Transcriptional enhancers in human neuronal differentiation provide clues to neuronal disorders.

IF 6.2 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Reports Pub Date : 2025-03-01 Epub Date: 2025-02-13 DOI:10.1038/s44319-025-00372-1

Masahito Yoshihara, Andrea Coschiera, Jörg A Bachmann, Mariangela Pucci, Haonan Li, Shruti Bhagat, Yasuhiro Murakawa, Jere Weltner, Eeva-Mari Jouhilahti, Peter Swoboda, Pelin Sahlén, Juha Kere

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Abstract

Genome-wide association studies (GWASs) have identified thousands of variants associated with complex phenotypes, including neuropsychiatric disorders. To better understand their pathogenesis, it is necessary to identify the functional roles of these variants, which are largely located in non-coding DNA regions. Here, we employ a human mesencephalic neuronal cell differentiation model, LUHMES, with sensitive and high-resolution methods to discover enhancers (NET-CAGE), perform DNA conformation analysis (Capture Hi-C) to link enhancers to their target genes, and finally validate selected interactions. We expand the number of known enhancers active in differentiating human LUHMES neurons to 47,350, and find overlap with GWAS variants for Parkinson's disease and schizophrenia. Our findings reveal a fine-tuned regulation of human neuronal differentiation, even between adjacent developmental stages; provide a valuable resource for further studies on neuronal development, regulation, and disorders; and emphasize the importance of exploring the vast regulatory potential of non-coding DNA and enhancers.

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人类神经元分化中的转录增强子为神经元疾病提供了线索。

全基因组关联研究（GWASs）已经确定了数千种与复杂表型相关的变异，包括神经精神疾病。为了更好地了解其发病机制，有必要确定这些变异的功能作用，这些变异主要位于非编码DNA区域。在这里，我们采用人类中脑神经元细胞分化模型LUHMES，用敏感和高分辨率的方法发现增强子（NET-CAGE），进行DNA构象分析（Capture Hi-C），将增强子与其靶基因联系起来，并最终验证所选择的相互作用。我们将已知的在分化人类LUHMES神经元中活跃的增强子数量扩大到47350个，并发现与帕金森病和精神分裂症的GWAS变体重叠。我们的发现揭示了人类神经元分化的精细调节，甚至在相邻的发育阶段之间；为进一步研究神经元的发育、调节和紊乱提供宝贵的资源；并强调探索非编码DNA和增强子的巨大调控潜力的重要性。

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

期刊介绍： EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry.