The epigenetic regulator Histone Deacetylase 3 regulates the ontogeny and maintenance of tissue-resident macrophage [scRNA-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. scRNA-sequencing of Csf1rCre+HDAC3fl/fl and Csf1rCre-HDAC3fl/fl adult lung alveolar macrophage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，调控TRMs起源与维持的具体机制仍不明确。本研究针对髓系特异性（Csf1rCre）敲除组蛋白去乙酰化酶3（HDAC3）的小鼠，采用批量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。研究发现，HDAC3缺失会导致胎肺TRMs出现代谢紊乱并增加细胞死亡风险，该效应可通过直接靶向过氧化物酶体增殖物激活受体γ（PPAR-γ）得到部分调控。尽管HDAC3缺失所致的肺泡巨噬细胞（AMs）丢失并非AM亚群特异性现象，但HDAC3缺陷型AM亚群的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TRMs的起源与维持。本研究对Csf1rCre+HDAC3fl/fl与Csf1rCre-HDAC3fl/fl成年小鼠肺脏的肺泡巨噬细胞开展了单细胞RNA测序。