来自美国加州大学旧金山分校格拉斯通研究所的研究人员揭示出利用胚胎心脏细胞构建出完全功能性的心脏所需的上百个基因开关的精确开闭次序和时间。这项发现有助于对一些人先天性心脏病的遗传基础产生新的认识。
在一项刊登于Cell期刊上的研究中，研究人员利用干细胞技术、下一代DNA测序和计算工具来将心脏细胞如何变成心脏的“基因组蓝图”拼接在一起。这些发现提供新的希望来对抗威胁生命的心脏缺陷，如心律不齐和室间隔缺损(ventricular septal defect)。
在这项研究中，研究人员获取来自小鼠的胚胎干细胞，然后通过在盘碟中模拟胚胎发育而让它们分化为跳动的心脏细胞。接着，他们提取发育中的心脏细胞和成熟的心脏细胞内的DNA，并利用一种被称作ChIP-seq的高级基因测序技术来观察DNA中的表观遗传标记。
论文共同第一作者Jeffrey Alexander说，“但是发现这些标记只是成功的一半，因此我们接着不得不破解它们编码心脏形成的哪些方面。为此，我们利用格拉斯通研究所生物信息学核心(Gladstone Bioinformatics Core)的计算能力。这允许我们获得基因测序中所收集的大量数据，并且将这些数据组装成一种可读的和有意义的将心脏细胞如何变成心脏的蓝图。”
研究人员获得了一些意料之外的发现。他们发现在心脏细胞中，一组基因似乎以一种协作的方式一起发挥作用：在胚胎发育的指定时间，这组基因一起开启和关闭。他们不仅鉴定出很多参与心脏形成的新基因，而且也精确地确定地这些新发现的基因如何与之前已知的基因相互作用。
绘制出心脏的基因组蓝图对人类健康的影响非常深远。鉴于研究人员理解这些基因如何控制心脏形成，他们能够开始将心脏病如何破坏这种调节的细节汇聚在一起。最终，他们能够寻找疗法来阻止、中断或抵消患有先天性心脏病的儿童体内这种调节遭到的破坏。
Dynamic and Coordinated Epigenetic Regulation of Developmental Transitions in the Cardiac Lineage
Joseph A. Wamstad, Jeffrey M. Alexander, Rebecca M. Truty, Avanti Shrikumar, Fugen Li, Kirsten E. Eilertson, Huiming Ding, John N. Wylie, Alexander R. Pico, John A. Capra, Genevieve Erwin, Steven J. Kattman, Gordon M. Keller, Deepak Srivastava, Stuart S. Levine, Katherine S. Pollard, Alisha K. Holloway, Laurie A. Boyer, Benoit G. Bruneau
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.
文献链接：Dynamic and Coordinated Epigenetic Regulation of Developmental Transitions in the Cardiac Lineage
