CHD4 is essential for transcriptional repression and lineage progression in B lymphopoiesis

Author:

Arends Tessa,Dege Carissa,Bortnick Alexandra,Danhorn ThomasORCID,Knapp Jennifer R.,Jia Haiqun,Harmacek Laura,Fleenor Courtney J.,Straign Desiree,Walton Kendra,Leach Sonia M.,Feeney Ann J.,Murre Cornelis,O’Connor Brian P.,Hagman James R.ORCID

Abstract

Cell lineage specification is a tightly regulated process that is dependent on appropriate expression of lineage and developmental stage-specific transcriptional programs. Here, we show that Chromodomain Helicase DNA-binding protein 4 (CHD4), a major ATPase/helicase subunit of Nucleosome Remodeling and Deacetylase Complexes (NuRD) in lymphocytes, is essential for specification of the early B cell lineage transcriptional program. In the absence of CHD4 in B cell progenitors in vivo, development of these cells is arrested at an early pro-B-like stage that is unresponsive to IL-7 receptor signaling and unable to efficiently complete V(D)J rearrangements at Igh loci. Our studies confirm that chromatin accessibility and transcription of thousands of gene loci are controlled dynamically by CHD4 during early B cell development. Strikingly, CHD4-deficient pro-B cells express transcripts of many non-B cell lineage genes, including genes that are characteristic of other hematopoietic lineages, neuronal cells, and the CNS, lung, pancreas, and other cell types. We conclude that CHD4 inhibits inappropriate transcription in pro-B cells. Together, our data demonstrate the importance of CHD4 in establishing and maintaining an appropriate transcriptome in early B lymphopoiesis via chromatin accessibility.

Funder

HHS | NIH | National Institute of Allergy and Infectious Diseases

Wendy Siegel Fund for Leukemia and Cancer Research

Victor W. Bolie and Earleen D. Bolie Graduate Scholarship Fund

Cancer Research Institute Predoctoral Emphasis Pathway in Tumor Immunology Fellowshi

HHS | NIH | National Institute of General Medical Sciences

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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