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

Nat Genet. 2020 Dec;52(12):1384-1396. doi: 10.1038/s41588-020-00729-3. Epub 2020 Nov 2.

Authors

Huitao Fan^#^{1

2}, Jiuwei Lu^#³, Yiran Guo^{1

4}, Dongxu Li^{1

2}, Zhi-Min Zhang³, Yi-Hsuan Tsai¹, Wen-Chieh Pi⁵, Jeong Hyun Ahn^{1

2}, Weida Gong¹, Yu Xiang⁶, David F Allison^{1

2}, Huimin Geng⁷, Shenghui He^{1

8}, Yarui Diao⁶, Wei-Yi Chen⁵, Brian D Strahl^{1

2}, Ling Cai^{1

8}, Jikui Song⁹, Gang Greg Wang^{10

11

12}

Affiliations

¹ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
² Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
³ Department of Biochemistry, University of California, Riverside, Riverside, CA, USA.
⁴ Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵ Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
⁶ Department of Cell Biology and Department of Orthopaedic Surgery, Duke University School of Medicine, Durham, NC, USA.
⁷ Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA.
⁸ Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
⁹ Department of Biochemistry, University of California, Riverside, Riverside, CA, USA. jikui.song@ucr.edu.
¹⁰ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. greg_wang@med.unc.edu.
¹¹ Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. greg_wang@med.unc.edu.
¹² Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. greg_wang@med.unc.edu.

^# Contributed equally.

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'.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Carcinogenesis / genetics*
Cell Differentiation / genetics
Cell Line, Tumor
Chromatin Immunoprecipitation
Gene Expression Regulation / genetics
Gene Silencing / physiology
HEK293 Cells
HeLa Cells
Histone Code / genetics*
Histones / metabolism*
Humans
Jurkat Cells
Leukemia / genetics*
Leukemia / pathology
Methylation
Mice
Mice, Transgenic
Neoplasm Transplantation
Protein Processing, Post-Translational / genetics
Proteins / genetics*
Proteins / metabolism*
Transplantation, Heterologous

Substances

BAHCC1 protein, human
Histones
Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding