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DNA methylation atlas of the mouse brain at single-cell resolution

机译：单细胞分辨率下小鼠脑的DNA甲基化地图集

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摘要

Mammalian brain cells show remarkable diversity in gene expression, anatomy and function, yet the regulatory DNA landscape underlying this extensive heterogeneity is poorly understood. Here we carry out a comprehensive assessment of the epigenomes of mouse brain cell types by applying single-nucleus DNA methylation sequencing~(1,2)to profile 103,982 nuclei (including 95,815 neurons and 8,167 non-neuronal cells) from 45 regions of the mouse cortex, hippocampus, striatum, pallidum and olfactory areas. We identified 161 cell clusters with distinct spatial locations and projection targets. We constructed taxonomies of these epigenetic types, annotated with signature genes, regulatory elements and transcription factors. These features indicate the potential regulatory landscape supporting the assignment of putative cell types and reveal repetitive usage of regulators in excitatory and inhibitory cells for determining subtypes. The DNA methylation landscape of excitatory neurons in the cortex and hippocampus varied continuously along spatial gradients. Using this deep dataset, we constructed an artificial neural network model that precisely predicts single neuron cell-type identity and brain area spatial location. Integration of high-resolution DNA methylomes with single-nucleus chromatin accessibility data~(3)enabled prediction of high-confidence enhancer-gene interactions for all identified cell types, which were subsequently validated by cell-type-specific chromatin conformation capture experiments~(4). By combining multi-omic datasets (DNA methylation, chromatin contacts, and open chromatin) from single nuclei and annotating the regulatory genome of hundreds of cell types in the mouse brain, our DNA methylation atlas establishes the epigenetic basis for neuronal diversity and spatial organization throughout the mouse cerebrum.
机译：哺乳动物脑细胞在基因表达，解剖学和功能方面表现出显着的多样性，但这种广泛的异质性下面的调节性DNA景观很差。在这里，我们通过将单核DNA甲基化测序〜（1,2）施加来自小鼠的45个区域的单核DNA甲基化测序〜（1,2）来综合评估小鼠脑细胞类型的表观脑细胞类型。（包括95,815个神经元和8,167个非神经元细胞）皮质，海马，纹状体，苍白和嗅觉区域。我们确定了具有不同空间位置和投影目标的161个细胞簇。我们构建了这些表观遗传类型的分类学，用签名基因，监管要素和转录因子注释。这些特征表明潜在的调节景观支持推定细胞类型的分配，并揭示兴奋性和抑制细胞中调节剂的重复使用，以确定亚型。皮质和海马兴奋性神经元的DNA甲基化景观沿空间梯度连续变化。使用该深度数据集，我们构建了一种人工神经网络模型，精确地预测单个神经元细胞型同一性和脑区域空间位置。高分辨率DNA甲基μ与单核染色质无障碍数据的集成〜（3）使所有识别的细胞类型的高置信增强剂 - 基因相互作用的预测，随后通过细胞型特异性染色质构象捕获实验验证〜（ 4）。通过将多OMIC数据集（DNA甲基化，染色质触点和开口染色质）与单一核相结合并注释小鼠脑中的数百个细胞类型的调节基因组，我们的DNA甲基化地图集为整个神经元多样性和空间组织的表观遗传基础小鼠大脑。

著录项

  • 来源
    《Nature》 |2021年第7879期|120-128|共9页
  • 作者

    Hanqing Liu; Jingtian Zhou; Wei Tian; Chongyuan Luo; Anna Bartlett; Andrew Aldridge; Jacinta Lucero; Julia K Osteen; Joseph R Nery; Huaming Chen; Angeline Rivkin; Rosa G Castanon; Ben Clock; Yang Eric Li; Xiaomeng Hou; Olivier B Poirion; Sebastian Preissl; Antonio Pinto-Duarte; Carolyn OConnor; Lara Boggeman; Conor Fitzpatrick; Michael Nunn; Eran A Mukamel; Zhuzhu Zhang; Edward M Callaway; Bing Ren; Jesse R Dixon; M Margarita Behrens; Joseph R Ecker;

  • 作者单位

    Genomic Analysis Laboratory The Salk Institute for Biological Studies|Division of Biological Sciences University of California;

    Genomic Analysis Laboratory The Salk Institute for Biological Studies|Bioinformatics and Systems Biology Program University of California;

    Genomic Analysis Laboratory The Salk Institute for Biological Studies;

    Genomic Analysis Laboratory The Salk Institute for Biological Studies|Department of Human Genetics University of California Los Angeles;

    Genomic Analysis Laboratory The Salk Institute for Biological Studies;

    Genomic Analysis Laboratory The Salk Institute for Biological Studies;

    Computational Neurobiology Laboratory The Salk Institute for Biological Studies;

    Computational Neurobiology Laboratory The Salk Institute for Biological Studies;

    Genomic Analysis Laboratory The Salk Institute for Biological Studies;

    Genomic Analysis Laboratory The Salk Institute for Biological Studies;

    Genomic Analysis Laboratory The Salk Institute for Biological Studies;

    Genomic Analysis Laboratory The Salk Institute for Biological Studies;

    Peptide Biology Laboratory The Salk Institute for Biological Studies;

    Ludwig Institute for Cancer Research;

    Center for Epigenomics University of California San Diego School of Medicine|Department of Cellular and Molecular Medicine University of California San Diego School of Medicine|Institute of Genomic Medicine University of California San Diego School of Medicine|Moores Cancer Center University of California San Diego School of Medicine;

    Center for Epigenomics University of California San Diego School of Medicine|Department of Cellular and Molecular Medicine University of California San Diego School of Medicine|Institute of Genomic Medicine University of California San Diego School of Medicine|Moores Cancer Center University of California San Diego School of Medicine;

    Center for Epigenomics University of California San Diego School of Medicine|Department of Cellular and Molecular Medicine University of California San Diego School of Medicine|Institute of Genomic Medicine University of California San Diego School of Medicine|Moores Cancer Center University of California San Diego School of Medicine;

    Computational Neurobiology Laboratory The Salk Institute for Biological Studies;

    Flow Cytometry Core Facility The Salk Institute for Biological Studies;

    Flow Cytometry Core Facility The Salk Institute for Biological Studies;

    Flow Cytometry Core Facility The Salk Institute for Biological Studies;

    Genomic Analysis Laboratory The Salk Institute for Biological Studies;

    Department of Cognitive Science University of California;

    Genomic Analysis Laboratory The Salk Institute for Biological Studies;

    Systems Neurobiology Laboratories The Salk Institute for Biological Studies;

    Ludwig Institute for Cancer Research|Center for Epigenomics University of California San Diego School of Medicine|Department of Cellular and Molecular Medicine University of California San Diego School of Medicine|Institute of Genomic Medicine University of California San Diego School of Medicine|Moores Cancer Center University of California San Diego School of Medicine;

    Peptide Biology Laboratory The Salk Institute for Biological Studies;

    Computational Neurobiology Laboratory The Salk Institute for Biological Studies;

    Genomic Analysis Laboratory The Salk Institute for Biological Studies|Howard Hughes Medical Institute The Salk Institute for Biological Studies;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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