Age-associated chromatin reorganization drives overexpression of a novel Btaf1 variant regulating HSC self-renewal and MkP differentiation in male mice

Age-associated hematopoietic stem cell (HSC) dysfunction is accompanied by dramatic transcription changes, but it remains unclear whether specific transcripts could orchestrate these HSC aging phenotypes. Here, we performed epigenetic profiling in male mice to investigate the regulatory mechanisms underlying the HSC aging transcriptome and screen for potential aging driver genes. We show dysregulated 3D chromatin organization, altered histone modifications and changed chromatin accessibility shape the HSC aging transcriptome. From the compilation of these data, we identified a new looping structure formed between part of the Btaf1 gene and the whole Ide gene in old HSCs (OHSCs) which is accompanied by overexpression of a novel, shorter variant of Btaf1 (nBtaf1). Mechanistically, elevated expression of nBtaf1 drives the aging-associated overexpression of HSC- and megakaryocyte progenitor (MkP)-related genes by regulating TBP binding at their promoters which contributes to HSC expansion and elevated MkP production in aged mice. ShRNA mediated knockdown of nBtaf1 restores a younger HSC transcriptome and specifically represses aging-associated HSC expansion and elevated MkP production. In summary, our data provide high resolution analysis of a dysregulated HSC aging epigenome and reveal a novel Btaf1 variant that drives HSC aging phenotypes in mice.