TY - JOUR
T1 - Differential chromatin binding of the lung lineage transcription factor NKX2-1 resolves opposing murine alveolar cell fates in vivo
AU - Little, Danielle R.
AU - Lynch, Anne M.
AU - Yan, Yun
AU - Akiyama, Haruhiko
AU - Kimura, Shioko
AU - Chen, Jichao
N1 - Funding Information:
We thank Drs. Elizabeth Grove and Eric Bellefroid for providing the Wnt3aCre mice, Dr. Harold Chapman for providing the SftpcCreER mice. We thank Dr. Jan Parker-Thornburg and Chad Smith at the University of Texas MD Anderson Genetically Engineered Mouse Facility for generating the Rtkn2CreER mice. We thank Dr. Lisandra Villa Ellis, Dr. Margo P. Cain, Kamryn N. Gerner-Mauro, and Odemaris Narváez del Pilar in our lab for generating scRNA-seq data for the control lungs. We thank Kamryn N. Gerner-Mauro for sequencing ChIP-seq samples. The University of Texas MD Anderson Cancer Center Genetically Engineered Mouse Facility, DNA Analysis Facility, and Flow Cytometry and Cellular Imaging Core Facility are supported by the Cancer Center Support Grant (CA #16672). This work was supported by the University of Texas MD Anderson Cancer Center Retention Fund and National Institutes of Health R01HL130129 and R01HL153511 (J.C.), and Gigli City Family Endowed Scholarship, City Federation of Women’s Clubs Endowed Scholarship, and National Institutes of Health F31HL139095 (D.R.L.).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Differential transcription of identical DNA sequences leads to distinct tissue lineages and then multiple cell types within a lineage, an epigenetic process central to progenitor and stem cell biology. The associated genome-wide changes, especially in native tissues, remain insufficiently understood, and are hereby addressed in the mouse lung, where the same lineage transcription factor NKX2-1 promotes the diametrically opposed alveolar type 1 (AT1) and AT2 cell fates. Here, we report that the cell-type-specific function of NKX2-1 is attributed to its differential chromatin binding that is acquired or retained during development in coordination with partner transcriptional factors. Loss of YAP/TAZ redirects NKX2-1 from its AT1-specific to AT2-specific binding sites, leading to transcriptionally exaggerated AT2 cells when deleted in progenitors or AT1-to-AT2 conversion when deleted after fate commitment. Nkx2-1 mutant AT1 and AT2 cells gain distinct chromatin accessible sites, including those specific to the opposite fate while adopting a gastrointestinal fate, suggesting an epigenetic plasticity unexpected from transcriptional changes. Our genomic analysis of single or purified cells, coupled with precision genetics, provides an epigenetic basis for alveolar cell fate and potential, and introduces an experimental benchmark for deciphering the in vivo function of lineage transcription factors.
AB - Differential transcription of identical DNA sequences leads to distinct tissue lineages and then multiple cell types within a lineage, an epigenetic process central to progenitor and stem cell biology. The associated genome-wide changes, especially in native tissues, remain insufficiently understood, and are hereby addressed in the mouse lung, where the same lineage transcription factor NKX2-1 promotes the diametrically opposed alveolar type 1 (AT1) and AT2 cell fates. Here, we report that the cell-type-specific function of NKX2-1 is attributed to its differential chromatin binding that is acquired or retained during development in coordination with partner transcriptional factors. Loss of YAP/TAZ redirects NKX2-1 from its AT1-specific to AT2-specific binding sites, leading to transcriptionally exaggerated AT2 cells when deleted in progenitors or AT1-to-AT2 conversion when deleted after fate commitment. Nkx2-1 mutant AT1 and AT2 cells gain distinct chromatin accessible sites, including those specific to the opposite fate while adopting a gastrointestinal fate, suggesting an epigenetic plasticity unexpected from transcriptional changes. Our genomic analysis of single or purified cells, coupled with precision genetics, provides an epigenetic basis for alveolar cell fate and potential, and introduces an experimental benchmark for deciphering the in vivo function of lineage transcription factors.
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U2 - 10.1038/s41467-021-22817-6
DO - 10.1038/s41467-021-22817-6
M3 - Article
C2 - 33947861
AN - SCOPUS:85105310731
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2509
ER -