Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Mol Cell. 2022 Dec 1;82(23):4410-4427.e12. doi: 10.1016/j.molcel.2022.10.022. Epub 2022 Nov 9.
Gene expression heterogeneity underlies cell states and contributes to developmental robustness. While heterogeneity can arise from stochastic transcriptional processes, the extent to which it is regulated is unclear. Here, we characterize the regulatory program underlying heterogeneity in murine embryonic stem cell (mESC) states. We identify differentially active and transcribed enhancers (DATEs) across states. DATEs regulate differentially expressed genes and are distinguished by co-binding of transcription factors Klf4 and Zfp281. In contrast to other factors that interact in a positive feedback network stabilizing mESC cell-type identity, Klf4 and Zfp281 drive opposing transcriptional and chromatin programs. Abrogation of factor binding to DATEs dampens variation in gene expression, and factor loss alters kinetics of switching between states. These results show antagonism between factors at enhancers results in gene expression heterogeneity and formation of cell states, with implications for the generation of diverse cell types during development.
基因表达的异质性是细胞状态的基础，并有助于发育的稳健性。虽然异质性可能源于随机的转录过程，但它受调控的程度尚不清楚。在这里，我们描述了调控小鼠胚胎干细胞（mESC）状态异质性的调控程序。我们在不同状态下识别出活性和转录不同的增强子（DATEs）。DATEs 调控差异表达的基因，并通过转录因子 Klf4 和 Zfp281 的共同结合来区分。与其他在稳定 mESC 细胞类型身份的正反馈网络中相互作用的因子不同，Klf4 和 Zfp281 驱动相反的转录和染色质程序。削弱因子与 DATEs 的结合会抑制基因表达的变化，并且因子的丢失会改变状态之间转换的动力学。这些结果表明，增强子上的因子之间的拮抗作用导致基因表达的异质性和细胞状态的形成，这对发育过程中产生不同的细胞类型具有重要意义。
