Unraveling mechanisms of genome regulation to understand and improve human health

摘要 人体是通过紧密协调的基因表达模式来构建的 在胚胎和出生后的发育过程中。基因调控过程中的扰动 发展被认为是自然选择的主要底物，并可能对 人类形态的进化。对人类雕塑做出贡献的分子过程 我们四肢和大脑的特定功能，当一个关键基因 或者调控序列受到影响。胚胎发育过程中的基因调控缺陷可能 导致各种结构和功能缺陷，如先天性心脏缺陷，口腔面部 裂隙，或神经功能障碍。在不容易观察到出生缺陷的情况下 相反，个人在以后的生活中可能容易患上各种疾病，包括糖尿病或 癌症。虽然我们对蛋白质编码基因的遗传密码的了解使我们能够 对疾病的预测可能会使我们对其余部分中编码的信息了解有限 我们的基因组阻止了这样的预测和因果分配。在过去几年里 基因组在组织和发育阶段特定背景下的功能注释有 揭示了50多万个潜在的监管要素。我们和其他人已经证明了 与疾病和特定组织表型相关的变体富含调控 在这些组织中或在其发育过程中活跃的序列。这一次尤其是 对于与颅面和心脏发育相关的缺陷有很好的治疗效果。拟议的工作旨在建立 在这些注释上识别由这些组织特异性调控基因控制的基因 序列和这些序列中变异的后果。使用培养物和有机化合物 早期人类心脏发育的模型，我们的目标是剖析 在先天性心脏病中建立心脏和功能障碍。

Summary The human body is constructed during through tightly orchestrated patterns of gene expression during embryonic and postnatal development. Perturbations in gene regulation during development are thought to be a major substrate for natural selection and have likely contributed to the evolution of the human form. The molecular processes that contributed to sculpting human specific features of our limbs and brains, can have deleterious consequences when a critical gene or regulatory sequence is affected. Defective gene regulation during embryonic development can result in a variety of structural and functional defects such as congenital heart defects, orofacial clefting, or neurological dysfunction. In cases where a birth defect is not readily observed the individual may be instead be predisposed to various diseases later in life including diabetes or cancer. While our understanding of the genetic code for protein coding genes allows us to make predictions about disease risk our limited understanding of the information encoded in the rest of our genome prevents such predictions and causative assignments. Over the past several years functional annotations of the genome in tissue and developmental stage specific contexts have revealed over half a million potential regulatory elements. We and others have shown that variants linked to diseases and phenotypes of particular tissues are enriched in regulatory sequences that are active in those tissues or during their development. This has been particularly fruitful for defects related to craniofacial and heart development. The work proposed aims to build on these annotations to identify the genes that are controlled by these tissue-specific regulatory sequences and the consequences of variation in those sequences. Using culture and organoid models of early human cardiac development we aim to dissect the regulatory architecture that build the heart and malfunctions in congenital heart defects.