DHX9 sustains hematopoietic stem cell function in cooperation with H3 acetylation

Hematopoietic stem cells (HSCs) self-renew to sustain stem cell pools and differentiate into all types of blood cells, whose properties are tightly regulated by epigenetic and transcriptional networks. Here, we identified DHX9 as a critical regulator of HSC maintenance. Dhx9 deletion caused bone marrow failure and impaired hematopoietic reconstitution in murine primary and secondary transplantation recipients due to loss of HSCs and defective self-renewal capacity. Further investigations revealed that Dhx9 deficiency led to aberrant cell cycle entry, increased apoptosis, and elevated ROS, which compromise HSC function. Mechanistically, DHX9 interacts with CBP/p300 acetyltransferase and maintains H3 acetylation at hematopoietic gene promoters to facilitate transcription activation. Inhibition of CBP/p300 disrupted their expression, whereas the enhancement of H3K27ac levels partially rescued hematopoietic defects caused by Dhx9 deficiency in both mouse models and human CD34⁺ cells. This study highlights DHX9 as a crucial factor linking epigenetic modifications with transcriptional programs in HSC biology.