BAHCC1 binds H3K27me3 via a conserved BAH module to mediate gene silencing and oncogenesis

Huitao Fan; Jiuwei Lu; Yiran Guo; Dongxu Li; Zhi Min Zhang; Yi Hsuan Tsai; Wen Chieh Pi; Jeong Hyun Ahn; Weida Gong; Yu Xiang; David F. Allison; Huimin Geng; Shenghui He; Yarui Diao; Wei Yi Chen; Brian D. Strahl; Ling Cai; Jikui Song; Gang Greg Wang

doi:10.1038/s41588-020-00729-3

BAHCC1 binds H3K27me3 via a conserved BAH module to mediate gene silencing and oncogenesis

Huitao Fan, Jiuwei Lu, Yiran Guo, Dongxu Li, Zhi Min Zhang, Yi Hsuan Tsai, Wen Chieh Pi, Jeong Hyun Ahn, Weida Gong, Yu Xiang, David F. Allison, Huimin Geng, Shenghui He, Yarui Diao, Wei Yi Chen, Brian D. Strahl, Ling Cai, Jikui Song, Gang Greg Wang^*

^*Corresponding author for this work

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

43 Scopus citations

Abstract

Trimethylated histone H3 lysine 27 (H3K27me3) regulates gene repression, cell-fate determination and differentiation. We report that a conserved bromo-adjacent homology (BAH) module of BAHCC1 (BAHCC1^BAH) ‘recognizes’ H3K27me3 specifically and enforces silencing of H3K27me3-demarcated genes in mammalian cells. Biochemical, structural and integrated chromatin immunoprecipitation-sequencing-based analyses demonstrate that direct readout of H3K27me3 by BAHCC1 is achieved through a hydrophobic trimethyl-l-lysine-binding ‘cage’ formed by BAHCC1^BAH, mediating colocalization of BAHCC1 and H3K27me3-marked genes. BAHCC1 is highly expressed in human acute leukemia and interacts with transcriptional corepressors. In leukemia, depletion of BAHCC1, or disruption of the BAHCC1^BAH–H3K27me3 interaction, causes derepression of H3K27me3-targeted genes that are involved in tumor suppression and cell differentiation, leading to suppression of oncogenesis. In mice, introduction of a germline mutation at Bahcc1 to disrupt its H3K27me3 engagement causes partial postnatal lethality, supporting a role in development. This study identifies an H3K27me3-directed transduction pathway in mammals that relies on a conserved BAH ‘reader’.

Original language	English
Pages (from-to)	1384-1396
Number of pages	13
Journal	Nature Genetics
Volume	52
Issue number	12
DOIs	https://doi.org/10.1038/s41588-020-00729-3
State	Published - Dec 2020

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Fan, H., Lu, J., Guo, Y., Li, D., Zhang, Z. M., Tsai, Y. H., Pi, W. C., Ahn, J. H., Gong, W., Xiang, Y., Allison, D. F., Geng, H., He, S., Diao, Y., Chen, W. Y., Strahl, B. D., Cai, L., Song, J., & Wang, G. G. (2020). BAHCC1 binds H3K27me3 via a conserved BAH module to mediate gene silencing and oncogenesis. Nature Genetics, 52(12), 1384-1396. https://doi.org/10.1038/s41588-020-00729-3

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title = "BAHCC1 binds H3K27me3 via a conserved BAH module to mediate gene silencing and oncogenesis",

abstract = "Trimethylated histone H3 lysine 27 (H3K27me3) regulates gene repression, cell-fate determination and differentiation. We report that a conserved bromo-adjacent homology (BAH) module of BAHCC1 (BAHCC1BAH) {\textquoteleft}recognizes{\textquoteright} H3K27me3 specifically and enforces silencing of H3K27me3-demarcated genes in mammalian cells. Biochemical, structural and integrated chromatin immunoprecipitation-sequencing-based analyses demonstrate that direct readout of H3K27me3 by BAHCC1 is achieved through a hydrophobic trimethyl-l-lysine-binding {\textquoteleft}cage{\textquoteright} formed by BAHCC1BAH, mediating colocalization of BAHCC1 and H3K27me3-marked genes. BAHCC1 is highly expressed in human acute leukemia and interacts with transcriptional corepressors. In leukemia, depletion of BAHCC1, or disruption of the BAHCC1BAH–H3K27me3 interaction, causes derepression of H3K27me3-targeted genes that are involved in tumor suppression and cell differentiation, leading to suppression of oncogenesis. In mice, introduction of a germline mutation at Bahcc1 to disrupt its H3K27me3 engagement causes partial postnatal lethality, supporting a role in development. This study identifies an H3K27me3-directed transduction pathway in mammals that relies on a conserved BAH {\textquoteleft}reader{\textquoteright}.",

author = "Huitao Fan and Jiuwei Lu and Yiran Guo and Dongxu Li and Zhang, {Zhi Min} and Tsai, {Yi Hsuan} and Pi, {Wen Chieh} and Ahn, {Jeong Hyun} and Weida Gong and Yu Xiang and Allison, {David F.} and Huimin Geng and Shenghui He and Yarui Diao and Chen, {Wei Yi} and Strahl, {Brian D.} and Ling Cai and Jikui Song and Wang, {Gang Greg}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2020",

month = dec,

doi = "10.1038/s41588-020-00729-3",

language = "English",

volume = "52",

pages = "1384--1396",

journal = "Nature Genetics",

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T1 - BAHCC1 binds H3K27me3 via a conserved BAH module to mediate gene silencing and oncogenesis

AU - Fan, Huitao

AU - Lu, Jiuwei

AU - Guo, Yiran

AU - Li, Dongxu

AU - Zhang, Zhi Min

AU - Tsai, Yi Hsuan

AU - Pi, Wen Chieh

AU - Ahn, Jeong Hyun

AU - Gong, Weida

AU - Xiang, Yu

AU - Allison, David F.

AU - Geng, Huimin

AU - He, Shenghui

AU - Diao, Yarui

AU - Chen, Wei Yi

AU - Strahl, Brian D.

AU - Cai, Ling

AU - Song, Jikui

AU - Wang, Gang Greg

PY - 2020/12

Y1 - 2020/12

N2 - Trimethylated histone H3 lysine 27 (H3K27me3) regulates gene repression, cell-fate determination and differentiation. We report that a conserved bromo-adjacent homology (BAH) module of BAHCC1 (BAHCC1BAH) ‘recognizes’ H3K27me3 specifically and enforces silencing of H3K27me3-demarcated genes in mammalian cells. Biochemical, structural and integrated chromatin immunoprecipitation-sequencing-based analyses demonstrate that direct readout of H3K27me3 by BAHCC1 is achieved through a hydrophobic trimethyl-l-lysine-binding ‘cage’ formed by BAHCC1BAH, mediating colocalization of BAHCC1 and H3K27me3-marked genes. BAHCC1 is highly expressed in human acute leukemia and interacts with transcriptional corepressors. In leukemia, depletion of BAHCC1, or disruption of the BAHCC1BAH–H3K27me3 interaction, causes derepression of H3K27me3-targeted genes that are involved in tumor suppression and cell differentiation, leading to suppression of oncogenesis. In mice, introduction of a germline mutation at Bahcc1 to disrupt its H3K27me3 engagement causes partial postnatal lethality, supporting a role in development. This study identifies an H3K27me3-directed transduction pathway in mammals that relies on a conserved BAH ‘reader’.

AB - Trimethylated histone H3 lysine 27 (H3K27me3) regulates gene repression, cell-fate determination and differentiation. We report that a conserved bromo-adjacent homology (BAH) module of BAHCC1 (BAHCC1BAH) ‘recognizes’ H3K27me3 specifically and enforces silencing of H3K27me3-demarcated genes in mammalian cells. Biochemical, structural and integrated chromatin immunoprecipitation-sequencing-based analyses demonstrate that direct readout of H3K27me3 by BAHCC1 is achieved through a hydrophobic trimethyl-l-lysine-binding ‘cage’ formed by BAHCC1BAH, mediating colocalization of BAHCC1 and H3K27me3-marked genes. BAHCC1 is highly expressed in human acute leukemia and interacts with transcriptional corepressors. In leukemia, depletion of BAHCC1, or disruption of the BAHCC1BAH–H3K27me3 interaction, causes derepression of H3K27me3-targeted genes that are involved in tumor suppression and cell differentiation, leading to suppression of oncogenesis. In mice, introduction of a germline mutation at Bahcc1 to disrupt its H3K27me3 engagement causes partial postnatal lethality, supporting a role in development. This study identifies an H3K27me3-directed transduction pathway in mammals that relies on a conserved BAH ‘reader’.

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U2 - 10.1038/s41588-020-00729-3

DO - 10.1038/s41588-020-00729-3

M3 - Article

C2 - 33139953

AN - SCOPUS:85094972149

SN - 1061-4036

VL - 52

SP - 1384

EP - 1396

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -

BAHCC1 binds H3K27me3 via a conserved BAH module to mediate gene silencing and oncogenesis

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