Baf155 establishes chromatin priming to promote hematopoietic regeneration and function [bulk ATAC]

Chromatin priming promotes cell type-specific gene expression, lineage differentiation, and development. The mechanism of chromatin priming has not been well understood. Mouse hematopoietic stem and progenitor cells (HSPCs) lacking the Baf155 subunit of the BAF (BRG1/BRM associated factor) chromatin-remodeler produced a significantly reduced number of mature blood cells, leading to a failure of hematopoietic regeneration upon transplantation and 5-FU injury. Baf155 deficient HSPCs, while showing impaired mature blood cell production, generated a higher frequency of myeloid cells with fewer B and CD8+ T cells at homeostasis, supporting a more immune-suppressive tumor microenvironment and enhanced tumor growth. Single-nuclei multi-omic analysis revealed that Baf155 deficient HSPCs failed to establish accessible chromatin and levels of lineage-specific transcripts were considerably lower. Regions that showed a substantial loss in chromatin accessibility were enriched for enhancers and binding motifs for hematopoietic lineage-specific transcription factors. Our study provides a fundamental mechanistic understanding of the role of Baf155 in establishing chromatin priming with functional consequences in regeneration or tumor immunity.