Plasticity in an embryonic gene regulatory network
胚胎基因调控网络的可塑性
基本信息
- 批准号:10299492
- 负责人:
- 金额:$ 32.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-04-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:Activator AppliancesAffectAnimalsArchitectureCaenorhabditis elegansCandidate Disease GeneCell divisionCellsChromatinComplexCongenital AbnormalityDevelopmentDevelopmental GeneEmbryoEmbryonic DevelopmentEndodermEnsureEpigenetic ProcessEventExcisionGene ExpressionGenesGeneticGenetic TranscriptionGenetic VariationGenomeGenotypeGerm LayersGoalsHeritabilityHistonesHumanIndividualLeadMAP Kinase GeneMalignant NeoplasmsMapsMedicalMethodsMethylationMolecularNuclearOutcomeOutputParentsPathway interactionsPharmaceutical PreparationsPharmacologyPhenotypePhosphotransferasesPhysiologicalProcessQuantitative Trait LociRNARNA InterferenceRegulationRegulator GenesResearchResolutionRoleSignal TransductionSmall RNASorting - Cell MovementSystemTCF Transcription FactorTestingTo specifyUntranslated RNAVariantWNT Signaling Pathwaybasebody systemcausal variantdifferential expressionendodermal progenitorepigenetic variationgenetic makeupgenetic variantgenome-widenetwork architecturenext generation sequencingnon-geneticpiRNAprecision medicineresponsestem cellstranscription factortransgenerational epigenetic inheritancezygote
项目摘要
SUMMARY
The major objective of the proposed research is to illuminate the molecular basis underlying genetic and
epigenetic variation in a major developmental gene regulatory network (GRN). Studies from this and other labs
have identified a cascade of “core” zygotically expressed GATA-type transcription factors, and maternal
regulatory inputs, that activate the GRN controlling development of the endoderm in C. elegans. The latter
include the maternally supplied SKN-1/Nrf2 transcription factor and a triply redundant Wnt, MAPK, and src
signaling system that acts through the LIT-1/NLK kinase and the POP-1/Tcf/Lef transcription factor to initiate
endoderm development. Removal of any one of these inputs results in an impenetrant phenotype, reflecting a
bistable state that shows wide variation between genetically distinct isotypes. Analysis of reciprocal crosses
between isotypes with quantitatively different requirements for SKN-1 in this process revealed that endoderm
GRN output is also influenced by long-term heritable epigenetic states that differ between natural C. elegans
isotypes. This transgenerational epigenetic inheritance (TEI) requires genes involved in piRNA function, the
nuclear RNAi pathway, and histone H3K9 methylation. These findings provide a springboard for unveiling the
molecular basis for genetic and epigenetic plasticity in the regulation of the endoderm GRN. In Aim 1, we will
evaluate hypotheses regarding the mechanisms of action of three genes that differentially alter the requirements
for SKN-1 and Wnt signaling. We will assess how expression of the core regulators of endoderm development
is influenced by quantitative variation in the requirement for the maternal GRN inputs. We will assess how
variation in the requirement for LIT-1 kinase is accommodated in the mechanism that controls asymmetric cell
division leading to activation of the endoderm GRN and will test the hypothesis that quantitative variation in the
requirement for LIT-1 extends to its global action in many asymmetric cell divisions. In Aim 2, we will develop
and implement high-resolution, high-throughput approaches to identifying causal genes underlying variation in
the requirement for the major endoderm regulatory inputs. We will test candidate genes for modulation of the
SKN-1-dependent activation of the endoderm GRN. In Aim 3, we will analyze the molecular basis for
transgenerational inheritance (TEI) of GRN output. We will assess the stages in the endoderm GRN that are
modulated by this TEI and test the hypothesis that epigenetic differences in SKN-1 requirement between
selected isotypes extends to other regulatory inputs. We will test the hypothesis that TEI results from differences
in chromatin states of endoderm genes and that differential expression of non-coding RNAs and endoderm
regulatory genes is associated with TEI. Findings from this research will help to illuminate mechanisms of birth
defects and can provide a paradigm for understanding relationships between an individual’s genotype and
responsiveness to pharmacological agents, of importance to advancing precision medicine. They will also reveal
factors that alter the outcome of Wnt signaling, a major regulatory mechanism associated with many cancers.
总结
这项研究的主要目的是阐明遗传和
主要发育基因调控网络(GRN)中的表观遗传变异。这个实验室和其他实验室的研究
已经确定了一个级联的“核心”合子表达的GATA型转录因子,
调控输入,激活GRN控制C.优美的后者
包括母源性SKN-1/Nrf 2转录因子和三重冗余的Wnt、MAPK和src
信号系统,通过LIT-1/NLK激酶和POP-1/Tcf/Lef转录因子起作用,启动
内胚层发育去除这些输入中的任何一个都会导致不渗透表型,反映了
在遗传上不同的同种型之间显示出广泛变异的状态。正反交分析
在这个过程中,对SKN-1有不同数量需求的同种型之间的差异表明,
GRN输出也受到长期遗传的表观遗传状态的影响,这些表观遗传状态在天然C。elegans
同种型。这种跨代表观遗传(TEI)需要参与皮尔纳功能的基因,即基因组。
核RNAi途径和组蛋白H3 K9甲基化。这些发现为揭开
内胚层GRN调节中遗传和表观遗传可塑性的分子基础。在目标1中,我们
评估关于三个基因的作用机制的假设,这些基因差异地改变了需求
SKN-1和Wnt信号。我们将评估内胚层发育的核心调节因子的表达
受母体GRN输入需求的定量变化的影响。我们将评估如何
对LIT-1激酶需求的变化被调节在控制不对称细胞的机制中,
分裂导致内胚层GRN的激活,并将测试的假设,定量变化,
对LIT-1的需求扩展到其在许多不对称细胞分裂中的全局作用。在目标2中,我们将开发
并实施高分辨率、高通量方法来识别导致变异的因果基因
主要内胚层调节输入的要求。我们将测试候选基因的调节,
内胚层GRN的SKN-1依赖性活化。在目标3中,我们将分析
GRN输出的跨代继承(TEI)。我们将评估内胚层GRN的各个阶段,
通过这种TEI调节,并测试以下假设,即SKN-1需求的表观遗传差异
选择的同种型延伸到其他调节输入。我们将检验这一假设,即TEI的结果,从差异
内胚层基因染色质状态以及非编码RNA和内胚层的差异表达
调节基因与TEI相关。这项研究的结果将有助于阐明出生的机制
缺陷,并可以提供一个范例,了解个人的基因型之间的关系,
对药物的反应性,对推进精准医疗至关重要。他们还将揭示
改变Wnt信号传导结果的因素,Wnt信号传导是与许多癌症相关的主要调节机制。
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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Joel H. Rothman其他文献
Joel H. Rothman的其他文献
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{{ truncateString('Joel H. Rothman', 18)}}的其他基金
A model for elimination of defective mitochondrial genomes
消除有缺陷的线粒体基因组的模型
- 批准号:
10043796 - 财政年份:2020
- 资助金额:
$ 32.04万 - 项目类别:
MARC at the University of California Santa Barbara
加州大学圣塔芭芭拉分校 MARC
- 批准号:
10625331 - 财政年份:2020
- 资助金额:
$ 32.04万 - 项目类别:
A model for elimination of defective mitochondrial genomes
消除有缺陷的线粒体基因组的模型
- 批准号:
10266765 - 财政年份:2020
- 资助金额:
$ 32.04万 - 项目类别:
Developmental reprogramming and transorganogenesis
发育重编程和跨器官发生
- 批准号:
10588050 - 财政年份:2015
- 资助金额:
$ 32.04万 - 项目类别:
UC Santa Barbara MARC Program: Bridges to Biomedical Research Careers
加州大学圣巴巴拉分校 MARC 项目:通向生物医学研究职业的桥梁
- 批准号:
8856392 - 财政年份:2015
- 资助金额:
$ 32.04万 - 项目类别:
Developmental reprogramming and transorganogenesis
发育重编程和跨器官发生
- 批准号:
8888152 - 财政年份:2015
- 资助金额:
$ 32.04万 - 项目类别:
Plasticity in an embryonic gene regulatory network
胚胎基因调控网络的可塑性
- 批准号:
9020247 - 财政年份:2015
- 资助金额:
$ 32.04万 - 项目类别:
UC Santa Barbara MARC Program: Bridges to Biomedical Research Careers
加州大学圣巴巴拉分校 MARC 项目:通向生物医学研究职业的桥梁
- 批准号:
9482449 - 财政年份:2015
- 资助金额:
$ 32.04万 - 项目类别:
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