Differential chromatin binding of the lung lineage transcription factor NKX2-1 resolves opposing murine alveolar cell fates in vivo.
Differential chromatin binding of the lung lineage transcription factor NKX2-1 resolves opposing murine alveolar cell fates in vivo.
复制标题
DOI：
10.1038/s41467-021-22817-6
复制
发表时间：
2021-05-04
影响因子：
16.6
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Little DR;Lynch AM;Yan Y;Akiyama H;Kimura S;Chen J
相同DNA序列的差异转录导致不同的组织谱系，然后在一个谱系中产生多种细胞类型，这是祖细胞和干细胞生物学的核心表观遗传过程。相关的全基因组变化，特别是在原生组织中，仍然没有得到充分的了解，因此在小鼠肺中进行了研究，其中相同的谱系转录因子NKX2-1促进完全相反的肺泡1型（AT1）和AT2细胞命运。在这里，我们报道NKX2-1的细胞类型特异性功能归因于其在发育过程中与伙伴转录因子协调获得或保留的差异染色质结合。YAP/TAZ的缺失将NKX2-1从其at1特异性结合位点重定向到AT2特异性结合位点，导致在祖细胞中被删除的AT2细胞转录扩增，或在命运承诺后被删除的AT1-to-AT2转化。Nkx2-1突变AT1和AT2细胞获得不同的染色质可接近位点，包括那些在采用胃肠道命运时特异性的染色质可接近位点，这表明转录变化意想不到的表观遗传可塑性。我们对单个或纯化细胞的基因组分析，加上精确遗传学，为肺泡细胞的命运和潜力提供了表观遗传学基础，并为破译谱系转录因子的体内功能提供了实验基准。转录因子如何调节原生组织中的细胞命运尚不清楚。在这里，作者报告了NKX2-1的不同染色质结合决定了小鼠肺中相反的肺泡细胞命运，表明YAP/TAZ的缺失将NKX2-1定向到其他结合位点，从而导致细胞命运的转变。
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. How transcription factors regulate cell fates in native tissues is unclear. Here, the authors report that differential chromatin binding of NKX2-1 determines opposing alveolar cell fates in the murine lung, showing loss of YAP/TAZ directs NKX2-1 to alternative binding sites leading to cell fate conversion.
登录
查看更多内容
影响因子：
23.9
作者：
Adam RC;Yang H;Ge Y;Lien WH;Wang P;Zhao Y;Polak L;Levorse J;Baksh SC;Zheng D;Fuchs E
通讯作者：
Fuchs E
影响因子：
16.6
作者：
Jain, Rajan;Barkauskas, Christina E.;Takeda, Norifumi;Bowie, Emily J.;Aghajanian, Haig;Wang, Qiaohong;Padmanabhan, Arun;Manderfield, Lauren J.;Gupta, Mudit;Li, Deqiang;Li, Li;Trivedi, Chinmay M.;Hogan, Brigid L. M.;Epstein, Jonathan A.
通讯作者：
Epstein, Jonathan A.
影响因子：
30.8
作者：
John S;Sabo PJ;Thurman RE;Sung MH;Biddie SC;Johnson TA;Hager GL;Stamatoyannopoulos JA
通讯作者：
Stamatoyannopoulos JA
影响因子：
14.9
作者：
Kantidze，Omar L.;Razin，Sergey
通讯作者：
Razin，Sergey
DOI：
10.1073/pnas.2002082117
发表时间：
2020-06-02
影响因子：
11.1
作者：
Gerner-Mauro, Kamryn N.;Akiyama, Haruhiko;Chen, Jichao
通讯作者：
Chen, Jichao