Abstract
AbstractLymphocyte development consists of sequential and mutually exclusive cell states of proliferative selection and antigen receptor gene recombination1. Transitions between each state require large, coordinated changes in epigenetic landscapes and transcriptional programs2,3. How this occurs remains unclear. Herein, we demonstrate that in small pre-B cells, the lineage and stagespecific epigenetic reader Bromodomain and WD Repeating Containing Protein 1 (BRWD1)2,4reorders three-dimensional chromatin topology to affect transition between proliferative and gene recombination molecular programs. BRWD1 regulated the switch between poised and active enhancers interacting with promoters and coordinated this withIgklocus contraction. BRWD1 did so by converting chromatin-bound static cohesin to dynamic complexes competent to mediate long-range looping. Remarkably, ATP depletion recapitulated cohesin distributions observed inBrwd1-/-cells. Therefore, in small pre-B cells, cohesin conversion is the main energetic mechanism dictating where dynamic looping occurs in the genome. Our findings provide a new mechanism of cohesin regulation and reveal how cohesin function can be dictated by lineage contextual mechanisms to facilitate specific cell fate transitions.
Publisher
Cold Spring Harbor Laboratory