Chromatin Reader Dido3 Regulates the Genetic Network of B Cell Differentiation

Abstract

BACKGROUNDThe development of hematopoietic lineages is based on a complex balance of transcription factors whose expression depends on the epigenetic signatures that characterize each differentiation step. The B cell lineage arises from hematopoietic stem cells through the stepwise silencing of stemness genes and balanced expression of mutually regulated transcription factors, as well as DNA rearrangement, in a complex process involving epigenetic remodeling.RESULTSHere we report the impact on B cell differentiation of the lack of DIDO3, a reader of histone post-translational modifications, in the mouse hematopoietic compartment. We found reduced DNA accessibility in hematopoietic precursors, leading to a severe deficiency specifically in the generation of successive stages of B-cell differentiation. The expression of essential transcription factors and differentiation markers is impaired, as is the process of somatic recombination. DIDO3-deficient cells show transcriptional alterations of a number of polycomb repressive complex 2, suggesting the involvement of DIDO3 in determining the specific activity of PRC2 in the B cell lineage, including VH-DJH rearrangement. CONCLUSIONSTaken together, our data suggest that DIDO3 is an epigenetic reader involved in the specific differentiation of B cell precursors in the hematopoietic compartment of mice.