Unbiased identification of regulatory region-target gene pairs in human adipocytes

人类基因组包含大量假定的调控元件和生理性状相关的单倍型；其中大部分位于非编码区，包含一些关联信号和遗传变异。在性状连锁单倍型中预测细胞类型特异性功能调控元件及其靶基因是一个主要的挑战。这种调控区域-基因对的复杂性是由细胞特异性生化相容性和/或三维基因组组织驱动的。集中的细胞类型特异性功能研究，以验证选定的调控区域的靶基因是有限的，往往缺乏规模。我们需要的是对特定细胞类型的调控区域进行高通量实验操作，结合基因组结构作图（GAM）3，以绘制重要区域/基因相互作用，并了解3D染色质组织的贡献。人类白色脂肪组织（WAT）是一个高度动态的代谢/内分泌器官，在营养、代谢和环境信号的反应中起着能量缓冲的作用。由脂肪祖细胞（APs）产生的脂肪细胞（ADs）是WAT的主要组成部分，它们的比例和功能与血糖、脂质和人体测量学特征密切相关。为了进一步了解人类脂肪细胞生物学及其在全身代谢中的作用，需要研究调节这种AD可塑性（即细胞命运和功能）的遗传回路。然而，目前的高通量方法往往缺乏特异性，而专注于特定位点的方法缺乏规模。

The human genome contains a vast number of putative regulatory elements and physiological trait linked haplotypes; the majority of which lie within non-coding regions and contain several association signals and genetic variants. Prediction of cell type-specific functional regulatory elements and their target genes within trait linked haplotypes is a major challenge. This complexity of regulatory region-gene pairs is driven by cell specific biochemical compatibility and/or 3D genome organisation. Focussed cell type-specific functional studies for validating target genes of selected regulatory regions have been limited and often lack scale. What is needed are highthroughput experimental manipulations of regulatory regions, combined with genome architecture mapping (GAM)3, in specific cell-types to map out important region/gene interactions and understand the contribution of 3D chromatin organisation. Human white adipose tissue (WAT) is a highly dynamic metabolic/endocrine organ functioning as an energy buffer in response to nutritional, metabolic, and environmental cues. Adipocytes (ADs), arising from adipose progenitors (APs), are the major constituent of WAT and their proportion and function are strongly associated with glycaemic, lipid, and anthropometric traits. Investigation of the genetic circuitry regulating this AD plasticity (i.e., cell fate and function) is required to further our understanding of human adipocyte biology and its role in systemic metabolism. However, current high throughput approaches often lack specificity whilst approaches focussed on specific loci lack scale.