Higher Order Chromatin and Genetic Risk for Schizophrenia

高阶染色质和精神分裂症的遗传风险

• 批准号: 10673136
• 负责人: Schahram Akbarian
• 金额: $ 81.56万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10673136
• 关键词: 3-Dimensional; ASCL1 gene; Adult; Affect; Algorithms; Architecture; Biological Assay; Brain; Cell Line; Cell Nucleus; Cell division; Chromatin; Chromosome Structures; Chromosomes; Clustered Regularly Interspaced Short Palindromic Repeats; Cognition Disorders; DNA; DNA-Directed RNA Polymerase; Data Set; Development; Dimerization; Disease; Distal; Enhancers; Fiber; Frequencies; Gene Expression; Genes; Genetic Diseases; Genetic Epistasis; Genetic Risk; Genome; Genomics; Glutamates; Goals; Heritability; Heterochromatin; Hi-C; Histone Acetylation; Human; In Situ; Ligands; Link; Maps; Mediating; Mental disorders; Midbrain structure; Modeling; Molecular Conformation; Monitor; Monte Carlo Method; NR4A2 gene; Neighborhoods; Neuroglia; Neuronal Differentiation; Neurons; Nuclear; Nuclear Lamina; Peripheral; Phenotype; Pluripotent Stem Cells; Positioning Attribute; Process; Proteins; Proteomics; Publishing; Quantitative Trait Loci; Regulation; Regulatory Element; Risk; Schizophrenia; Site; Specific qualifier value; Structure; Territoriality; Testing; Transcript; Untranslated RNA; brain tissue; cell type; cofilin; connectome; dopaminergic neuron; emerin; epigenome; fetal; genome wide association study; genome-wide; genome-wide analysis; genomic locus; human embryonic stem cell; immunoreactivity; induced pluripotent stem cell; nerve stem cell; promoter; risk variant; schizophrenia risk; statistics; success; synaptic function; trait; transcriptome; transcriptomics; whole genome

The large majority of genomic loci linked to schizophrenia heritability by genome-wide association harbor regulatory non-coding DNA, including enhancers and repressors, that are not bound to the nearest TSS but instead tethered via chromosomal contacts to genes located elsewhere on the chromosome. Therefore, unsurprisingly, `linear genome' based approaches such as gene expression quantitative trait loci (eQTL) and SNP prioritization algorithms have very limited success in assigning specific target genes to risk loci. Guided by recent Hi-C genome-scale chromosomal contact mapping studies by us and others, we will test in this proposal whether the genetic risk architecture of schizophrenia is associated with cell-type specific vulnerabilities as it pertains to the developmental reorganization of the chromosomal connectome. We predict that neuronal specification into glutamatergic, GABAergic and dopaminergic lineages associated with cell-type specific genome-scale prunings of chromosomal contacts and loss of smaller-scaled chromatin domains. This includes the domain protoype of many of the smaller self-folded `topologically-associated domain' (TAD), with the developmental dissolution of many subTADs nested into larger and megadomain TADs. Furthermore, we predict that differentiating neurons show a disproportionate increase in chromosomal contacts anchored in sequences conferring heritable risk for schizophrenia and related cognitive disorders and traits. We will monitor developmentally regulated shufflings of intranuclear positions for specific GWAS loci and predict mportant differences between the various neural cell types isogenically generated from hiPSCs. If so, then the `functional epistasis', or least co-regulation, of subsets of risk loci sharing the same nuclear sub-territory could be highly dependent on cell type. Last but not least, we predict that targeted mobilization of specific chromatin domains by CRISPR-Genome Organization (CRISPR-GO) approaches can be harnessed for simultaneous targeting of multiple GWAS locis to to specific nuclear compartments such as the nuclear lamina or Cajal body, resulting in multi-layered transcriptome and epigenome changes and cell-type specific phenotypic alterations.

大部分基因组基因座与基因组范围关联的精神分裂症遗传力有关 调节性非编码DNA，包括增强剂和阻遏物，不与最近的TSS结合，但 取而代之的是通过染色体接触束缚至染色体其他地方的基因。所以， 毫不奇怪，基于“线性基因组”的方法，例如基因表达定量性状基因座（EQTL）和 SNP优先算法在将特定靶基因分配给风险基因座方面的成功非常有限。指导 通过美国和其他人最近的Hi-C基因组规模尺寸染色体接触映射研究，我们将在此中进行测试 建议精神分裂症的遗传风险结构是否与细胞类型有关 与染色体连接组的发展重组有关的脆弱性。我们预测 与细胞类型相关的谷氨酸能，GABA能和多巴胺能谱系的神经元规范 染色体接触的特定基因组尺度修剪和较小的染色质结构域的丧失。这 包括许多较小的自我折叠的“拓扑相关域”（TAD）的域原型 许多字体的发育解散嵌套在较大和巨大的tads中。此外，我们 预测区分神经元显示出锚定在 序列赋予精神分裂症和相关认知障碍和特征的遗传风险。我们将监视 特定GWAS基因座的核内位置的开发调节的改组，并预测 hipscs生成的各种神经细胞类型之间的差异。如果是这样，那么 风险基因基因群共享相同核子境内的“功能性上课”或最少共同调节 高度依赖细胞类型。最后但并非最不重要的一点是，我们预测针对特定染色质的动员 CRISPR基因组组织（CRISPR-GO）的域名可以同时利用 将多个GWAS LOCIS靶向特定的核室，例如核层或Cajal体， 导致多层转录组和表观基因组变化以及细胞类型的特定表型改变。

项目成果

Neuron-specific chromosomal megadomain organization is adaptive to recent retrotransposon expansions.

• DOI: 10.1038/s41467-021-26862-z
• 发表时间: 2021-12-13
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Chandrasekaran S;Espeso-Gil S;Loh YE;Javidfar B;Kassim B;Zhu Y;Zhang Y;Dong Y;Bicks LK;Li H;Rajarajan P;Peter CJ;Sun D;Agullo-Pascual E;Iskhakova M;Estill M;Lesch BJ;Shen L;Jiang Y;Akbarian S
• 通讯作者: Akbarian S

In utero exposure to maternal smoking is associated with DNA methylation alterations and reduced neuronal content in the developing fetal brain.

• DOI: 10.1186/s13072-017-0111-y
• 发表时间: 2017
• 期刊: Epigenetics & chromatin
• 影响因子: 3.9
• 作者: Chatterton Z;Hartley BJ;Seok MH;Mendelev N;Chen S;Milekic M;Rosoklija G;Stankov A;Trencevsja-Ivanovska I;Brennand K;Ge Y;Dwork AJ;Haghighi F
• 通讯作者: Haghighi F

Common genetic variation in humans impacts in vitro susceptibility to SARS-CoV-2 infection.

• DOI: 10.1101/2020.09.20.300574
• 发表时间: 2020-09-21
• 期刊: bioRxiv : the preprint server for biology
• 作者: Dobrindt, Kristina;Hoagland, Daisy A;Brennand, Kristen J
• 通讯作者: Brennand, Kristen J

The Role of H3K4me3 in Transcriptional Regulation Is Altered in Huntington's Disease.

• DOI: 10.1371/journal.pone.0144398
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Dong X;Tsuji J;Labadorf A;Roussos P;Chen JF;Myers RH;Akbarian S;Weng Z
• 通讯作者: Weng Z

Cerebral organoids reveal early cortical maldevelopment in schizophrenia-computational anatomy and genomics, role of FGFR1.

• DOI: 10.1038/s41398-017-0054-x
• 发表时间: 2017-11-17
• 期刊: Translational psychiatry
• 影响因子: 6.8
• 作者: Stachowiak EK;Benson CA;Narla ST;Dimitri A;Chuye LEB;Dhiman S;Harikrishnan K;Elahi S;Freedman D;Brennand KJ;Sarder P;Stachowiak MK
• 通讯作者: Stachowiak MK