Gregoire Serge, Li Guang, Sturzu Anthony C, Schwartz Robert J, Wu Sean M
Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Cardiovascular Institute, Institute of Stem Cell and Regenerative Biology, Stanford University School of Medicine, Stanford, California, USA.
Stem Cells. 2017 Aug;35(8):1913-1923. doi: 10.1002/stem.2646. Epub 2017 Jun 27.
During cardiac development, DNA binding transcription factors and epigenetic modifiers regulate gene expression in cardiac progenitor cells (CPCs). We have previously shown that Yin Yang 1 (YY1) is essential for the commitment of mesodermal precursors into CPCs. However, the role of YY1 in the maintenance of CPC phenotype and their differentiation into cardiomyocytes is unknown. In this study, we found, by genome-wide transcriptional profiling and phenotypic assays, that YY1 overexpression prevents cardiomyogenic differentiation and maintains the proliferative capacity of CPCs. We show further that the ability of YY1 to regulate CPC phenotype is associated with its ability to modulate histone modifications specifically at a developmentally critical enhancer of Nkx2-5 and other key cardiac transcription factor such as Tbx5. Specifically, YY1 overexpression helps to maintain markers of gene activation such as the acetylation of histone H3 at lysine 9 (H3K9Ac) and lysine 27 (H3K27Ac) as well as trimethylation at lysine 4 (H3K4Me3) at the Nkx2-5 cardiac enhancer. Furthermore, transcription factors associated proteins such as PoIII, p300, and Brg1 are also enriched at the Nkx2-5 enhancer with YY1 overexpression. The biological activities of YY1 in CPCs appear to be cell autonomous, based coculture assays in differentiating embryonic stem cells. Altogether, these results demonstrate that YY1 overexpression is sufficient to maintain a CPC phenotype through its ability to sustain the presence of activating epigenetic/chromatin marks at key cardiac enhancers. Stem Cells 2017;35:1913-1923.
在心脏发育过程中，DNA结合转录因子和表观遗传修饰因子调节心脏祖细胞（CPCs）中的基因表达。我们之前已经表明，阴阳1（YY1）对于中胚层前体细胞向CPCs的定向分化至关重要。然而，YY1在维持CPCs表型及其向心肌细胞分化中的作用尚不清楚。在本研究中，我们通过全基因组转录谱分析和表型分析发现，YY1过表达可阻止心肌发生分化并维持CPCs的增殖能力。我们进一步表明，YY1调节CPCs表型的能力与其在发育关键的Nkx2-5增强子以及其他关键心脏转录因子（如Tbx5）上特异性调节组蛋白修饰的能力相关。具体而言，YY1过表达有助于维持基因激活标记，如Nkx2-5心脏增强子处组蛋白H3赖氨酸9（H3K9Ac）和赖氨酸27（H3K27Ac）的乙酰化以及赖氨酸4（H3K4Me3）的三甲基化。此外，转录因子相关蛋白如PoIII、p300和Brg1在YY1过表达时也在Nkx2-5增强子处富集。基于分化胚胎干细胞的共培养实验，YY1在CPCs中的生物学活性似乎是细胞自主的。总之，这些结果表明，YY1过表达通过其维持关键心脏增强子处激活的表观遗传/染色质标记的能力足以维持CPCs表型。《干细胞》2017年；35卷：1913 - 1923页
