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PRDM3/16 regulate chromatin accessibility required for NKX2-1 mediated alveolar epithelial differentiation and
Hua He1,2, Sheila M Bell3, Ashley Kuenzi Davis3
1Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China. Hua.he@scu.edu.cn.
Nature Communications
|September 16, 2024
Summary
Histone methyltransferases PRDM3 and PRDM16 are crucial for lung development. Their absence leads to respiratory failure by impairing alveolar epithelial cell differentiation and function.
Area of Science:
- Pulmonary Medicine
- Developmental Biology
- Epigenetics
Background:
- The transcription factor NKX2-1 is vital for lung development and differentiation.
- Mechanisms of chromatin accessibility and co-activator interactions in alveolar epithelial cell differentiation remain unclear.
Purpose of the Study:
- To investigate the role of PRDM3 and PRDM16 in regulating chromatin accessibility and NKX2-1 targets during lung development.
- To understand how PRDM3 and PRDM16 influence alveolar epithelial cell differentiation and function.
Main Methods:
- Combined deletion of Prdm3 and Prdm16 in early lung endoderm.
- Single-cell RNA-seq, bulk ATAC-seq, and CUT&RUN analyses.
- Lineage-specific deletion of PRDM3/16 in alveolar type 2 (AT2) cells.
Main Results:
- Combined deletion of Prdm3 and Prdm16 caused perinatal lethality due to respiratory failure, loss of AT2 cells, and accumulation of AT1 cells.
- PRDM3 and PRDM16 were shown to regulate chromatin accessibility at key NKX2-1 targets essential for AT2 cell differentiation and surfactant homeostasis.
- Loss of PRDM3/16 in AT2 cells resulted in lineage infidelity, with cells adopting a partial AT1 fate.
Conclusions:
- NKX2-1-dependent regulation of alveolar epithelial cell differentiation is mediated by epigenomic modulation through PRDM3 and PRDM16.
- PRDM3 and PRDM16 are critical epigenetic regulators for maintaining AT2 cell identity and function during lung development.
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