Unraveling mechanisms of genome regulation to understand and improve human health

总结 人体是通过基因表达的紧密协调模式构建的 在胚胎和出生后的发育过程中。基因调控中的扰动 发育被认为是自然选择的主要基质， 人类形态的进化。塑造人类的分子过程 我们的四肢和大脑的特定特征，当一个关键基因 或调控序列受到影响。胚胎发育过程中基因调控的缺陷， 导致多种结构和功能缺陷，例如先天性心脏缺陷、口面部缺陷、 裂缝或神经功能障碍如果不容易观察到出生缺陷， 个体在以后生活中可能反而易患各种疾病， 癌虽然我们对蛋白质编码基因的遗传密码的理解使我们能够 对疾病的预测可能会使我们对编码在其余部分中的信息的理解有限。 我们的基因组阻止了这样的预测和因果分配。在过去几年中 基因组在组织和发育阶段特异性背景下的功能注释 揭示了超过50万个潜在的监管要素。我们和其他人已经证明， 与特定组织的疾病和表型相关的变异体富含调节性蛋白。 在这些组织中或在它们的发育过程中具有活性的序列。这尤其是 对颅面和心脏发育相关的缺陷富有成效。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节基因控制的基因， 序列以及这些序列变异的后果。利用培养物和类器官 早期人类心脏发育的模型，我们的目标是剖析调控结构， 先天性心脏病的心脏构造和功能障碍。

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.