Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, USA.
Cell. 2012 Sep 28;151(1):206-20. doi: 10.1016/j.cell.2012.07.035. Epub 2012 Sep 12.
Heart development is exquisitely sensitive to the precise temporal regulation of thousands of genes that govern developmental decisions during differentiation. However, we currently lack a detailed understanding of how chromatin and gene expression patterns are coordinated during developmental transitions in the cardiac lineage. Here, we interrogated the transcriptome and several histone modifications across the genome during defined stages of cardiac differentiation. We find distinct chromatin patterns that are coordinated with stage-specific expression of functionally related genes, including many human disease-associated genes. Moreover, we discover a novel preactivation chromatin pattern at the promoters of genes associated with heart development and cardiac function. We further identify stage-specific distal enhancer elements and find enriched DNA binding motifs within these regions that predict sets of transcription factors that orchestrate cardiac differentiation. Together, these findings form a basis for understanding developmentally regulated chromatin transitions during lineage commitment and the molecular etiology of congenital heart disease.
心脏发育对数千个基因的精确时间调控极为敏感，这些基因在分化过程中决定着发育决策。然而，我们目前还不清楚染色质和基因表达模式在心脏谱系的发育转变过程中是如何协调的。在这里，我们在心脏分化的特定阶段检测了基因组中的转录组和几种组蛋白修饰。我们发现了与功能相关基因（包括许多与人类疾病相关的基因）的特定阶段特异性表达相协调的独特染色质模式。此外，我们在与心脏发育和心脏功能相关的基因的启动子处发现了一种新的预激活染色质模式。我们进一步鉴定了特定阶段的远端增强子元件，并在这些区域内发现了丰富的 DNA 结合基序，这些基序预测了协调心脏分化的转录因子集合。总之，这些发现为理解谱系决定和先天性心脏病的分子病因学过程中发育调控的染色质转变奠定了基础。
