Histone Deacetylase 3 controls lung alveolar macrophage development and homeostasis by regulation of PPAR-γ expression through deacetylating PU.1

Abstract

Abstract Alveolar macrophages (AMs) are derived from embryonic precursors that seed the lung before birth and self-maintain locally throughout adulthood but can be regenerated by bone marrow (BM) under stress conditions. However, how to precisely regulate AM development still remains unknown. Here we report that histone deacetylase 3 (HDAC3) is a key epigenetic factor required for AM embryonic development, postnatal homeostasis, maturation, and regeneration from BM. Loss of HDAC3 in early embryonic development affects AM development starting at E14.5, while loss of HDAC3 after birth affects AM homeostasis and maturation. HDAC3-deficient AMs exhibit severe mitochondrial oxidative dysfunction and deteriorative cell death. Single-cell RNA sequencing analyses further identified four distinct AM sub-clusters and a lack of HDAC3 dysregulated AM transcriptome in a cluster-specific manner. Mechanistically, HDAC3 serves as a co-activator via deacetylation of PU.1 to promote Pparg transcription. Our findings identify HDAC3 as a key epigenetic regulator of lung AM development and homeostasis.