Department of Molecular Biosciences, Northwestern University, Evanston, IL, 60208, USA.
Simpson Querrey Institute for Epigenetics, Northwestern University, Chicago, IL, 60611, USA.
Nat Commun. 2022 Jul 29;13(1):4408. doi: 10.1038/s41467-022-32098-2.
Progenitors in epithelial tissues, such as human skin epidermis, continuously make fate decisions between self-renewal and differentiation. Here we show that the Super Elongation Complex (SEC) controls progenitor fate decisions by directly suppressing a group of "rapid response" genes, which feature high enrichment of paused Pol II in the progenitor state and robust Pol II elongation in differentiation. SEC's repressive role is dependent on the AFF1 scaffold, but not AFF4. In the progenitor state, AFF1-SEC associates with the HEXIM1-containing inactive CDK9 to suppress these rapid-response genes. A key rapid-response SEC target is ATF3, which promotes the upregulation of differentiation-activating transcription factors (GRHL3, OVOL1, PRDM1, ZNF750) to advance terminal differentiation. SEC peptidomimetic inhibitors or PKC signaling activates CDK9 and rapidly induces these transcription factors within hours in keratinocytes. Thus, our data suggest that the activity switch of SEC-associated CDK9 underlies the initial processes bifurcating progenitor fates between self-renewal and differentiation.
上皮组织中的祖细胞，如人类皮肤表皮，在自我更新和分化之间不断做出命运决定。在这里，我们表明超级延伸复合物（SEC）通过直接抑制一组“快速反应”基因来控制祖细胞命运决定，这些基因的特征是在祖细胞状态下高度富集暂停的 Pol II 和在分化中强大的 Pol II 延伸。SEC 的抑制作用依赖于 AFF1 支架，但不依赖于 AFF4。在祖细胞状态下，AFF1-SEC 与包含无活性 CDK9 的 HEXIM1 相关联，以抑制这些快速反应基因。SEC 的一个关键快速反应靶标是 ATF3，它促进分化激活转录因子（GRHL3、OVOL1、PRDM1、ZNF750）的上调，以推进终端分化。SEC 肽模拟抑制剂或 PKC 信号激活 CDK9，并在数小时内在角质细胞中迅速诱导这些转录因子。因此，我们的数据表明，SEC 相关 CDK9 的活性开关是决定祖细胞命运在自我更新和分化之间分叉的初始过程的基础。
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