Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98101;
Department of Ophthalmology, University of Washington School of Medicine, Seattle, WA 98101.
Proc Natl Acad Sci U S A. 2020 Apr 21;117(16):9001-9012. doi: 10.1073/pnas.1922501117. Epub 2020 Apr 7.
The interplay of transcription factors and -regulatory elements (CREs) orchestrates the dynamic and diverse genetic programs that assemble the human central nervous system (CNS) during development and maintain its function throughout life. Genetic variation within CREs plays a central role in phenotypic variation in complex traits including the risk of developing disease. We took advantage of the retina, a well-characterized region of the CNS known to be affected by pathogenic variants in CREs, to establish a roadmap for characterizing regulatory variation in the human CNS. This comprehensive analysis of tissue-specific regulatory elements, transcription factor binding, and gene expression programs in three regions of the human visual system (retina, macula, and retinal pigment epithelium/choroid) reveals features of regulatory element evolution that shape tissue-specific gene expression programs and defines regulatory elements with the potential to contribute to Mendelian and complex disorders of human vision.
转录因子和调控元件 (CREs) 的相互作用协调了动态和多样化的基因程序，这些程序在发育过程中组装了人类中枢神经系统 (CNS)，并在整个生命周期中维持其功能。CRE 内的遗传变异在包括疾病风险在内的复杂特征的表型变异中起着核心作用。我们利用视网膜（CNS 的一个特征明确的区域，已知其受到 CRE 中致病性变异的影响）来制定人类 CNS 中调控变异的特征描述路线图。对人类视觉系统三个区域（视网膜、黄斑和视网膜色素上皮/脉络膜）的组织特异性调控元件、转录因子结合和基因表达程序进行的全面分析揭示了调控元件进化的特征，这些特征塑造了组织特异性基因表达程序，并定义了具有潜在能力的调控元件，以促进人类视觉的孟德尔和复杂疾病。
