Wnt activity reveals context-specific genetic effects on gene regulation in neural progenitors.
Wnt activity reveals context-specific genetic effects on gene regulation in neural progenitors.
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Wnt 活性揭示了神经祖细胞基因调控的特定遗传效应。
DOI：
10.1101/2023.02.07.527357
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Stein,JasonL
中科院分区：
文献类型：
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作者：
Matoba,Nana;Le,BrandonD;Valone,JordanM;Wolter,JustinM;Mory,Jessica;Liang,Dan;Aygün,Nil;Broadaway,KAlaine;Bond,MarielleL;Mohlke,KarenL;Zylka,MarkJ;Love,MichaelI;Stein,JasonL
在大体积死后脑组织中的基因调控效应在许多非编码脑性状相关位点未被检测到。我们假设，在刺激发育信号通路的过程中，环境特异性遗传变异功能可以解释额外的调控机制。我们测量了来自82个供体的原代人神经祖细胞中经典Wnt通路激活后的染色质可及性和基因表达。TCF/LEF基序，脑结构，和神经精神疾病相关的变体内Wnt反应的调节元件（RE）丰富。遗传影响的RE富集在基因组区域的正选择沿着人类谱系。Wnt通路的刺激增加了66.2%/52.7%的遗传影响的RE/基因的检测，并导致397个RE的鉴定，这些RE对基因表达有影响。上下文特异性分子数量性状基因座增加大脑性状共定位高达70%，这表明在早期神经发育模式的遗传变异效应导致成人大脑和行为特征的差异。
Gene regulatory effects in bulk-post mortem brain tissues are undetected at many non-coding brain trait-associated loci. We hypothesized that context-specific genetic variant function during stimulation of a developmental signaling pathway would explain additional regulatory mechanisms. We measured chromatin accessibility and gene expression following activation of the canonical Wnt pathway in primary human neural progenitors from 82 donors. TCF/LEF motifs, brain structure-, and neuropsychiatric disorder-associated variants were enriched within Wnt-responsive regulatory elements (REs). Genetically influenced REs were enriched in genomic regions under positive selection along the human lineage. Stimulation of the Wnt pathway increased the detection of genetically influenced REs/genes by 66.2%/52.7%, and led to the identification of 397 REs primed for effects on gene expression. Context-specific molecular quantitative trait loci increased brain-trait colocalizations by up to 70%, suggesting that genetic variant effects during early neurodevelopmental patterning lead to differences in adult brain and behavioral traits.