脳の初期遺伝子発達のマッピング(Early genetic development of the brain mapped)

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2024-05-02 カロリンスカ研究所(KI)

カロリンスカ研究所の研究者が、脳の初期発達のアトラスを発表しました。アトラスは、子供の脳腫瘍の発症原因の解明や新しい治療法の発見に役立ちます。国際的な研究チームは、妊娠6週から13週の胚発育をマッピングしました。この研究は、脳全体の遺伝子調節に焦点を当てた初の包括的な研究で、脳のすべての領域を比較しています。研究は、スウェーデンの「ヒト発生細胞アトラス」プロジェクトの一環で、脳、心臓、肺などの遺伝子発達を研究しています。このアトラスを使い、子供の脳がんの原因解明に取り組んでいます。

<関連情報>

ヒトの第一期神経発達におけるクロマチンアクセシビリティ Chromatin accessibility during human first-trimester neurodevelopment

Camiel C. A. Mannens,Lijuan Hu,Peter Lönnerberg,Marijn Schipper,Caleb C. Reagor,Xiaofei Li,Xiaoling He,Roger A. Barker,Erik Sundström,Danielle Posthuma & Sten Linnarsson
Nature  Published:01 May 2024
DOI:https://doi.org/10.1038/s41586-024-07234-1

脳の初期遺伝子発達のマッピング(Early genetic development of the brain mapped)

Abstract

The human brain develops through a tightly organized cascade of patterning events, induced by transcription factor expression and changes in chromatin accessibility. Although gene expression across the developing brain has been described at single-cell resolution1, similar atlases of chromatin accessibility have been primarily focused on the forebrain2,3,4. Here we describe chromatin accessibility and paired gene expression across the entire developing human brain during the first trimester (6–13 weeks after conception). We defined 135 clusters and used multiomic measurements to link candidate cis-regulatory elements to gene expression. The number of accessible regions increased both with age and along neuronal differentiation. Using a convolutional neural network, we identified putative functional transcription factor-binding sites in enhancers characterizing neuronal subtypes. We applied this model to cis-regulatory elements linked to ESRRB to elucidate its activation mechanism in the Purkinje cell lineage. Finally, by linking disease-associated single nucleotide polymorphisms to cis-regulatory elements, we validated putative pathogenic mechanisms in several diseases and identified midbrain-derived GABAergic neurons as being the most vulnerable to major depressive disorder-related mutations. Our findings provide a more detailed view of key gene regulatory mechanisms underlying the emergence of brain cell types during the first trimester and a comprehensive reference for future studies related to human neurodevelopment.

細胞遺伝子工学
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