Differential chromatin binding of the lung lineage transcription factor NKX2-1 resolves opposing murine alveolar cell fates in vivo

Danielle R Little,Anne M Lynch,Shioko Kimura,Yun Yan,Haruhiko Akiyama,Jichao Chen

doi:10.1038/s41467-021-22817-6

Abstract

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.

Highlights

Differential transcription of identical DNA sequences leads to distinct tissue lineages and multiple cell types within a lineage, an epigenetic process central to progenitor and stem cell biology
We found that NKX2-1 binding sites that were differential in the adult alveolar type 1 (AT1) versus alveolar type 2 (AT2) cells could range from absent to abundant in the progenitors: the 20% least present sites showed a gradual increase in NKX2-1 binding over time in the expected cell type with little increase in the alternative cell type, which we termed acquired sites; whereas the 20% most present sites maintained NKX2-1 binding in the expected cell type but showed a gradual loss in the alternative cell type, which we termed retained sites (Fig. 3a, b and Supplementary Data 2)
Our native tissue-derived genomic data have delineated the in vivo function of the lung lineage transcription factor NKX2-1 in opposing cell types and across developmental stages

Summary

Introduction

Differential transcription of identical DNA sequences leads to distinct tissue lineages and multiple cell types within a lineage, an epigenetic process central to progenitor and stem cell biology. AT1 cells are extremely thin yet expansive, allowing passive gas diffusion, whereas AT2 cells are cuboidal and secret surfactants to reduce surface tension[1] Both cell types arise from embryonic SOX9 progenitors, and their opposing cell fates must be resolved during development and their identities guarded afterwards, especially given that AT2 cells are able to differentiate into AT1 cells during injury-repair[9,10]. We show that in native tissues, the lineage transcription factor NKX2-1 resolves opposite cell fates and exerts cell-type-specific functions via differential binding in part under the control of YAP/TAZ transcriptional cofactors, and that NKX2-1 binding regulates a cell-type-specific epigenetic landscape that is not predicted by the transcriptome, providing insights into cell fate determination during lung development and injury-repair

Methods

Results

Conclusion