Bmi1 Is a Key Epigenetic Barrier to Direct Cardiac Reprogramming.
Bmi1 Is a Key Epigenetic Barrier to Direct Cardiac Reprogramming.
复制标题
DOI：
10.1016/j.stem.2016.02.003
复制
发表时间：
2016-03-03
期刊：
影响因子：
23.9
通讯作者：
Qian L
中科院分区：
文献类型：
--
作者：
Zhou Y;Wang L;Vaseghi HR;Liu Z;Lu R;Alimohamadi S;Yin C;Fu JD;Wang GG;Liu J;Qian L
诱导的心肌细胞（iCM）的直接重编程效率低，需要广泛的表观遗传重新模式化，尽管其潜在的机制在很大程度上是未知的。为了解决这些问题，我们筛选了iCM重编程的表观遗传调节因子，发现降低polycomb复合体基因Bmi1的水平显著增强了新生和成年小鼠成纤维细胞对iCM跳动的诱导。Bmi1在iCM重编程中的抑制作用是通过与心源性基因的调控区直接相互作用介导的，而不是调节细胞增殖。Bmi 1表达的降低与心源性基因座处的活性组蛋白标记H3K4me3水平的增加和抑制性H2AK199ub水平的降低以及iCM转化期间心源性基因表达的去抑制相对应。此外，在iCM重编程过程中，Bmi1缺失可以替代Gata4。因此，Bmi1作为一个关键的表观遗传屏障iCM生产。克服这一屏障简化了iCM的产生并提高了产量，从而可能简化用于治疗目的的iCM生产。
Direct reprogramming of induced cardiomyocytes (iCMs) suffers from low efficiency and requires extensive epigenetic repatterning, although the underlying mechanisms are largely unknown. To address these issues, we screened for epigenetic regulators of iCM reprogramming and found that reducing levels of the polycomb complex gene Bmi1 significantly enhanced induction of beating iCMs from neonatal and adult mouse fibroblasts. The inhibitory role of Bmi1 in iCM reprogramming is mediated through direct interactions with regulatory regions of cardiogenic genes, rather than regulation of cell proliferation. Reduced Bmi1 expression corresponded with increased levels of the active histone mark H3K4me3 and reduced levels of repressive H2AK199ub at cardiogenic loci, and de-repression of cardiogenic gene expression during iCM conversion. Furthermore, Bmi1 deletion could substitute for Gata4 during iCM reprogramming. Thus, Bmi1 acts as a critical epigenetic barrier to iCM production. Bypassing this barrier simplifies iCM generation and increases yield, potentially streamlining iCM production for therapeutic purposes.