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

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.

The chromatin remodeling enzyme Chd4 regulates genome architecture in the mouse brain

“…1A-D). Corroborating our results of increased genomic accessibility upon Chd4 loss in granule neurons, recent data suggest Chd4 may reduce nucleosome accessibility in murine embryonic stem cells and immature B cells [32][33][34][35] . Taken together, these data demonstrate that Chd4 suppresses genomic accessibility in the mammalian brain.…”

Chromatin Remodeling in the Brain-a NuRDevelopmental Odyssey

“…Indeed, the recently described ChAHP complex, containing Chd4 and Adnp, was similarly shown to suppress cohesin recruitment to cryptic Ctcf sites found within repetitive elements [ 149 ]. Nonetheless, the finding that Chd4 is required to suppress accessibility at enhancer and promoter elements agrees very well with genomic work from non-neural model systems [ 28 , 113 , 150 , 151 ].…”

Genome-Wide Estrogen Receptor Activity in Breast Cancer

“…In addition to the mutually exclusive NuRD ATPase subunits CHD3 and CHD4, the complex contains several other proteins including the HDAC1/2 deacetylases, the metastasis-associated proteins MTA1/2/3, the GATA zinc-finger domain containing GATAD2A/2B factors or the histone lysine demethylase 1A KDM1A/LSD1, although the specific composition of proteins appears to be context-dependent ( 128-130 ). Taken together, NuRD combines chromatin remodeling and HDAC activity to mediate target gene repression, and its essential role in cell fate specification across a range of developmental contexts has been reported ( 131 , 132 ).…”