Smarcd1 Subunit of SWI/SNF Chromatin Remodeling Complexes Collaborates with E2A to Promote Lymphoid Specification

Lymphocyte development from hematopoietic stem cells (HSCs) is accompanied by a loss of self-renewal capacity and a progressive restriction of developmental potential. Although the molecular mechanisms for the generation of mature B- or T- lymphocytes are beginning to be revealed, a major unanswered question is how multipotent HSCs initiate commitment toward lymphoid fate. Work from our laboratory indicates that specialized assemblies of ATP-dependent SWI/SNF chromatin remodeling complexes perform lineage-specific roles during hemopoiesis. Here we show that the Smarcd1 subunit is specifically required for the development of the lymphoid lineage. Acute deletion of Smarcd1 in adult hematopoiesis causes lymphopenia with near complete absence of progenitors and mature B/T-lymphocytes, whereas the myeloid and erythroid lineages remain unaffected. Smarcd1 is required for the generation of lymphoid-primed multipotent progenitors from HSCs, indicating a role in early lymphoid specification. Using transcriptomics and ATAC-seq analyses we discovered a functional collaboration between Smarcd1 and the bHLH transcription factor E2A in activating the lymphoid-specific program of gene expression. Mechanistically, we show that Smarcd1 physically interacts with E2A and is required for its recruitment to a set of H3K27a/H3K4me1-enriched enhancers that coordinate activation of the early lymphoid signature in hemopoietic stem cells. Altogether, these studies identify Smarcd1 as a chromatin remodeler that collaborates with E2A to determine the lymphoid cell fate during hemopoiesis.