PRDM3/16 regulate chromatin accessibility required for NKX2-1 mediated alveolar epithelial differentiation and function

Hua He (), Sheila M. Bell, Ashley Kuenzi Davis, Shuyang Zhao, Anusha Sridharan, Cheng-Lun Na, Minzhe Guo, Yan Xu, John Snowball, Daniel T. Swarr, William J. Zacharias and Jeffrey A. Whitsett ()
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Hua He: Sichuan University
Sheila M. Bell: Cincinnati Children’s Hospital Medical Center
Ashley Kuenzi Davis: Cincinnati Children’s Hospital Medical Center
Shuyang Zhao: Cincinnati Children’s Hospital Medical Center
Anusha Sridharan: Cincinnati Children’s Hospital Medical Center
Cheng-Lun Na: Cincinnati Children’s Hospital Medical Center
Minzhe Guo: Cincinnati Children’s Hospital Medical Center
Yan Xu: Cincinnati Children’s Hospital Medical Center
John Snowball: Cincinnati Children’s Hospital Medical Center
Daniel T. Swarr: Cincinnati Children’s Hospital Medical Center
William J. Zacharias: Cincinnati Children’s Hospital Medical Center
Jeffrey A. Whitsett: Cincinnati Children’s Hospital Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract While the critical role of NKX2-1 and its transcriptional targets in lung morphogenesis and pulmonary epithelial cell differentiation is increasingly known, mechanisms by which chromatin accessibility alters the epigenetic landscape and how NKX2-1 interacts with other co-activators required for alveolar epithelial cell differentiation and function are not well understood. Combined deletion of the histone methyl transferases Prdm3 and Prdm16 in early lung endoderm causes perinatal lethality due to respiratory failure from loss of AT2 cells and the accumulation of partially differentiated AT1 cells. Combination of single-cell RNA-seq, bulk ATAC-seq, and CUT&RUN data demonstrate that PRDM3 and PRDM16 regulate chromatin accessibility at NKX2-1 transcriptional targets critical for perinatal AT2 cell differentiation and surfactant homeostasis. Lineage specific deletion of PRDM3/16 in AT2 cells leads to lineage infidelity, with PRDM3/16 null cells acquiring partial AT1 fate. Together, these data demonstrate that NKX2-1-dependent regulation of alveolar epithelial cell differentiation is mediated by epigenomic modulation via PRDM3/16.

Date: 2024
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DOI: 10.1038/s41467-024-52154-3

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