Transcriptional Control of Hemoglobin Synthesis
血红蛋白合成的转录控制
基本信息
- 批准号:9302889
- 负责人:
- 金额:$ 38.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-08-15 至 2021-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdoptedAnabolismAnemiaAwardBerylliumBindingBinding SitesBiological AssayBiologyBoxingCD34 geneCRISPR/Cas technologyCell LineCellsChromatin LoopDevelopmentDiseaseDown-RegulationElementsEngineeringEnhancersErythroblastsErythroidErythroid CellsEtiologyFoundationsGATA1 geneGene ExpressionGene TargetingGenerationsGenesGlobinHematopoieticHemeHemoglobinHumanInstructionIntronsLinkMaintenanceMediatingModelingMusMutant Strains MiceNuclearNucleotidesPathologyPathway interactionsPorphyriasPrincipal InvestigatorReagentRegulationRepressionResearchResourcesSiteStatistical Data InterpretationStem cellsSystemTechnologyTestingThalassemiaTherapeuticTranscriptional ActivationTranscriptional RegulationWorkbasechromatin modificationchromosome conformation capturecohortdesignheme biosynthesisin vivoinsightloss of functionsmall hairpin RNAstemsynthetic biologytranscriptome
项目摘要
This application is to request a MERIT Award extension. Our progress validated our hypothesis that globin
gene expression and heme biosynthesis are interlinked through GATA-1-dependent mechanisms. Aim 1. To
distinguish between models for how heme amplifies GATA-1 activity to coordinate hemoglobin
biosynthesis and erythroid cell development/function. We will test whether heme permits or enhances
the GATA-1-dependent subnuclear transition that expels target loci from the nuclear periphery (Model 1) or
enhances GATA-1 activity subsequent to the transition (Model 2). If heme enhances the GATA-1-dependent
subnuclear transition of Bach1-sensitive genes, we will analyze the relationship between Bach1 and other
factors/coregulators that drive locus relocalization. As the relationship between subnuclear transitions and
chromatin looping remains elusive, we will determine whether heme and Bach1 regulate GATA-1-mediated
looping. If heme enhances activation subsequent to the transition, we will dissect late mechanistic steps.
Aim 2. To assemble activation and repression matrices and use these unique resources to elucidate
how the GATA-1/heme circuit establishes a critical sector of the erythroid cell transcriptome. We
hypothesize that GATA-1 target gene cohorts requiring unique ensembles of factors (including heme) and
coregulators share common mechanisms/pathways. We assembled first-gen. matrices illustrating
relationships between target gene expression and factor/coregulator requirements. Considerably expanded
second-gen. matrices will be developed. Unraveling the mechanisms/pathways will yield vital insights into
hemoglobin synthesis and erythroid cell development/function. Aim 3. To use a synthetic biology
approach involving cis-element engineering to ascertain how GATA-1-binding cis-elements control
heme biosynthesis and erythroid biology. Using CRISPR/Cas9, we will rewire the cis-element circuitry
controlling heme biosynthesis to determine why the Alas2 intron1 GATA-1-binding cis-element is much more
important than the intron8 GATA-1-binding cis-element. We will test the hypothesis that the difference
reflects intrinsic differences between the elements, or distinct flanking sequences render the elements
differentially active at endogenous loci. We will generate G1E-ER-GATA-1 cells in which the cis-elements
are swapped to determine if they retain or adopt new attributes at the ectopic chromosomal site. Concepts
will be validated in primary erythroblasts and in vivo. These studies will establish rules governing cis-element
function in erythroid cells, which will inform GATA factor-dependent mechanisms, biology, and pathologies.
RELEVANCE (See instructions):
The proposed studies shall provide fundamental insights into mechanisms underlying disorders of
hemoglobin synthesis, including thalassemias and anemias and diseases associated with aberrant heme
biosynthesis, including porphyrias. Moreover, the work shall provide a conceptual framework for the design
and implementation of translational and therapeutic strategies for these disorders.
此申请是为了申请延长MERIT奖。我们的进展证实了我们的假设,
基因表达和血红素生物合成通过加塔-1依赖性机制相互关联。目标1。到
区分血红素如何放大加塔-1活性以协调血红蛋白的模型
生物合成和红系细胞发育/功能。我们将测试血红素是否允许或增强
从核周边排出靶基因座的加塔-1依赖性亚核转变(模型1)或
增强了转变后的加塔-1活性(模型2)。如果血红素增强了依赖于加塔-1的
Bach 1敏感基因的亚核转换,我们将分析Bach 1与其他基因的关系。
驱动基因座重定位的因子/辅助调节因子。由于亚核跃迁和
染色质环仍然难以捉摸,我们将确定血红素和Bach 1是否调节加塔-1介导的
循环如果血红素增强激活后的过渡,我们将剖析后期的机制步骤。
目标二。组装激活和抑制矩阵,并使用这些独特的资源来阐明
加塔-1/血红素回路如何建立红系细胞转录组的关键部分。我们
假设加塔-1靶向基因群需要独特因子集合(包括血红素),
协同调节因子有共同的机制/途径。我们组装了第一代矩阵,
靶基因表达与因子/辅助调节因子需求之间的关系。大大扩展
将制定第二代矩阵。解开机制/途径将产生重要的见解,
血红蛋白合成和红系细胞发育/功能。目标3。利用合成生物学
一种涉及顺式元件工程以确定加塔-1结合顺式元件如何控制
血红素生物合成和红系生物学。使用CRISPR/Cas9,我们将重新连接顺式元件电路,
控制血红素的生物合成,以确定为什么Alas 2内含子1加塔-1结合顺式元件
比内含子8加塔-1结合顺式元件更重要。我们将检验这个假设,
反映了元件之间的内在差异,或者不同的侧翼序列使元件
在内源基因座上有差异活性。我们将产生G1 E-ER-加塔-1细胞,其中顺式元件
以确定它们是否在异位染色体位点保留或采用新的属性。概念
将在原代成红细胞和体内进行验证。这些研究将建立顺式元件的规则
在红系细胞中起作用,这将告知加塔因子依赖性机制、生物学和病理学。
相关性(参见说明):
拟议的研究将提供基本的洞察机制的疾病,
血红蛋白合成,包括地中海贫血和贫血以及与异常血红素相关的疾病
生物合成,包括卟啉症。此外,该工作应为设计提供概念框架
以及针对这些疾病的转化和治疗策略的实施。
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)
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Emery H Bresnick其他文献
Emery H Bresnick的其他文献
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{{ truncateString('Emery H Bresnick', 18)}}的其他基金
New Tools to Decipher the Role of lncRNAs and Their Protein Interactomes in Hematopoiesis
破译lncRNA及其蛋白质相互作用组在造血作用中作用的新工具
- 批准号:
10368117 - 财政年份:2020
- 资助金额:
$ 38.47万 - 项目类别:
New Tools to Decipher the Role of lncRNAs and Their Protein Interactomes in Hematopoiesis
破译lncRNA及其蛋白质相互作用组在造血作用中作用的新工具
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Statistical Methods For Annotating Repetitive Genomic Regions Through ENCODE-deri
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9060461 - 财政年份:2012
- 资助金额:
$ 38.47万 - 项目类别:
Novel Determinants of Terminal Erythroid Maturation
红细胞终末成熟的新决定因素
- 批准号:
8550827 - 财政年份:2012
- 资助金额:
$ 38.47万 - 项目类别:
Novel Determinants of Terminal Erythroid Maturation
红细胞终末成熟的新决定因素
- 批准号:
8681511 - 财政年份:2012
- 资助金额:
$ 38.47万 - 项目类别:
Novel Determinants of Terminal Erythroid Maturation
红细胞终末成熟的新决定因素
- 批准号:
8875745 - 财政年份:2012
- 资助金额:
$ 38.47万 - 项目类别:
Novel Determinants of Terminal Erythroid Maturation
红细胞终末成熟的新决定因素
- 批准号:
8417051 - 财政年份:2012
- 资助金额:
$ 38.47万 - 项目类别:
Statistical Methods For Annotating Repetitive Genomic Regions Through ENCODE-deri
通过 ENCODE-deri 注释重复基因组区域的统计方法
- 批准号:
8402305 - 财政年份:2012
- 资助金额:
$ 38.47万 - 项目类别:
Statistical Methods For Annotating Repetitive Genomic Regions Through ENCODE-deri
通过 ENCODE-deri 注释重复基因组区域的统计方法
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8687990 - 财政年份:2012
- 资助金额:
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