美国杰克逊实验室Laura G. Reinholdt等研究人员合作通过绘制遗传变异对染色质状态和基因表达的影响，揭示了控制基态多能性的基因座。相关论文于2020年8月13日在线发表在《细胞—干细胞》杂志上。

据研究人员介绍，在LIF存在下培养的小鼠胚胎干细胞（mESC）处于基态，其具有高度活跃的多能性相关转录和表观遗传回路。但是，在缺乏ERK1/2和GSK3抑制的情况下，某些近交细胞株背景的基态多能性不稳定。

使用无偏遗传方法，研究人员通过对170种遗传异源mESC中的基因表达和染色质可及性进行了检测，从而剖析了这种对细胞外信号不同反应的基础。研究人员绘制了成千上万个影响染色质可及性和/或转录本丰度的基因座，包括10个QTL热点，其中单个位点的遗传变异协调了整个基因组中基因的调控。

对于单个热点，研究人员确定了Lifr上游约10 kb的单个增强子变体，其与染色质可及性相关，并介导了影响多能性的一系列分子事件。研究人员通过相互等位基因互换验证因果关系，证明了在稳定体外多能状态的基因调控网络中非编码变异的功能后果。

附：英文原文

Title: Mapping the Effects of Genetic Variation on Chromatin State and Gene Expression Reveals Loci That Control Ground State Pluripotency

Author: Daniel A. Skelly, Anne Czechanski, Candice Byers, Selcan Aydin, Catrina Spruce, Chris Olivier, Kwangbom Choi, Daniel M. Gatti, Narayanan Raghupathy, Gregory R. Keele, Alexander Stanton, Matthew Vincent, Stephanie Dion, Ian Greenstein, Matthew Pankratz, Devin K. Porter, Whitney Martin, Callan O’Connor, Wenning Qin, Alison H. Harrill, Ted Choi, Gary A. Churchill, Steven C. Munger, Christopher L. Baker, Laura G. Reinholdt

Issue&Volume: 2020-08-13

Abstract: Mouse embryonic stem cells (mESCs) cultured in the presence of LIF occupy a groundstate with highly active pluripotency-associated transcriptional and epigenetic circuitry.However, ground state pluripotency in some inbred strain backgrounds is unstable inthe absence of ERK1/2 and GSK3 inhibition. Using an unbiased genetic approach, wedissect the basis of this divergent response to extracellular cues by profiling geneexpression and chromatin accessibility in 170 genetically heterogeneous mESCs. Wemap thousands of loci affecting chromatin accessibility and/or transcript abundance,including 10 QTL hotspots where genetic variation at a single locus coordinates theregulation of genes throughout the genome. For one hotspot, we identify a single enhancervariant ～10 kb upstream of Lifr associated with chromatin accessibility and mediating a cascade of molecular eventsaffecting pluripotency. We validate causation through reciprocal allele swaps, demonstratingthe functional consequences of noncoding variation in gene regulatory networks thatstabilize pluripotent states in vitro.

DOI: 10.1016/j.stem.2020.07.005

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30343-X