1021 – SWI/SNF CHROMATIN REMODELING COMPLEXES GOVERN LYMPHOID LINEAGE COMMITMENT

Abstract

Lymphocyte development from hemopoietic stem cells (HSCs) is accompanied by a loss of self-renewal capacity and a progressive restriction of developmental potential. Although key transcriptional pathways controlling lymphoid development have been identified, detailed molecular mechanisms explaining how multipotent HSCs initially commit to the lymphoid lineage are still lacking. Work from our laboratory indicates that combinatorial assembly of SWI/SNF chromatin remodeling complexes is a key epigenetic mechanism controlling cell fate decisions in the hemopoietic tissue. Single-cell RNA-seq analyses in bone marrow cells revealed that expression of the Smarcd1 subunit is enriched in lymphoid-primed multipotent progenitors. Using a conditional knock-out mouse model, we showed that Smarcd1 is specifically required for the development of the lymphoid lineage. Acute deletion of Smarcd1 in adult hematopoiesis causes lymphopenia with near complete absence of lymphoid-primed multipotent progenitors, indicating a role in lymphoid lineage commitment. Genome-wide studies revealed a functional collaboration between Smarcd1 and the bHLH transcription factor E2A in activating the lymphoid program of gene expression. Mechanistically, we show that Smarcd1 binds to and regulates chromatin accessibility of E2A at H3K27ac/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. Lymphocyte development from hemopoietic stem cells (HSCs) is accompanied by a loss of self-renewal capacity and a progressive restriction of developmental potential. Although key transcriptional pathways controlling lymphoid development have been identified, detailed molecular mechanisms explaining how multipotent HSCs initially commit to the lymphoid lineage are still lacking. Work from our laboratory indicates that combinatorial assembly of SWI/SNF chromatin remodeling complexes is a key epigenetic mechanism controlling cell fate decisions in the hemopoietic tissue. Single-cell RNA-seq analyses in bone marrow cells revealed that expression of the Smarcd1 subunit is enriched in lymphoid-primed multipotent progenitors. Using a conditional knock-out mouse model, we showed that Smarcd1 is specifically required for the development of the lymphoid lineage. Acute deletion of Smarcd1 in adult hematopoiesis causes lymphopenia with near complete absence of lymphoid-primed multipotent progenitors, indicating a role in lymphoid lineage commitment. Genome-wide studies revealed a functional collaboration between Smarcd1 and the bHLH transcription factor E2A in activating the lymphoid program of gene expression. Mechanistically, we show that Smarcd1 binds to and regulates chromatin accessibility of E2A at H3K27ac/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.