TY - JOUR
T1 - Histone deacetylase 3 controls lung alveolar macrophage development and homeostasis
AU - Yao, Yi
AU - Liu, Queping
AU - Adrianto, Indra
AU - Wu, Xiaojun
AU - Glassbrook, James
AU - Khalasawi, Namir
AU - Yin, Congcong
AU - Yi, Qijun
AU - Dong, Zheng
AU - Geissmann, Frederic
AU - Zhou, Li
AU - Mi, Qing Sheng
N1 - Funding Information:
We thank Dr. Hongmei Peng, Dr. Yu Wang, Dr. Jun Zhang, Dr. Xuan Wang, and Dr. Yi Yang for helping prepare samples. We thank Dr. Keji Zhao from the Lung and Blood Institute, National Institutes of Health, for valuable technical support in RNA-Seq. This study is partially supported by National Institutes of Health grants R01AR069681, R61AR076803, R01AI119041 (Q-S.M.), R01AR087659 (L.Z.), and the Henry Ford Immunology Program grants (T71016, Q-S.M.; T71017, L. Z.).
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-17630-6
DO - 10.1038/s41467-020-17630-6
M3 - Article
C2 - 32732898
AN - SCOPUS:85088822717
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3822
ER -