The epigenetic regulator Histone Deacetylase 3 regulates the ontogeny and maintenance of tissue-resident macrophage [RNA-Seq]

Tissue-resident macrophages (TRMs) play central roles in local tissue development and immunity. However, how to control TRM ontogeny and maintenance remains unclear. We performed transcriptional and histone modification analyses of alveolar macrophages in mice with myeloid-specific (Csf1rCre) deletion of HDAC3 using bulk RNA-seq, single-cell RNA-seq and ChIP-seq. We report that HDAC3 deficiency results in metabolic disorders and increased cell death of the fetal lung TRMs, which is partially regulated through directly targeting PPAR-gamma. Although the loss of AMs in the absence of HDAC3 is not AM subset specific, the transcriptome changes in HDAC3 deficient AM subsets are different. We propose that HDAC3 serves a key epigenetic regulator that controls embryonic TRM ontogeny and maintenance. RNA-sequencing of Csf1rCre+HDAC3fl/fl and Csf1rCre-HDAC3fl/fl fetal preAMs at E18.5组织驻留巨噬细胞（Tissue-resident macrophages, TRMs）在局部组织发育与免疫调控中发挥核心作用。然而，目前针对TRM起源与维持的调控机制仍未阐明。本研究针对髓系特异性Cre重组酶（Csf1rCre）介导的HDAC3条件性敲除小鼠，利用批量RNA测序（bulk RNA-seq）、单细胞RNA测序（single-cell RNA-seq）及染色质免疫沉淀测序（ChIP-seq），对其肺泡巨噬细胞开展了转录组与组蛋白修饰分析。研究结果显示，HDAC3缺陷会引发胎肺TRMs发生代谢紊乱并导致细胞死亡增多，该效应部分通过直接靶向过氧化物酶体增殖物激活受体γ（PPAR-γ）实现。尽管HDAC3缺失所引起的肺泡巨噬细胞（alveolar macrophages, AMs）丢失并非局限于特定AM亚群，但HDAC3缺陷的AM亚群其转录组变化存在显著差异。本研究提出，HDAC3作为关键表观遗传调控因子，可调控胚胎期TRM的起源与维持。本研究对E18.5胎龄的Csf1rCre+HDAC3fl/fl与Csf1rCre-HDAC3fl/fl胎肺前肺泡巨噬细胞进行了RNA测序。