Chatterjee Sumantra, Kapoor Ashish, Akiyama Jennifer A, Auer Dallas R, Lee Dongwon, Gabriel Stacey, Berrios Courtney, Pennacchio Len A, Chakravarti Aravinda
Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Cell. 2016 Oct 6;167(2):355-368.e10. doi: 10.1016/j.cell.2016.09.005. Epub 2016 Sep 29.
Common sequence variants in cis-regulatory elements (CREs) are suspected etiological causes of complex disorders. We previously identified an intronic enhancer variant in the RET gene disrupting SOX10 binding and increasing Hirschsprung disease (HSCR) risk 4-fold. We now show that two other functionally independent CRE variants, one binding Gata2 and the other binding Rarb, also reduce Ret expression and increase risk 2- and 1.7-fold. By studying human and mouse fetal gut tissues and cell lines, we demonstrate that reduced RET expression propagates throughout its gene regulatory network, exerting effects on both its positive and negative feedback components. We also provide evidence that the presence of a combination of CRE variants synergistically reduces RET expression and its effects throughout the GRN. These studies show how the effects of functionally independent non-coding variants in a coordinated gene regulatory network amplify their individually small effects, providing a model for complex disorders.
顺式调控元件（CREs）中的常见序列变异被怀疑是复杂疾病的病因。我们之前在RET基因中鉴定出一个内含子增强子变异，它破坏了SOX10的结合并将先天性巨结肠病（HSCR）风险增加了4倍。我们现在表明，另外两个功能独立的CRE变异，一个结合Gata2，另一个结合Rarb，也会降低Ret表达并将风险分别增加2倍和1.7倍。通过研究人类和小鼠胎儿肠道组织及细胞系，我们证明Ret表达降低会在其整个基因调控网络中传播，对其正反馈和负反馈成分均产生影响。我们还提供证据表明，CRE变异组合的存在会协同降低Ret表达及其在基因调控网络中的作用。这些研究展示了在一个协调的基因调控网络中，功能独立的非编码变异的作用如何放大其各自微小的效应，为复杂疾病提供了一个模型。
