BRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state

Muran Xiao, Shinji Kondo, Masaki Nomura, Shinichiro Kato, Koutarou Nishimura, Weijia Zang, Yifan Zhang, Tomohiro Akashi, Aaron Viny, Tsukasa Shigehiro, Tomokatsu Ikawa, Hiromi Yamazaki, Miki Fukumoto, Atsushi Tanaka, Yasutaka Hayashi, Yui Koike, Yumi Aoyama, Hiromi Ito, Hiroyoshi Nishikawa, Toshio Kitamura, Akinori Kanai, Akihiko Yokoyama, Tohru Fujiwara, Susumu Goyama, Hideki Noguchi, Stanley C. Lee, Atsushi Toyoda, Kunihiko Hinohara, Omar Abdel-Wahab and Daichi Inoue ()
Additional contact information
Muran Xiao: Foundation for Biomedical Research and Innovation at Kobe
Shinji Kondo: National Institute of Genetics
Masaki Nomura: Foundation for Biomedical Research and Innovation at Kobe
Shinichiro Kato: Nagoya University Graduate School of Medicine
Koutarou Nishimura: Foundation for Biomedical Research and Innovation at Kobe
Weijia Zang: Foundation for Biomedical Research and Innovation at Kobe
Yifan Zhang: Foundation for Biomedical Research and Innovation at Kobe
Tomohiro Akashi: Nagoya University Graduate School of Medicine
Aaron Viny: Columbia University Irving Medical Center
Tsukasa Shigehiro: Tokyo University of Science
Tomokatsu Ikawa: Tokyo University of Science
Hiromi Yamazaki: Foundation for Biomedical Research and Innovation at Kobe
Miki Fukumoto: Foundation for Biomedical Research and Innovation at Kobe
Atsushi Tanaka: Foundation for Biomedical Research and Innovation at Kobe
Yasutaka Hayashi: Foundation for Biomedical Research and Innovation at Kobe
Yui Koike: Foundation for Biomedical Research and Innovation at Kobe
Yumi Aoyama: Foundation for Biomedical Research and Innovation at Kobe
Hiromi Ito: Foundation for Biomedical Research and Innovation at Kobe
Hiroyoshi Nishikawa: Nagoya University Graduate School of Medicine
Toshio Kitamura: Foundation for Biomedical Research and Innovation at Kobe
Akinori Kanai: Hiroshima University
Akihiko Yokoyama: National Cancer Center
Tohru Fujiwara: Tohoku University Graduate School of Medicine
Susumu Goyama: The University of Tokyo
Hideki Noguchi: National Institute of Genetics
Stanley C. Lee: Fred Hutchinson Cancer Center
Atsushi Toyoda: National Institute of Genetics
Kunihiko Hinohara: Nagoya University Graduate School of Medicine
Omar Abdel-Wahab: Memorial Sloan Kettering Cancer Center
Daichi Inoue: Foundation for Biomedical Research and Innovation at Kobe

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: Abstract ATP-dependent chromatin remodeling SWI/SNF complexes exist in three subcomplexes: canonical BAF (cBAF), polybromo BAF (PBAF), and a newly described non-canonical BAF (ncBAF). While cBAF and PBAF regulate fates of multiple cell types, roles for ncBAF in hematopoietic stem cells (HSCs) have not been investigated. Motivated by recent discovery of disrupted expression of BRD9, an essential component of ncBAF, in multiple cancers, including clonal hematopoietic disorders, we evaluate here the role of BRD9 in normal and malignant HSCs. BRD9 loss enhances chromatin accessibility, promoting myeloid lineage skewing while impairing B cell development. BRD9 significantly colocalizes with CTCF, whose chromatin recruitment is augmented by BRD9 loss, leading to altered chromatin state and expression of myeloid-related genes within intact topologically associating domains. These data uncover ncBAF as critical for cell fate specification in HSCs via three-dimensional regulation of gene expression and illuminate roles for ncBAF in normal and malignant hematopoiesis.

Date: 2023
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DOI: 10.1038/s41467-023-44081-6

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