Histone deacetylase 3 controls lung alveolar macrophage development and homeostasis

Yi Yao, Queping Liu, Indra Adrianto, Xiaojun Wu, James Glassbrook, Namir Khalasawi, Congcong Yin, Qijun Yi, Zheng Dong, Frederic Geissmann, Li Zhou, Qing Sheng Mi

Research output: Contribution to journalArticle

Abstract

Alveolar macrophages (AMs) derived from embryonic precursors seed the lung before birth and self-maintain locally throughout adulthood, but are regenerated by bone marrow (BM) under stress conditions. However, the regulation of AM development and maintenance remains poorly understood. Here, we show 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. Single-cell RNA sequencing analyses reveal four distinct AM sub-clusters and a dysregulated cluster-specific pathway in the HDAC3-deficient AMs. Moreover, HDAC3-deficient AMs exhibit severe mitochondrial oxidative dysfunction and deteriorative cell death. Mechanistically, HDAC3 directly binds to Pparg enhancers, and HDAC3 deficiency impairs Pparg expression and its signaling pathway. Our findings identify HDAC3 as a key epigenetic regulator of lung AM development and homeostasis.

Original languageEnglish (US)
Article number3822
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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  • Cite this

    Yao, Y., Liu, Q., Adrianto, I., Wu, X., Glassbrook, J., Khalasawi, N., Yin, C., Yi, Q., Dong, Z., Geissmann, F., Zhou, L., & Mi, Q. S. (2020). Histone deacetylase 3 controls lung alveolar macrophage development and homeostasis. Nature communications, 11(1), [3822]. https://doi.org/10.1038/s41467-020-17630-6