Regulation of pDC fate determination by histone deacetylase 3

Author:

Zhang Yijun12,Wu Tao12ORCID,He Zhimin12,Lai Wenlong12,Shen Xiangyi12ORCID,Lv Jiaoyan12,Wang Yuanhao12,Wu Li12ORCID

Affiliation:

1. Institute for Immunology, Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University

2. Beijing Key Laboratory for Immunological Research on Chronic Diseases

Abstract

Dendritic cells (DCs), the key antigen-presenting cells, are primary regulators of immune responses. Transcriptional regulation of DC development had been one of the major research interests in DC biology; however, the epigenetic regulatory mechanisms during DC development remains unclear. Here, we report that Histone deacetylase 3 (Hdac3), an important epigenetic regulator, is highly expressed in pDCs, and its deficiency profoundly impaired the development of pDCs. Significant disturbance of homeostasis of hematopoietic progenitors was also observed in HDAC3-deficient mice, manifested by altered cell numbers of these progenitors and defective differentiation potentials for pDCs. Using the in vitro Flt3L supplemented DC culture system, we further demonstrated that HDAC3 was required for the differentiation of pDCs from progenitors at all developmental stages. Mechanistically, HDAC3 deficiency resulted in enhanced expression of cDC1-associated genes, owing to markedly elevated H3K27 acetylation (H3K27ac) at these gene sites in BM pDCs. In contrast, the expression of pDC-associated genes was significantly downregulated, leading to defective pDC differentiation.

Funder

Ministry of Science and Technology of the People's Republic of China

National Natural Science Foundation of China

Tsinghua-Peking Center for Life Sciences

National Basic Research Center of China

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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