Stimulating Wnt signaling reveals context-dependent genetic effects on gene regulation in primary human neural progenitors

IF 21.2 1区 医学 Q1 NEUROSCIENCES Nature neuroscience Pub Date : 2024-09-30 DOI:10.1038/s41593-024-01773-6
Nana Matoba, Brandon D. Le, Jordan M. Valone, Justin M. Wolter, Jessica T. Mory, Dan Liang, Nil Aygün, K. Alaine Broadaway, Marielle L. Bond, Karen L. Mohlke, Mark J. Zylka, Michael I. Love, Jason L. Stein
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Abstract

Gene regulatory effects have been difficult to detect at many non-coding loci associated with brain-related traits, likely because some genetic variants have distinct functions in specific contexts. To explore context-dependent gene regulation, we measured chromatin accessibility and gene expression after activation of the canonical Wnt pathway in primary human neural progenitors (n = 82 donors). We found that TCF/LEF motifs and brain-structure-associated and neuropsychiatric-disorder-associated variants were enriched within Wnt-responsive regulatory elements. Genetically influenced regulatory elements were enriched in genomic regions under positive selection along the human lineage. Wnt pathway stimulation increased detection of genetically influenced regulatory elements/genes by 66%/53% and enabled identification of 397 regulatory elements primed to regulate gene expression. Stimulation also increased identification of shared genetic effects on molecular and complex brain traits by up to 70%, suggesting that genetic variant function during neurodevelopmental patterning can lead to differences in adult brain and behavioral traits. Matoba, Le, Valone et al. characterized context-dependent genetic effects on gene regulatory activity during Wnt stimulation, finding that genetic variant function during neurodevelopment patterning can lead to differences in adult brain traits.

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刺激 Wnt 信号揭示了人类原代神经祖细胞基因调控的环境依赖性遗传效应
在许多与大脑相关性状有关的非编码基因座上很难检测到基因调控效应,这可能是因为一些基因变异在特定环境中具有不同的功能。为了探索依赖于环境的基因调控,我们测量了原代人类神经祖细胞(n = 82 名供体)激活典型 Wnt 通路后的染色质可及性和基因表达。我们发现,在 Wnt 反应调控元件中富集了 TCF/LEF 矩阵以及与大脑结构相关的变体和与神经精神障碍相关的变体。受基因影响的调控元件富集在人类血统中正选择的基因组区域。Wnt通路刺激使受基因影响的调控元件/基因的检测率提高了66%/53%,并能识别出397个调控基因表达的调控元件。刺激还使对分子和复杂大脑特征的共同遗传效应的识别率提高了 70%,这表明神经发育模式化过程中的遗传变异功能可导致成年大脑和行为特征的差异。
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来源期刊
Nature neuroscience
Nature neuroscience 医学-神经科学
CiteScore
38.60
自引率
1.20%
发文量
212
审稿时长
1 months
期刊介绍: Nature Neuroscience, a multidisciplinary journal, publishes papers of the utmost quality and significance across all realms of neuroscience. The editors welcome contributions spanning molecular, cellular, systems, and cognitive neuroscience, along with psychophysics, computational modeling, and nervous system disorders. While no area is off-limits, studies offering fundamental insights into nervous system function receive priority. The journal offers high visibility to both readers and authors, fostering interdisciplinary communication and accessibility to a broad audience. It maintains high standards of copy editing and production, rigorous peer review, rapid publication, and operates independently from academic societies and other vested interests. In addition to primary research, Nature Neuroscience features news and views, reviews, editorials, commentaries, perspectives, book reviews, and correspondence, aiming to serve as the voice of the global neuroscience community.
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