Epigenomic mapping approaches for cell-type classification in the brain

用于大脑细胞类型分类的表观基因组图谱方法

• 批准号: 9107493
• 负责人: M MARGARITA BEHRENS
• 金额: $ 91.33万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-26 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9107493
• 关键词: Adult; Age-associated memory impairment; Alzheimer' s Disease; Atlases; BRAIN initiative; Base of the Brain; Behavioral; Brain; Brain Mapping; Brain region; Cataloging; Catalogs; Categories; Cells; Censuses; Characteristics; Classification; Cortical Cell Layer; Cytosine; DNA; DNA Methylation; Data; Detection; Development; Epigenetic Process; Equipment and supply inventories; Evaluation; Foundations; Gene Expression; Genome; Genomics; Goals; Human; In Situ; Individual; Label; Learning; Location; Maps; Memory; Methylation; Mitotic; Modification; Molecular; Mus; Neuroglia; Neuronal Plasticity; Neurons; Parvalbumins; Pattern; Physiological; Population; Primary Cell Cultures; Primates; Process; Reading; Research; Resolution; Rodent; Schizophrenia; Slice; Specificity; Structure; Systems Biology; Technology; Testing; base; bisulfite; brain cell; cell type; design; epigenomics; frontal lobe; genome-wide; methylome; nervous system disorder; neurochemistry; novel; public health relevance

 DESCRIPTION (provided by applicant): Understanding the exact cell-type composition in brain regions is fundamental to integrating physiological, behavioral and neurochemical data to systematically understand the brain structure and function. At present, although the major categories of cell-types present in brain have been defined, the different subtypes within these categories, as well as their location and connectivity are far from understood. DNA methylation (mC) is a stable covalent modification that persists in post-mitotic cells throughout their lifetim, defining their cellular identity. It was recently demonstrated that mC patterns in brain are highly dynamic throughout development, and that there are clear differences between the major types of cells i.e., neurons and glia, in the rodent and human cortex. These analyses have been taken a step further and have produced data at the cell-type level that shows that each neuronal type carry specific mC signatures in their genomes that define the population they belong to. These results now open the possibility of producing a catalog of cell-types in brain defined by methylome signatures. This proposal will utilize this cell-type-specific base-resolution methylome data to produce complete maps of cell-types in the rodent brain in situ, and by this means develop a systematic inventory and census of cell types in the brain based on an integrated view of their molecular identity. Based on preliminary results showing clear-cut differences between the methylomes of specific neuronal types, we propose to use cutting edge technology to discover and test specific differentially methylated regions that define, at the molecular level, cell-populations in the frontal cortex of mice. The results obtained will be made publically available, and will serve as foundation to produce a complete genomic census of cell-types in a brain region that can be scaled to the whole brain. If successful, the approach could be ultimately tested in the primate brain. This proposal is thus responsive to RFA MH-14-215 "BRAIN Initiative: Transformative Approaches for Cell-Type Classification in the Brain (U01)".

 描述（由申请人提供）：了解大脑区域的确切细胞类型组成对于整合生理、行为和神经化学数据以系统地了解大脑结构和功能至关重要。目前，尽管大脑中存在的细胞类型的主要类别已经被定义，但这些类别中的不同亚型以及它们的位置和连接性还远未了解。 DNA 甲基化 (mC) 是一种稳定的共价修饰，在有丝分裂后细胞的整个生命周期中持续存在，从而定义了它们的细胞身份。最近证明大脑中的 mC 模式高度 整个发育过程中的动态变化，并且啮齿动物和人类皮质中的主要细胞类型（即神经元和神经胶质细胞）之间存在明显差异。这些分析更进一步，产生了细胞类型水平的数据，表明每种神经元类型在其基因组中携带特定的 mC 特征，这些特征定义了它们所属的群体。这些结果现在开启了产生由甲基化组特征定义的大脑细胞类型目录的可能性。该提案将利用这种细胞类型特异性碱基分辨率甲基化组数据来原位生成啮齿动物大脑中细胞类型的完整图谱，并通过这种方式根据分子身份的综合观点对大脑中的细胞类型进行系统的清查和普查。基于显示特定神经元类型的甲基化组之间明显差异的初步结果，我们建议使用尖端技术来发现和测试特定的差异甲基化区域，这些区域在分子水平上定义了小鼠额叶皮质中的细胞群。获得的结果将公开，并将作为对大脑区域细胞类型进行完整基因组普查的基础，该普查可以扩展到整个大脑。如果成功，该方法最终可以在灵长类动物的大脑中进行测试。因此，该提案响应 RFA MH-14-215“BRAIN Initiative：大脑细胞类型分类的变革方法 (U01)”。

项目成果

Epigenomic landscapes of retinal rods and cones.

• DOI: 10.7554/elife.11613
• 发表时间: 2016-03-07
• 期刊: eLife
• 影响因子: 7.7
• 作者: Mo A;Luo C;Davis FP;Mukamel EA;Henry GL;Nery JR;Urich MA;Picard S;Lister R;Eddy SR;Beer MA;Ecker JR;Nathans J
• 通讯作者: Nathans J

Robust single-cell DNA methylome profiling with snmC-seq2.

• DOI: 10.1038/s41467-018-06355-2
• 发表时间: 2018-09-20
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Luo C;Rivkin A;Zhou J;Sandoval JP;Kurihara L;Lucero J;Castanon R;Nery JR;Pinto-Duarte A;Bui B;Fitzpatrick C;O'Connor C;Ruga S;Van Eden ME;Davis DA;Mash DC;Behrens MM;Ecker JR
• 通讯作者: Ecker JR

Epigenomic Signatures of Neuronal Diversity in the Mammalian Brain.

• DOI: 10.1016/j.neuron.2015.05.018
• 发表时间: 2015-06-17
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Mo A;Mukamel EA;Davis FP;Luo C;Henry GL;Picard S;Urich MA;Nery JR;Sejnowski TJ;Lister R;Eddy SR;Ecker JR;Nathans J
• 通讯作者: Nathans J