Department of Cell Biology, Yale University, New Haven, CT, 06520, USA.
Yale Stem Cell Center, Yale University, New Haven, CT, 06520, USA.
Nat Commun. 2019 Apr 12;10(1):1695. doi: 10.1038/s41467-019-09636-6.
Actin cytoskeleton is well-known for providing structural/mechanical support, but whether and how it regulates chromatin and cell fate reprogramming is far less clear. Here, we report that MKL1, the key transcriptional co-activator of many actin cytoskeletal genes, regulates genomic accessibility and cell fate reprogramming. The MKL1-actin pathway weakens during somatic cell reprogramming by pluripotency transcription factors. Cells that reprogram efficiently display low endogenous MKL1 and inhibition of actin polymerization promotes mature pluripotency activation. Sustained MKL1 expression at a level seen in typical fibroblasts yields excessive actin cytoskeleton, decreases nuclear volume and reduces global chromatin accessibility, stalling cells on their trajectory toward mature pluripotency. In addition, the MKL1-actin imposed block of pluripotency can be bypassed, at least partially, when the Sun2-containing linker of the nucleoskeleton and cytoskeleton (LINC) complex is inhibited. Thus, we unveil a previously unappreciated aspect of control on chromatin and cell fate reprogramming exerted by the MKL1-actin pathway.
肌动蛋白细胞骨架以提供结构/机械支持而闻名，但它是否以及如何调节染色质和细胞命运重编程还远不清楚。在这里，我们报告肌球蛋白轻链激酶 1（MKL1）是许多肌动蛋白细胞骨架基因的关键转录共激活因子，调节基因组可及性和细胞命运重编程。MKL1-肌动蛋白通路在多能性转录因子介导的体细胞重编程过程中减弱。有效地进行重编程的细胞显示出低水平的内源性 MKL1，并且肌动蛋白聚合的抑制促进成熟多能性的激活。在典型成纤维细胞中所见的持续的 MKL1 表达水平会导致过多的肌动蛋白细胞骨架，减少核体积并降低整体染色质可及性，从而使细胞在向成熟多能性的轨迹上停滞。此外，当抑制核骨架和细胞骨架（LINC）复合物的 Sun2 包含连接蛋白时，至少部分地可以绕过由 MKL1-肌动蛋白引起的多能性阻断。因此，我们揭示了 MKL1-肌动蛋白通路对染色质和细胞命运重编程的控制的一个以前未被重视的方面。
