1/3 High-resolution mapping of cell type-specific DNA (hydroxy)methylation in the human brain during postnatal development and in psychiatric disease.

1/3 出生后发育和精神疾病期间人脑中细胞类型特异性 DNA(羟基)甲基化的高分辨率图谱。

基本信息

  • 批准号:
    10360523
  • 负责人:
  • 金额:
    $ 16.12万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-05-01 至 2025-02-28
  • 项目状态:
    未结题

项目摘要

Project Summary: Most genetic variants associated with disease in genome-wide association studies (GWAS) lie in non-coding gene regulatory elements (GRE; e.g., promoters and enhancers). GREs are tissue- and cell type-specific and are identified through their epigenomic signatures, including low DNA methylation (DNAm), DNA accessibility and certain histone modifications. The PsychENCODE Consortium has characterized brain GREs across brain regions and developmental time points, as well as in the brains of psychiatric patients using mostly DNA accessibility and histone modification marks. These marks, however, identify large regions of enrichment (~300-2,000bp), providing only low resolution coverage of the important regulatory nucleotides, e.g., transcription factor binding sites. DNAm (especially cell type-specific DNAm) has received less attention, although it has been linked to psychiatric disorders, including schizophrenia (SZ) and bipolar disorder (BD). In the adult human brain, ~80% of CG and 1.5% of non-CG (CH) sites are methylated, and can be converted to hydroxymethylcytosine (hmC) and further demethylated. In postmitotic neuronal genomes, mCH and hmC accumulate to a significantly higher level than in other tissues--a distinct feature of the brain's epigenome. Bisulfite sequencing (BS)-based approaches that are used to measure (h)mC can pinpoint GREs with single base resolution, presenting a unique opportunity to refine the gene regulatory landscape of the brain cell types. Here we aim to create reference DNAm maps [mC and hmC, using BS and oxidative (ox)BS sequencing] and transcriptional profiles (using RNA-seq) in two major subtypes of neurons in the human dorsolateral prefrontal cortex (DLPFC), namely excitatory glutamatergic (Glu) and inhibitory GABA-ergic neurons. The proposed work is based on fluorescence-activated nuclear sorting (FANS) methods that we recently developed to separate nuclei of different cell types from autopsied human brain, and on our recent findings that showed unexpected relationships between DNA(h)m, GREs, and gene expression in the DLPFC Glu and GABA neurons. We will perform these studies at key time points of postnatal brain development and adulthood to map DNA(h)m within active neuron subtype-specific GREs that may be vulnerable to disruption during childhood and adolescence periods that coincide with the critical processes of brain maturation and circuit refinement (Aim 1). This work will be complemented with single nucleus mC profiling, which will allow us to define the developmental trajectories of mC in discrete subpopulations of Glu and GABA neurons (Aim2). Finally, we will profile Glu and GABA neurons in 150 autopsied DLPFC samples obtained from controls and cases of SZ and BD, and will then map neuron subtype-specific gene expression and (hydroxy)methylation quantitative trait loci (eQTL, mQTLS, hmQTLs) (Aim3). We will integrate QTL, transcriptome, and DNA(h)m data with the results of SZ and BP GWAS to reveal DNA(h)m and gene expression-mediated causal risk variants and genes, and to distinguish specific neuronal subtype(s) that are critical in the etiology of these disorders.
项目摘要:全基因组关联研究(GWAS)中与疾病相关的大多数遗传变异 存在于非编码基因调控元件(GRE;例如,启动子和增强子)。GRES是组织和细胞 类型特异性,并通过其表观基因组特征,包括低DNA甲基化(DNAm), DNA可及性和某些组蛋白修饰。PsychENCODE联盟将大脑 跨脑区和发育时间点的GRES,以及使用 主要是DNA可及性和组蛋白修饰标记。然而,这些标记识别了大面积的 富集(~300-2,000 bp),仅提供重要调控核苷酸的低分辨率覆盖,例如, 转录因子结合位点。DNAm(特别是细胞类型特异性DNAm)受到的关注较少, 尽管它与精神疾病有关,包括精神分裂症(SZ)和双相情感障碍(BD)。 在成年人脑中,约80%的CG和1.5%的非CG(CH)位点被甲基化,并且可以被转化为 转化为羟甲基胞嘧啶(hmC)并进一步去甲基化。在有丝分裂后神经元基因组中,mCH和hmC 积累到比其他组织高得多的水平--这是大脑表观基因组的一个明显特征。 用于测量(h)mC的基于亚硫酸氢盐测序(BS)的方法可以用单个 基本分辨率,提供了一个独特的机会,以完善脑细胞类型的基因调控景观。 在这里,我们的目标是创建参考DNAm图谱[mC和hmC,使用BS和氧化(ox)BS测序] 和转录谱(使用RNA-seq)在两个主要亚型的神经元在人类背外侧 前额叶皮层(DLPFC),即兴奋性谷氨酸能(Glu)和抑制性GABA能神经元。的 我们提出的工作是基于我们最近开发的荧光激活核分选(FANS)方法 从解剖的人脑中分离出不同类型细胞的细胞核, DLPFC Glu和GABA神经元中DNA(h)m、GRES和基因表达之间的意外关系。 我们将在出生后大脑发育和成年的关键时间点进行这些研究, 活性神经元亚型特异性GR内的DNA(h)m可能在儿童时期容易受到破坏, 青春期与大脑成熟和回路完善的关键过程相吻合(目标1)。 这项工作将与单核mC分析相补充,这将使我们能够定义发育过程。 Glu和GABA神经元的离散亚群中的mC轨迹(Aim 2)。 最后,我们将在150例尸检的DLPFC样本中分析Glu和GABA神经元,这些样本来自对照组, SZ和BD的病例,然后将神经元亚型特异性基因表达和(羟基)甲基化 数量性状基因座(eQTL、mQTL、hmQTL)(Aim 3)。我们将整合QTL、转录组和DNA(h)m数据 SZ和BP GWAS的结果揭示了DNA(h)m和基因表达介导的因果风险变异, 基因,并区分在这些疾病的病因学中至关重要的特定神经元亚型。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Chunyu Liu其他文献

Chunyu Liu的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Chunyu Liu', 18)}}的其他基金

Gene Expression Regulation in Brains of East Asian, African, and European Descent Explains Schizophrenia GWAS in Diverse Populations.
东亚、非洲和欧洲血统大脑中的基因表达调控解释了不同人群中的精神分裂症 GWAS。
  • 批准号:
    10382057
  • 财政年份:
    2022
  • 资助金额:
    $ 16.12万
  • 项目类别:
Gene Expression Regulation in Brains of East Asian, African, and European Descent Explains Schizophrenia GWAS in Diverse Populations.
东亚、非洲和欧洲血统大脑中的基因表达调控解释了不同人群中的精神分裂症 GWAS。
  • 批准号:
    10597054
  • 财政年份:
    2022
  • 资助金额:
    $ 16.12万
  • 项目类别:
Trans-omic Analysis of Alcohol Consumption and its Relation to Cardiovascular Disease
酒精消耗及其与心血管疾病关系的跨组学分析
  • 批准号:
    10436830
  • 财政年份:
    2021
  • 资助金额:
    $ 16.12万
  • 项目类别:
Mitochondrial DNA, Nuclear DNA Methylation, and Cardiometabolic Disease Traits
线粒体 DNA、核 DNA 甲基化和心脏代谢疾病特征
  • 批准号:
    10646401
  • 财政年份:
    2021
  • 资助金额:
    $ 16.12万
  • 项目类别:
Mitochondrial DNA, Nuclear DNA Methylation, and Cardiometabolic Disease Traits
线粒体 DNA、核 DNA 甲基化和心脏代谢疾病特征
  • 批准号:
    10475148
  • 财政年份:
    2021
  • 资助金额:
    $ 16.12万
  • 项目类别:
Mitochondrial DNA, Nuclear DNA Methylation, and Cardiometabolic Disease Traits
线粒体 DNA、核 DNA 甲基化和心脏代谢疾病特征
  • 批准号:
    10297789
  • 财政年份:
    2021
  • 资助金额:
    $ 16.12万
  • 项目类别:
Trans-omic Analysis of Alcohol Consumption and its Relation to Cardiovascular Disease
酒精消耗及其与心血管疾病关系的跨组学分析
  • 批准号:
    10616528
  • 财政年份:
    2021
  • 资助金额:
    $ 16.12万
  • 项目类别:
Trans-omic Analysis of Alcohol Consumption and its Relation to Cardiovascular Disease
酒精消耗及其与心血管疾病关系的跨组学分析
  • 批准号:
    10209156
  • 财政年份:
    2021
  • 资助金额:
    $ 16.12万
  • 项目类别:
1/3 High-resolution mapping of cell type-specific DNA (hydroxy)methylation in the human brain during postnatal development and in psychiatric disease.
1/3 出生后发育和精神疾病期间人脑中细胞类型特异性 DNA(羟基)甲基化的高分辨率图谱。
  • 批准号:
    10576891
  • 财政年份:
    2020
  • 资助金额:
    $ 16.12万
  • 项目类别:
Mitochondrial DNA Copy Number and Sequence Variation in Relation to Age, Alzheimer's Disease Related Phenotypes and Age-related Metabolic Traits
线粒体 DNA 拷贝数和序列变异与年龄、阿尔茨海默病相关表型和年龄相关代谢特征的关系
  • 批准号:
    10212947
  • 财政年份:
    2018
  • 资助金额:
    $ 16.12万
  • 项目类别:

相似海外基金

Cognitive and non-cognitive abilities and career development during adolescence and adult development: from the perspective of genetic and environmental structure
青春期和成人发展期间的认知和非认知能力与职业发展:从遗传和环境结构的角度
  • 批准号:
    23K02900
  • 财政年份:
    2023
  • 资助金额:
    $ 16.12万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
ADOLESCENCE: A SENSITIVE PERIOD FOR SHAPING THE ADULT SOCIAL BRAIN
青春期:塑造成人社交大脑的敏感时期
  • 批准号:
    RGPIN-2022-05266
  • 财政年份:
    2022
  • 资助金额:
    $ 16.12万
  • 项目类别:
    Discovery Grants Program - Individual
Joint contributions of affiliative social contact, stress in adolescence and oxytocin to fear behaviour in adult rats
亲和性社会接触、青春期压力和催产素对成年大鼠恐惧行为的共同作用
  • 批准号:
    RGPIN-2019-04790
  • 财政年份:
    2022
  • 资助金额:
    $ 16.12万
  • 项目类别:
    Discovery Grants Program - Individual
Joint contributions of affiliative social contact, stress in adolescence and oxytocin to fear behaviour in adult rats
亲和性社会接触、青春期压力和催产素对成年大鼠恐惧行为的共同作用
  • 批准号:
    RGPIN-2019-04790
  • 财政年份:
    2021
  • 资助金额:
    $ 16.12万
  • 项目类别:
    Discovery Grants Program - Individual
ADOLESCENCE: A SENSITIVE PERIOD FOR SHAPING THE ADULT SOCIAL BRAIN
青春期:塑造成人社交大脑的敏感时期
  • 批准号:
    RGPIN-2016-03714
  • 财政年份:
    2021
  • 资助金额:
    $ 16.12万
  • 项目类别:
    Discovery Grants Program - Individual
Impact on adult mouse brain of oral THC and CBD consumption during adolescence
青春期口服 THC 和 CBD 对成年小鼠大脑的影响
  • 批准号:
    10206087
  • 财政年份:
    2020
  • 资助金额:
    $ 16.12万
  • 项目类别:
Joint contributions of affiliative social contact, stress in adolescence and oxytocin to fear behaviour in adult rats
亲和性社会接触、青春期压力和催产素对成年大鼠恐惧行为的共同作用
  • 批准号:
    RGPIN-2019-04790
  • 财政年份:
    2020
  • 资助金额:
    $ 16.12万
  • 项目类别:
    Discovery Grants Program - Individual
Investigating the Social Determinant and Developmental Risk Patterns in Childhood and Adolescence Associated with Adult Asthma and Diabetes Onset
调查儿童期和青少年期与成人哮喘和糖尿病发病相关的社会决定因素和发育风险模式
  • 批准号:
    450250
  • 财政年份:
    2020
  • 资助金额:
    $ 16.12万
  • 项目类别:
    Studentship Programs
ADOLESCENCE: A SENSITIVE PERIOD FOR SHAPING THE ADULT SOCIAL BRAIN
青春期:塑造成人社交大脑的敏感时期
  • 批准号:
    RGPIN-2016-03714
  • 财政年份:
    2020
  • 资助金额:
    $ 16.12万
  • 项目类别:
    Discovery Grants Program - Individual
Impact on adult mouse brain of oral THC and CBD consumption during adolescence
青春期口服 THC 和 CBD 对成年小鼠大脑的影响
  • 批准号:
    10039866
  • 财政年份:
    2020
  • 资助金额:
    $ 16.12万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了