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CHAF1A sustains hematopoietic stem cell stemness by enhancing the activity of the NF-Y transcription factor family

LIU Jin¹, XIAO Meng-Du², YOU Wan-Ling³, SHENG Yue¹, WANG Hu^2,*

¹Department of Hematology, the Second Xiangya Hospital, Central South University, Changsha 410011, China；²Zhejiang Key Laboratory of Medical Epigenetics, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China；³Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou 510632, China

Abstract

This study aimed to investigate the regulatory role and underlying molecular mechanisms of chromatin assembly factor 1 subunit CHAF1A in the function of hematopoietic stem cells (HSCs) in adult mice. A hematopoietic-specific Chaf1a knockout mouse model was established, and multiple approaches including flow cytometry, RNA-seq, ATAC-seq, and HINT-ATAC were integrated for multidimensional systematic analysis. CHAF1A depletion led to a pronounced reduction in peripheral blood platelet count. In the bone marrow, the number of LSK (lineage- Sca-1+ c-Kit+) cells and HSCs was markedly decreased, while no significant difference was observed in the number of hematopoietic progenitor cells (common myeloid progenitors, megakaryocyte-erythroid progenitors and granulocyte-monocyte progenitors) in the CHAF1A-deficient group. Additionally, no significant differences were observed in HSC cell cycle distribution or apoptosis. RNA-seq identified 904 upregulated and 781 downregulated genes in CHAF1A-deficient HSCs. Gene set enrichment analysis (GSEA) showed that stemness-related genes were significantly enriched in wild-type HSCs, while differentiation-related genes were significantly enriched in CHAF1A-deficient HSCs. ATAC-seq revealed reduced chromatin accessibility at the transcription start site (TSS) regions of HSCs in the CHAF1A-deficient group. HINT-ATAC analysis further showed that the activity of NF-Y family transcription factors was significantly higher in wild-type HSCs than in CHAF1A-deficient HSCs, while the activities of CEBPA and CEBPD were significantly higher in CHAF1A-deficient HSCs. Collectively, these results suggest that CHAF1A is essential for the maintenance of adult mouse HSCs. Specifically, CHAF1A enhances the activity of NF-Y family transcription factors to sustain HSC stemness and inhibits the function of CEBP family transcription factors to block HSC differentiation. Its regulatory mechanism involves the coordinated regulation of chromatin accessibility and transcription factor activity.

Key words: Chaf1a; hematopoietic stem cells; chromatin accessibility; transcription factor NF-Y; transcription factor CEBP

Received: 　　Accepted:

Corresponding author: 汪虎　　E-mail:

DOI: 10.13294/j.aps.2026.0069

Citing This Article：

LIU Jin, XIAO Meng-Du, YOU Wan-Ling, SHENG Yue, WANG Hu. CHAF1A sustains hematopoietic stem cell stemness by enhancing the activity of the NF-Y transcription factor family. Acta Physiol Sin 2026; 78 (4): 931-942 (in Chinese with English abstract).