Analysis of combinatorial cis-regulation in synthetic and genomic promoters
Analysis of combinatorial cis-regulation in synthetic and genomic promoters
批准号:
10752486
负责人:
Barak A Cohen
金额:
$47.02万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2011
资助国家:
美国
项目状态:
未结题
起止时间:
2011-01-01 至 2027-08-31
关键词:
AddressAffectAffinityAmacrine CellsAstrocytesBinding SitesBiological AssayBiophysicsBrainCellsDNADNA SequenceDataDependenceDiseaseFree EnergyGene Expression ProfileGenesGenetic VariationGenomeGenomicsGoalsGrantHeritabilityHuman GenomeLibrariesLogicMeasuresMethodsModelingMuller&aposs cellMusNeuronsOligodendrogliaRegulationReporterReporter GenesResearchRetinaSiteSpecific qualifier valueSpecificityTestingThermodynamicsTissuesTrainingUntranslated RNAVariantWorkbillboardcell typecombinatorialgene functiongenetic variantin vivoinfancynovelpromoterretinal rodstranscription factor
中文摘要
项目摘要/摘要
大多数可遗传的致病变异存在于人类的非编码部分
基因组。一种主要的假说是,这种变异的大部分作用于特定细胞类型的顺式调节因子。
调控序列(CRSS)。因此,解释这种变化将需要对
控制CRSS特定细胞类型活动的“调控语法”。我们定义了监管
一种细胞类型的语法是转录因子结合的独立和相互作用的贡献
站点(TFBs)到顺式调控活动。规则语法的模型还必须包括依存关系
在TFBs的数量、取向、间距和亲和力方面的贡献。详细的模型
监管语法仍处于初级阶段,部分原因是我们缺乏系统的培训数据来说明CRSS如何
在体内跨越不同类型的细胞的行为。我们建议通过系统地衡量
在完整的哺乳动物组织中,CRSS在不同细胞类型中的活性。为了收集这些数据,我们将介绍
单细胞大规模平行报告基因分析(ScMPRA)测量细胞类型特异性
CRSS在体内的活性。我们将使用正式的热力学模型对结果数据进行建模
每一种Tf-DNA或Tf-Tf相互作用均由其相互作用自由能(ΔG)表示。通过比较
产生的ΔG值的大小,我们将量化
特定的TFBs,从而推导出捕捉细胞之间差异的定量调控语法
哺乳动物视网膜的类型(目标1)和哺乳动物大脑的类型(目标2)。通过验证我们的模型
内源性CRSS的序列变异,我们希望朝着准确的框架取得进展
预测非编码遗传变异对CRSS功能的影响。
英文摘要
Project Summary/Abstract
A majority of heritable disease-causing variation resides in the non-coding portions of the human
genome. A leading hypothesis is that most of this variation exerts its effects on cell-type-specific cis-
regulatory sequences (CRSs). Interpreting such variation will therefore require quantitative models of the
‘regulatory grammar’ that controls the cell-type-specific activities of CRSs. We define the regulatory
grammar of a cell type to be the independent and interacting contributions of transcription factor binding
sites (TFBSs) to cis-regulatory activity. Models of regulatory grammar must also include the dependencies
of those contributions on the number, orientation, spacing, and affinity of TFBSs. Detailed models of
regulatory grammars are still in their infancy, partly because we lack systematic training data for how CRSs
behave across diverse cell types in vivo. We propose to address this gap by systematically measuring the
activities of CRSs across cell types within intact mammalian tissues. To collect this data, we will introduce
a single-cell massively parallel reporter gene assay (scMPRA) that measures the cell-type-specific
activities of CRSs in vivo. We will model the resulting data using a formal thermodynamic model in which
each TF-DNA or TF-TF interaction is represented by its free energy (ΔG) of interaction. By comparing the
magnitudes of the resulting ΔG values, we will quantify the independent and interacting contributions of
specific TFBSs, thus deriving quantitative regulatory grammars that capture the differences between cell
types within the mammalian retina (Aim 1) and the mammalian brain (Aim 2). By validating our models on
sequence variants of endogenous CRSs, we hope to make progress towards a framework for accurately
predicting the effects of non-coding genetic variation on the function of CRSs.
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DOI:
10.1101/gr.226530.117
发表时间:
2018-03
期刊:
Genome research
影响因子:
7
作者:
[Chaudhari HG, Cohen BA]
通讯作者:
Cohen BA
DOI:
10.1093/nar/gkw942
发表时间:
2017-02-28
期刊:
Nucleic acids research
影响因子:
14.9
作者:
[Maricque BB, Dougherty JD, Cohen BA]
通讯作者:
Cohen BA
DOI:
10.1101/gr.173518.114
发表时间:
2014-10
期刊:
Genome research
影响因子:
7
作者:
[Kwasnieski JC, Fiore C, Chaudhari HG, Cohen BA]
通讯作者:
Cohen BA
DOI:
10.1101/gr.200733.115
发表时间:
2016-06
期刊:
Genome research
影响因子:
7
作者:
[Fiore C, Cohen BA]
通讯作者:
Cohen BA
Transcription factor fluctuations underlie cell-to-cell variability in a signaling pathway response.
转录因子波动是信号通路反应中细胞间变异的基础。
DOI:
10.1093/genetics/iyad094
发表时间:
2023
期刊:
Genetics
影响因子:
3.3
作者:
[Ramu,Avinash, Cohen,BarakA]
通讯作者:
Cohen,BarakA
共 13 条
High-throughput analysis of the effects of gene promoters and chromosomal environments on single-cell gene expression
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批准号:10391739
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项目类别:
-
资助金额:$41.07万
-
财政年份:2022
-
负责人:Barak A Cohen
-
依托单位:
High-throughput analysis of the effects of gene promoters and chromosomal environments on single-cell gene expression
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批准号:10574606
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项目类别:
-
资助金额:$41.54万
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财政年份:2022
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负责人:Barak A Cohen
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依托单位:
Cell-Based Assays For Deep Mutational Scans of Transcription Factors
-
批准号:10317226
-
项目类别:
-
资助金额:$43.31万
-
财政年份:2021
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负责人:Barak A Cohen
-
依托单位:
Molecular Properties of Transcription Factors that Control Cell-to-Cell Variability in Gene Expression
-
批准号:10400231
-
项目类别:
-
资助金额:$32.23万
-
财政年份:2021
-
负责人:Barak A Cohen
-
依托单位:
Molecular Properties of Transcription Factors that Control Cell-to-Cell Variability in Gene Expression
-
批准号:10576904
-
项目类别:
-
资助金额:$32.23万
-
财政年份:2021
-
负责人:Barak A Cohen
-
依托单位:
Connecting transposable elements and regulatory innovation using ENCODE data
-
批准号:10241106
-
项目类别:
-
资助金额:$46.5万
-
财政年份:2020
-
负责人:Barak A Cohen
-
依托单位:
Connecting transposable elements and regulatory innovation using ENCODE data
-
批准号:9247278
-
项目类别:
-
资助金额:$47.94万
-
财政年份:2017
-
负责人:Barak A Cohen
-
依托单位:
MASSIVELY PARALLEL CHARACTERIZATION OF CIS-REGULATORY ELEMENTS IN THE BRAIN
-
批准号:8964602
-
项目类别:
-
资助金额:$34.31万
-
财政年份:2015
-
负责人:Barak A Cohen
-
依托单位:
MASSIVELY PARALLEL CHARACTERIZATION OF CIS-REGULATORY ELEMENTS IN THE BRAIN
-
批准号:9309018
-
项目类别:
-
资助金额:$34.31万
-
财政年份:2015
-
负责人:Barak A Cohen
-
依托单位:
MASSIVELY PARALLEL CHARACTERIZATION OF CIS-REGULATORY ELEMENTS IN THE BRAIN
-
批准号:9215863
-
项目类别:
-
资助金额:$0.48万
-
财政年份:2015
-
负责人:Barak A Cohen
-
依托单位:
Omics of Inflammatory Airway Diseases
-
批准号:8575240
-
项目类别:
-
资助金额:$11.31万
-
财政年份:2013
-
负责人:Barak A Cohen
-
依托单位:
Omics of Inflammatory Airway Diseases
-
批准号:8857251
-
项目类别:
-
资助金额:$26.73万
-
财政年份:2013
-
负责人:Barak A Cohen
-
依托单位:
Omics of Inflammatory Airway Diseases
-
批准号:8722620
-
项目类别:
-
资助金额:$26.81万
-
财政年份:2013
-
负责人:Barak A Cohen
-
依托单位:
PROMOTERS
-
批准号:9280975
-
项目类别:
-
资助金额:$39.73万
-
财政年份:2011
-
负责人:Barak A Cohen
-
依托单位:
ANALYSIS OF COMBINATORIAL CIS-REGULATION IN SYNTHETIC AND GENOMIC PROMOTERS
-
批准号:8600698
-
项目类别:
-
资助金额:$34.96万
-
财政年份:2011
-
负责人:Barak A Cohen
-
依托单位:
ANALYSIS OF COMBINATORIAL CIS-REGULATION IN SYNTHETIC AND GENOMIC PROMOTERS
-
批准号:8037934
-
项目类别:
-
资助金额:$34.96万
-
财政年份:2011
-
负责人:Barak A Cohen
-
依托单位:
Analysis of combinatorial cis-regulation in synthetic and genomic promoters
-
批准号:10225563
-
项目类别:
-
资助金额:$42.53万
-
财政年份:2011
-
负责人:Barak A Cohen
-
依托单位:
Analysis of combinatorial cis-regulation in synthetic and genomic promoters
-
批准号:10455447
-
项目类别:
-
资助金额:$42.53万
-
财政年份:2011
-
负责人:Barak A Cohen
-
依托单位:
ANALYSIS OF COMBINATORIAL CIS-REGULATION IN SYNTHETIC AND GENOMIC PROMOTERS
-
批准号:8403073
-
项目类别:
-
资助金额:$33.74万
-
财政年份:2011
-
负责人:Barak A Cohen
-
依托单位:
ANALYSIS OF COMBINATORIAL CIS-REGULATION IN SYNTHETIC AND GENOMIC PROMOTERS
-
批准号:8206669
-
项目类别:
-
资助金额:$34.96万
-
财政年份:2011
-
负责人:Barak A Cohen
-
依托单位:
海外基金