Chromatin remodeling factor BRM maintains HSC via epigenetic regulation

Recent observations shed light on epigenetic regulation systems as the great contributors to the decision of hematopoietic stem cell (HSC) fates; self-renew or differentiation to respective lineages. HSC soundness is fine-tuned, but its dysregulation leads to the development of hematological diseases, including bone marrow failure and hematological malignancies. Among many players in the epigenetic regulation, the SWI/SNF ATP-dependent chromatin remodeling factor BRG1 has recently been demonstrated to be essential for leukemic stem cell (LSC) maintenance. Whereas BRG1 is implicated in the pathogenesis of Fanconi anemia and bone marrow failure, BRM, the homologue of BRG1, is expressed more specifically in HSCs compared with BRG1 and appeared to be involved in physiological regulation of HSCs. We have elucidated an essential role of BRM in the maintenance of HSCs using genetically modified BRM-null mice. BRM-null HSCs showed profoundly impaired reconstitution capacity in competitive BMT assays and exhibited more activate cell cycling than wild type HSCs after bone marrow transplantation, suggesting that BRM plays a role in reversion of cycling HSCs into a quiescent state. Latest studies have revealed that SWI/SNF chromatin remodeling complex has a critical role in both development and disease by opposing Polycomb group (PcG) proteins by rapid ATP-dependent eviction, leading to the formation of accessible chromatin. PcG proteins maintain the self-renewal capacity of HSCs by keeping differentiation programs poised for activation in HSCs by repressing a cohort of hematopoietic developmental regulator genes via bivalent chromatin domains. These aspects prompt us to support the hypothesis that BRM maintain self-renewal capacity of HSCs by controlling the transcriptional regulation of stem cell factors or differential genes by PcG proteins. Now we are identifying the epigenetic status on target genes of BRM by executing ChIP- and ATAC-sequences and will demonstrate the molecular mechanisms underlying HSC regulation by BRM.