM106416 and GM125195 to T.G.K., CA204020 to X.S., GM126900 to B.D.S., R01GM121584 to W.R.L., and GM110174 and CA196539 to B.A.G., by JSPS KAKENHI JP18H05534 and Platform Project for Supporting Drug Discovery and Life Science Research (BINDS) from AMED JP18am0101106j0002, JP19am0101106j0003 to H.K., by Canadian Institutes of Health Research (CIHR FDN-143314) to J.C., Welch Grant A-1715 to W.R.L., and Leukemia & Lymphoma Society Career Development Award (1339-17) to X.S. and by the Australian Government's National Health and Medical Research Council through Project Grants 1084352 (to A.K.V. and T.T.) and 1084248 (A.K.V. and T.T.) and Research Fellowships (to A.K.V. 575512 and 1081421; and to T.T. 1003435), and by the Independent Research Institutes Infrastructure Support (IRIIS) Scheme and a Victorian State Government OIS (Operational Infrastructure Support) Grant. J.C. holds the Canada Research Chair in Chromatin Biology and Molecular Epigenetics. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-12551-5",

language = "English (US)",

volume = "10",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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TY - JOUR

T1 - Histone H3K23-specific acetylation by MORF is coupled to H3K14 acylation

AU - Klein, Brianna J.

AU - Jang, Suk Min

AU - Lachance, Catherine

AU - Mi, Wenyi

AU - Lyu, Jie

AU - Sakuraba, Shun

AU - Krajewski, Krzysztof

AU - Wang, Wesley W.

AU - Sidoli, Simone

AU - Liu, Jiuyang

AU - Zhang, Yi

AU - Wang, Xiaolu

AU - Warfield, Becka M.

AU - Kueh, Andrew J.

AU - Voss, Anne K.

AU - Thomas, Tim

AU - Garcia, Benjamin A.

AU - Liu, Wenshe R.

AU - Strahl, Brian D.

AU - Kono, Hidetoshi

AU - Li, Wei

AU - Shi, Xiaobing

AU - Côté, Jacques

AU - Kutateladze, Tatiana G.

N1 - Funding Information: We thank X.J. Yang for kindly providing the cDNA of wild-type FLAG-MORFN and R.A. Dickins for kindly providing the Trp53 shRNA knockdown construct. This work was supported by NIH grants R01 GM100907, GM106416 and GM125195 to T.G.K., CA204020 to X.S., GM126900 to B.D.S., R01GM121584 to W.R.L., and GM110174 and CA196539 to B.A.G., by JSPS KAKENHI JP18H05534 and Platform Project for Supporting Drug Discovery and Life Science Research (BINDS) from AMED JP18am0101106j0002, JP19am0101106j0003 to H.K., by Canadian Institutes of Health Research (CIHR FDN-143314) to J.C., Welch Grant A-1715 to W.R.L., and Leukemia & Lymphoma Society Career Development Award (1339-17) to X.S. and by the Australian Government's National Health and Medical Research Council through Project Grants 1084352 (to A.K.V. and T.T.) and 1084248 (A.K.V. and T.T.) and Research Fellowships (to A.K.V. 575512 and 1081421; and to T.T. 1003435), and by the Independent Research Institutes Infrastructure Support (IRIIS) Scheme and a Victorian State Government OIS (Operational Infrastructure Support) Grant. J.C. holds the Canada Research Chair in Chromatin Biology and Molecular Epigenetics. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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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U2 - 10.1038/s41467-019-12551-5

DO - 10.1038/s41467-019-12551-5

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VL - 10

JO - Nature communications

JF - Nature communications

IS - 1

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ER -

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

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