Elucidating the cis-regulatory grammar of human photoreceptors
阐明人类光感受器的顺式调节语法
基本信息
- 批准号:10601005
- 负责人:
- 金额:$ 53.92万
- 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:2020-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAddressAdultAffectAffinityBar CodesBinding SitesBioinformaticsBiological AssayBlindnessCRISPR/Cas technologyCodeComplexConeDNADataData SetDiseaseEngineeringEnhancersGene ExpressionGenesGeneticGenetic VariationGenomeGenomicsGoalsHeritabilityHumanHuman GenomeIndividualKnowledgeLibrariesLocationMapsMeasuresMendelian disorderModelingMusMutagenesisMutagensMutationNucleic Acid Regulatory SequencesOrganoidsPhotoreceptorsPlayPublishingRegulatory ElementReporterReporter GenesRetinaRetinal DiseasesRetinal gene therapyRodRoleTechniquesTestingTherapeuticTranscriptUntranslated RNAVariantVertebrate PhotoreceptorsVisionblindcandidate identificationcausal variantcell typeembryonic stem cellepigenomicsfallsgene therapygenetic analysisgenetic variantgenome wide association studygenome-widehuman diseaseimprovednovel diagnosticsnovel strategiesnovel therapeuticspromoterscreeningtranscription factortranscriptome sequencingwhole genome
项目摘要
Project Summary
One of the major unsolved challenges of the genomic era is to understand how individual sequence
variation contributes to disease. Coding variation is increasingly well understood, but our knowledge of the
effects of non-coding variation remains rudimentary. The goal of this proposal is to develop a platform for the
analysis of non-coding cis-regulatory variation in human retinal disease. We hypothesize that sequence
variants in photoreceptor-specific cis-regulatory elements (CREs; e.g., enhancer/promoters) play an important
role in retinal disease by altering the expression levels of disease-related genes. Currently, assessing the
effects of variants that fall within non-coding DNA represents a challenging problem, in part, because our ability
to assay CREs in a high-throughput fashion is limited. To address this challenge, we have developed a
technique called CRE-seq (Cis-Regulatory Element analysis by sequencing). In CRE-seq, individual CREs are
fused to reporter genes, each containing a unique DNA barcode. The resultant CRE-reporter library, consisting
of thousands of constructs, is introduced into living retina, and reporter gene expression is quantified by
counting barcoded transcripts with RNA-seq. CRE-seq promises to revolutionize our ability to measure the
effects of human cis-regulatory variants. To achieve this goal, we propose three Specific Aims. In Aim 1, we
will use ATAC-seq to identify candidate CREs in both developing and mature human photoreceptors. In Aim 2,
we will utilize a combination of computational and experimental approaches (including CRE-seq analysis) to
analyze the CREs identified in Aim 1 and thereby elucidate the cis-regulatory grammar of human
photoreceptors. CRE-seq will be performed in both mouse retinas as well as ES cell-derived human retinal
organoids. These studies will provide the first comprehensive view of the human photoreceptor 'cis-regulome'
and will begin to decipher the cis-regulatory code of human photoreceptors. In Aim 3, we will use a
‘mutagenesis and screening’ approach to engineer a library of compact (150 bp), highly active enhancers for
targeting human photoreceptors in gene therapy applications. If successful, these studies will establish a
quantitative platform for the analysis of non-coding cis-regulatory variation, thereby enabling comprehensive
interpretation of whole-genome sequence data in the context of retinal disease. In addition, they will engineer a
suite of new enhancers for human retinal gene therapy.
项目概要
基因组时代尚未解决的主要挑战之一是了解个体序列如何
变异会导致疾病。编码变异越来越被人们所理解,但我们对编码变异的了解
非编码变异的影响仍然处于初级阶段。该提案的目标是开发一个平台
人类视网膜疾病中非编码顺式调控变异的分析。我们假设该序列
光感受器特异性顺式调节元件(CRE;例如增强子/启动子)的变异发挥着重要作用
通过改变疾病相关基因的表达水平在视网膜疾病中发挥作用。目前,正在评估
非编码 DNA 内变异的影响是一个具有挑战性的问题,部分原因是我们的能力
以高通量方式测定 CRE 是有限的。为了应对这一挑战,我们开发了
称为 CRE-seq(顺式调控元件测序分析)的技术。在 CRE-seq 中,各个 CRE 是
与报告基因融合,每个基因都包含独特的 DNA 条形码。由此产生的 CRE 报告库,包括
数千个构建体被引入活体视网膜,报告基因表达通过以下方式量化
使用 RNA-seq 对带条形码的转录本进行计数。 CRE-seq 有望彻底改变我们衡量
人类顺式调节变异的影响。为了实现这一目标,我们提出了三个具体目标。在目标 1 中,我们
将使用 ATAC-seq 来识别发育中和成熟的人类光感受器中的候选 CRE。在目标 2 中,
我们将结合计算和实验方法(包括 CRE-seq 分析)来
分析目标 1 中确定的 CRE,从而阐明人类的顺式调控语法
光感受器。 CRE-seq 将在小鼠视网膜以及 ES 细胞衍生的人视网膜中进行
类器官。这些研究将提供人类光感受器“顺式调节组”的第一个全面视图
并将开始破译人类光感受器的顺式调控密码。在目标 3 中,我们将使用
“诱变和筛选”方法设计一个紧凑(150 bp)、高活性增强子文库
在基因治疗应用中针对人类光感受器。如果成功的话,这些研究将建立一个
用于分析非编码顺式调控变异的定量平台,从而实现全面的分析
视网膜疾病背景下全基因组序列数据的解释。此外,他们还将设计一个
用于人类视网膜基因治疗的一套新增强剂。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Partitioning of gene expression among zebrafish photoreceptor subtypes.
- DOI:10.1038/s41598-021-96837-z
- 发表时间:2021-08-30
- 期刊:
- 影响因子:4.6
- 作者:Ogawa Y;Corbo JC
- 通讯作者:Corbo JC
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{{ truncateString('JOSEPH CORBO', 18)}}的其他基金
Targeting Nr2e3 to prevent photoreceptor degeneration
靶向 Nr2e3 预防光感受器变性
- 批准号:
10587113 - 财政年份:2023
- 资助金额:
$ 53.92万 - 项目类别:
High-throughput identification of causal variants underlying neuropsychiatric disease-related GWAS hits
高通量鉴定神经精神疾病相关 GWAS 命中的因果变异
- 批准号:
10339452 - 财政年份:2020
- 资助金额:
$ 53.92万 - 项目类别:
High-throughput identification of causal variants underlying cardiac arrhythmia-related GWAS hits
高通量识别心律失常相关 GWAS 命中的因果变异
- 批准号:
10615090 - 财政年份:2020
- 资助金额:
$ 53.92万 - 项目类别:
High-throughput identification of causal variants underlying cardiac arrhythmia-related GWAS hits
高通量识别心律失常相关 GWAS 命中的因果变异
- 批准号:
10397430 - 财政年份:2020
- 资助金额:
$ 53.92万 - 项目类别:
High-throughput identification of causal variants underlying neuropsychiatric disease-related GWAS hits
高通量鉴定神经精神疾病相关 GWAS 命中的因果变异
- 批准号:
10569114 - 财政年份:2020
- 资助金额:
$ 53.92万 - 项目类别:
High-throughput identification of causal variants underlying cardiac arrhythmia-related GWAS hits
高通量识别心律失常相关 GWAS 命中的因果变异
- 批准号:
10191029 - 财政年份:2020
- 资助金额:
$ 53.92万 - 项目类别:
Elucidating the cis-regulatory grammar of human photoreceptors
阐明人类光感受器的顺式调节语法
- 批准号:
10372052 - 财政年份:2020
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DECIPHERING THE MECHANISTIC BASIS OF INFRARED VISION FOR OPTOGENETIC APPLICATIONS
破译红外视觉光遗传学应用的机制基础
- 批准号:
9082683 - 财政年份:2016
- 资助金额:
$ 53.92万 - 项目类别:
DISSECTING THE CIS-REGULATORY ARCHITECTURE OF THE RETINA BY EPIGENOMIC PROFILING
通过表观基因组分析剖析视网膜的 CIS 调控架构
- 批准号:
9043099 - 财政年份:2015
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CONVERTING BIPOLAR CELLS INTO RED-SHIFTED OPTOGENETIC SENSORS FOR RETINAL THERAPY
将双极细胞转化为红移光遗传学传感器用于视网膜治疗
- 批准号:
8989104 - 财政年份:2015
- 资助金额:
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