Chromodomain helicase DNA-binding 4 is required for proliferation, distal VH rearrangements and developmental progression of B cell progenitors (HEM1P.221)

Chromodomain Helicase DNA-binding protein 4 (CHD4, or Mi-2β) is a catalytic core subunit of Nucleosome Remodeling and Deacetylase (NuRD) complexes, which regulate chromatin structure and transcription in lymphocytes. CHD4 activities include ATP-dependent mobilization of nucleosomes, DNA binding and binding to histone tails. Here, we investigated requirements for CHD4 in B cell development in a mouse model system. We utilized Chd4 flox/flox : Cd79a-Cre ( Chd4 cko ) mice, which inactivate Chd4 genes selectively in early B cell progenitors. These mice confirmed that CHD4 is essential for B lymphopoiesis. Following the loss of CHD4 expression, B cell development is arrested at the pro-B cell stage. Peripheral B220 + cells were nearly absent. To address the basis of the observed developmental arrest, we measured effects of the lack of CHD4 on proliferation and Igh gene rearrangements. CHD4-deficient pro-B cells fail to proliferate in response to IL-7. Furthermore, pro-B cells lacking CHD4 complete proximal V H to DJ H rearrangements, but rearrange distal V H segments only rarely. Overall, our data demonstrate that CHD4 and NuRD complexes are essential for multiple aspects of early B cell development, including V(D)J recombination, proliferation and survival of pro-B cells.