Regulation of DNA methylation by TETs and QSER1
TET 和 QSER1 对 DNA 甲基化的调节
基本信息
- 批准号:10709595
- 负责人:
- 金额:$ 67.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-22 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAberrant DNA MethylationAgingAnimal ModelBindingBinding ProteinsBiochemicalBiological AssayBiological ModelsCRISPR screenCell Differentiation processCellsChromatinChromatin StructureCollaborationsComplexCongenital AbnormalityCoronary ArteriosclerosisDNADNA MethylationDNA Methylation RegulationDNA methylation profilingDataDevelopmentDevelopmental GeneDiseaseEmbryonic DevelopmentEndodermEnhancersEnzymesEpiblastEpigenetic ProcessExcisionFamilyFamily memberFragile X SyndromeGene ExpressionGenesGeneticGenetic TranscriptionGerm LayersGoalsHistonesHumanHydroxylationIn Situ HybridizationKnowledgeLarvaLinkMalignant NeoplasmsMesodermMethylationModelingMusMutationNeurodegenerative DisordersNeuroectodermNucleic Acid Regulatory SequencesOrganOrganogenesisPathway interactionsPatternPhenotypePlayProductivityProtein TruncationProteinsProteomicsPublishingReaderRegulationRegulator GenesRegulatory ElementReporterRepressionResearch PersonnelRoleScienceSeckel syndromeSiteSpecific qualifier valueStructural Congenital AnomaliesStructureSyndromeTestingValidationVertebratesZebrafishchromatin modificationdemethylationdirected differentiationepigenomicsexperimental studygenetic analysisgenetic variantgenome-widehuman embryonic stem cellimmunodeficiency-centromeric instability-facial anomalies syndromemembermethylomemutantneuralnovelparalogous geneprogenitorprogramspromoterprotein complexsingle-cell RNA sequencingstemstem cell fate specificationstem cell modelstem cellstool
项目摘要
The goal of this project is to discover fundamental epigenomic regulatory mechanisms that commit cells to
defined fates during early stages of embryogenesis. Early in development, commitment of the epiblast to germ
layers is followed by activation of key regulatory genes that drive lineage fate. These genes control normal
development and underlie the genetic basis for a broad range of human structural birth defects. We have studied
members of the TET family of hydroxylation enzymes, which regulate the demethylation of DNA, or block active
methylation of DNA, to control gene expression. We discovered requirements for TET enzymes during early
development in the zebrafish model, and for progenitor specification from human embryonic stem cells (hESCs).
Major gaps in understanding include: i) whether common or distinct mechanisms control demethylation for
progenitors from different germ layers, ii) whether different TET family members distinguish developmental
programs, and iii) how TETs are targeted to regulatory regions such as bivalent promoters. Suspecting that
additional proteins beyond TETs are needed to target DNA demethylation, we carried out a genome-wide
CRISPR screen and discovered QSER1, a previously uncharacterized chromatin-binding protein. We showed
that QSER1 is a key guardian of bivalent promoters and poised enhancers of developmental genes, especially
those residing in DNA methylation valleys, broadly across different cell fates. We found biochemical and genetic
interactions between QSER1 and TETs, suggesting that they cooperate to safeguard transcriptional and
developmental programs from methylation. QSER1 variant alleles were recently linked to coronary artery
disease, while haploinsufficiency of a QSER1 paralog, PRR12, is associated with multi-organ developmental
birth defect syndromes. We propose to fully explore the genetic relationships and downstream networks of
TET/QSER1 (TQ) family members, including how they function to control methylation and impact chromatin
structure in the context of two complementary model systems, zebrafish and hESCs. The zebrafish model allows
full genetic analysis of potentially compensatory or cooperating family members (including tet1, tet2, tet3, qser1,
and prr12), in an animal model with highly conserved developmental programs. The hESC model provides
outstanding biochemical and “omics” capacity, and validation in developing human progenitor and differentiated
cells. The multi-PI project represents a continued collaboration among investigators with complementary and
overlapping expertise, with a strong record of productivity. Specific Aims are proposed to determine the relative
contribution of these genes for directing early progenitor fate, discover the regulatory networks in which they
function, and to test interacting factors as candidates for linking TQ methylation control to chromatin modification.
Because regulation of methylation is a fundamental step of progenitor fate determination, our results will be
broadly relevant to organogenesis and structural birth defects.
该项目的目标是发现基本的表观基因组调控机制,使细胞
在胚胎发生的早期阶段就确定了命运。在发育早期,外胚层对细菌的承诺
层数之后是驱动谱系命运的关键调控基因的激活。这些基因控制正常
发育并构成了广泛的人类结构性出生缺陷的遗传基础。我们研究过
羟基化酶 TET 家族的成员,可调节 DNA 的去甲基化,或阻断活性
DNA甲基化,以控制基因表达。我们在早期发现了对 TET 酶的需求
斑马鱼模型的发育以及人类胚胎干细胞(hESC)的祖细胞规范。
理解上的主要差距包括:i) 控制去甲基化的机制是共同的还是不同的
来自不同胚层的祖细胞,ii) 不同的 TET 家族成员是否区分发育
计划,以及 iii) TET 如何靶向二价启动子等调控区域。怀疑
需要除 TET 之外的其他蛋白质来靶向 DNA 去甲基化,我们进行了全基因组范围的研究
CRISPR 筛选并发现了 QSER1,一种以前未表征的染色质结合蛋白。我们展示了
QSER1 是发育基因的二价启动子和增强子的关键守护者,尤其是
那些存在于 DNA 甲基化谷中的细胞,广泛地跨越不同的细胞命运。我们发现生化和遗传
QSER1 和 TET 之间的相互作用,表明它们合作保护转录和
甲基化的发育程序。 QSER1 变异等位基因最近与冠状动脉有关
疾病,而 QSER1 旁系同源物 PRR12 的单倍体不足与多器官发育相关
出生缺陷综合症。我们建议充分探索遗传关系和下游网络
TET/QSER1 (TQ) 家族成员,包括它们如何发挥控制甲基化和影响染色质的作用
斑马鱼和人胚胎干细胞这两个互补模型系统的结构。斑马鱼模型允许
对潜在补偿或合作家庭成员(包括 tet1、tet2、tet3、qser1、
和 prr12),在具有高度保守的发育程序的动物模型中。 hESC 模型提供
杰出的生化和“组学”能力,以及在开发人类祖细胞和分化细胞方面的验证
细胞。多 PI 项目代表了研究人员之间的持续合作,具有互补性和
重叠的专业知识,具有良好的生产力记录。提出具体目标以确定相对
这些基因对指导早期祖细胞命运的贡献,发现它们所在的调控网络
功能,并测试相互作用的因素作为将 TQ 甲基化控制与染色质修饰联系起来的候选因素。
因为甲基化的调节是祖细胞命运决定的基本步骤,所以我们的结果将是
与器官发生和结构性出生缺陷广泛相关。
项目成果
期刊论文数量(0)
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Todd R Evans其他文献
Todd R Evans的其他文献
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{{ truncateString('Todd R Evans', 18)}}的其他基金
Methods for detection of dynamic intracellular signals in single adult spermatogonial stem cells
单个成体精原干细胞动态细胞内信号的检测方法
- 批准号:
10666116 - 财政年份:2023
- 资助金额:
$ 67.1万 - 项目类别:
Regulation of DNA methylation by TETs and QSER1
TET 和 QSER1 对 DNA 甲基化的调节
- 批准号:
10585325 - 财政年份:2022
- 资助金额:
$ 67.1万 - 项目类别:
Negative feedback regulation of growth factor signaling in adult spermatogonial stem cells
成体精原干细胞生长因子信号传导的负反馈调节
- 批准号:
10570919 - 财政年份:2021
- 资助金额:
$ 67.1万 - 项目类别:
A molecular pathway controlling cardiomyocyte specification.
控制心肌细胞规格的分子途径。
- 批准号:
8975788 - 财政年份:2011
- 资助金额:
$ 67.1万 - 项目类别:
A molecular pathway controlling cardiomyocyte specification.
控制心肌细胞规格的分子途径。
- 批准号:
8388798 - 财政年份:2011
- 资助金额:
$ 67.1万 - 项目类别:
A molecular pathway controlling cardiomyocyte specification.
控制心肌细胞规格的分子途径。
- 批准号:
8584322 - 财政年份:2011
- 资助金额:
$ 67.1万 - 项目类别:
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