# DHX9 sustains hematopoietic stem cell function in cooperation with H3 acetylation

## TL;DR

This study shows that DHX9 helps maintain hematopoietic stem cells by regulating histone acetylation, and its absence leads to blood cell production issues.

## Contribution

DHX9 is identified as a novel regulator of hematopoietic stem cell function through its role in maintaining H3 acetylation.

## Key findings

- Dhx9 deletion causes bone marrow failure and impaired hematopoietic reconstitution due to loss of HSCs.
- DHX9 maintains H3 acetylation at hematopoietic gene promoters to promote transcription activation.
- Restoring H3K27ac levels partially rescues hematopoietic defects in DHX9-deficient cells.

## Abstract

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.

•Deletion of Dhx9 causes HSC loss and impairs hematopoietic reconstitution•DHX9 promotes hematopoietic gene transcription by maintaining histone H3 acetylation•Restoration of H3K27ac partially rescues DHX9-deficient mouse and human HSC function

Deletion of Dhx9 causes HSC loss and impairs hematopoietic reconstitution

DHX9 promotes hematopoietic gene transcription by maintaining histone H3 acetylation

Restoration of H3K27ac partially rescues DHX9-deficient mouse and human HSC function

In this article, Zhu and colleagues show that DHX9 regulates hematopoietic stem cell self-renewal and quiescence by maintaining H3 acetylation at hematopoietic gene promoters. Loss of DHX9 impairs hematopoiesis, while restoring H3 acetylation partially rescues defects, providing mechanistic insights and potential therapeutic avenues for hematopoietic disorders.