BCLAF1 restrains stress responses in hematopoietic stem cells to support expansion and repopulation Open Access

• BCLAF1 is a novel transcriptional regulator that promotes HSC expansion during fetal development and after stem cell transplant.

• BCLAF1 restrains expression of stress response genes in hematopoietic progenitors via indirect or transient mechanisms.

Hematopoietic stem cells (HSC) rapidly expand during fetal development and after stress. Here, we identify BCLAF1 as a regulator of HSC repopulation activity with functions in expansion of fetal HSCs and hematopoietic reconstitution after stem cell transplantation. Using mice with hematopoietic-specific and inducible deletion of Bclaf1, we find that BCLAF1 promotes fetal HSC development but is dispensible for maintenance of adult HSCs at steady state. Loss of BCLAF1 in either fetal or adult HSCs significantly impairs their self-renewal and multi-lineage reconstitution activity after stem cell transplantation. Single-cell RNA sequencing of fetal hematopoietic progenitors reveals that loss of BCLAF1 reduces long-term HSCs and restrains expression of stress response genes. BCLAF1 associates with chromatin throughout the genome of fetal and adult hematopoietic cells, likely through indirect mechanisms, to regulate transcriptional programs. These results establish a novel function for the transcriptional regulator BCLAF1 in limiting stress responses in HSCs to preserve HSC development during embryogenesis and repopulation function after stem cell transplant.