Chromatin architectural protein CTCF and regulation of skin development and tumorigenesis
染色质结构蛋白 CTCF 与皮肤发育和肿瘤发生的调节
基本信息
- 批准号:9318763
- 负责人:
- 金额:$ 55.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-02-15 至 2021-12-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAddressAnimal GeneticsAnimal ModelAntineoplastic AgentsArchitectureAreaAutoimmunityBiologyCCCTC-binding factorCell LineageCell NucleusCellsChromatinChronicDNADataDevelopmentDistal Enhancer ElementsEnhancersEnzymesEpidermisEpigenetic ProcessEpithelialEpithelial CellsFormaldehydeGene ActivationGene ExpressionGene Expression RegulationGene OrderGene SilencingGenesGeneticGenetic Enhancer ElementGenomeGoalsHairHair follicle structureHigher Order Chromatin StructureHistonesHomeostasisHumanImpairmentKnowledgeLinkMaintenanceMalignant NeoplasmsMediatingModificationMusMutateNeoplastic Cell TransformationNeuronsOncogene ActivationOncogenesPathologicPatternPhenotypePlayPolycombPopulationProteinsQuality of lifeRegulationRegulatory ElementResearchRoleSignal TransductionSkinSkin CancerStem cellsTechniquesTestingTherapeutic InterventionTranscriptional RegulationTumor Suppressor GenesTumor Suppressor ProteinsUntranslated RNAWNT Signaling PathwayZinc Fingersbasecarcinogenesischromosome conformation capturecrosslinkepigenetic drughistone modificationinhibitor/antagonistkeratinocytememberneoplastic cellnovelpostnatalprogramspromoterskin barrierskin disorderskin organogenesisskin regenerationstem cell differentiationtissue regenerationtranscription factortumortumorigenesis
项目摘要
PROJECT SUMMARY
The long-term goal of this project is to understand how epithelial stem cells in the skin establish distinct
patterns of gene activation and silencing during their differentiation into specialized cell lineages and how these
genetic programs are re-organized during skin regeneration and tumorigenesis.
It is now widely accepted that in addition to signaling/transcription factor-mediated mechanisms, lineage-
specific gene expression programs are also regulated epigenetically, i.e., via covalent DNA/histone
modifications, as well as via spatial arrangements of the genes and their enhancer elements in the nucleus.
Enhancer-promoter interactions serve as key determinants providing functional and structural frameworks
for cell-specific transcription controlled by lineage-specific transcription factors. However, enhancer-promoter
regulatory networks are substantially re-organized during cell transition towards malignancy, which include an
aberrant exposure of gene promoters to inappropriate regulatory elements resulting in activation of pro-
oncogenes, as well as in silencing of the tumor suppressor genes.
CCCTC-binding factor (CTCF) serves as one of the core architectural proteins that plays a key role in the
control the establishment and maintenance of enhancer/promoter interactions. CTCF gene is frequently mutated
in cancers, and abrogation of its tumor-suppressor activity contributes to cancer development and progression.
Our preliminary data demonstrate that CTCF is expressed in both mouse and human epidermis, while
Krt14-driven Ctcf genetic ablation results in severe alterations in skin development, epidermal barrier
maintenance, and tumorigenesis. In this multi-PI proposal, we will test a hypothesis that CTCF serves as critical
determinant that control the establishment and maintenance of the enhancer-promoter regulatory networks in
skin epithelial stem cells and their progenies during development and postnatal homeostasis, while alterations
in such networks result in skin tumorigenesis. We will address this hypothesis via two Specific Aims:
1. Define the roles of CTCF in the establishment and maintenance of lineage-specific higher-order
chromatin structure, enhancer-promoter regulatory networks and gene expression in distinct
populations of skin epithelial cells during development and hair cycle-associated skin regeneration.
2. Delineate the roles for Ctcf in regulation of gene expression, 3D chromatin organization and
enhancer-promoter interactions in the skin epithelial cells during tumorigenesis.
This project will have a fundamental impact on our current knowledge of epigenetic mechanisms that
regulate genome reorganization in stem cells during their differentiation and tumorigenesis and will promote the
progress towards the development of novel epigenetic drugs as a new paradigm for treatment of skin disorders.
项目总结
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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VLADIMIR A BOTCHKAREV其他文献
VLADIMIR A BOTCHKAREV的其他文献
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{{ truncateString('VLADIMIR A BOTCHKAREV', 18)}}的其他基金
Transposable elements in the keratinocyte genome and their regulation during skin development and epidermal differentiation
角质形成细胞基因组中的转座元件及其在皮肤发育和表皮分化过程中的调节
- 批准号:
10560618 - 财政年份:2021
- 资助金额:
$ 55.37万 - 项目类别:
Transposable elements in the keratinocyte genome and their regulation during skin development and epidermal differentiation
角质形成细胞基因组中的转座元件及其在皮肤发育和表皮分化过程中的调节
- 批准号:
10372905 - 财政年份:2021
- 资助金额:
$ 55.37万 - 项目类别:
The skin of naked mole rats as a model for scar-free wound healing
裸鼹鼠皮肤作为无疤痕伤口愈合模型
- 批准号:
10083984 - 财政年份:2020
- 资助金额:
$ 55.37万 - 项目类别:
The skin of naked mole rats as a model for scar-free wound healing
裸鼹鼠皮肤作为无疤痕伤口愈合模型
- 批准号:
10238154 - 财政年份:2020
- 资助金额:
$ 55.37万 - 项目类别:
The skin of naked mole rats as a model for scar-free wound healing
裸鼹鼠皮肤作为无疤痕伤口愈合模型
- 批准号:
10831130 - 财政年份:2020
- 资助金额:
$ 55.37万 - 项目类别:
DNA hydroxymethylation and Tet-enzymes in the control of the skin development and hair growth
DNA 羟甲基化和 Tet 酶在控制皮肤发育和毛发生长中的作用
- 批准号:
10641894 - 财政年份:2019
- 资助金额:
$ 55.37万 - 项目类别:
DNA hydroxymethylation and Tet-enzymes in the control of the skin development and hair growth
DNA 羟甲基化和 Tet 酶在控制皮肤发育和毛发生长中的作用
- 批准号:
10433970 - 财政年份:2019
- 资助金额:
$ 55.37万 - 项目类别:
DNA hydroxymethylation and Tet-enzymes in the control of the skin development and hair growth
DNA 羟甲基化和 Tet 酶在控制皮肤发育和毛发生长中的作用
- 批准号:
9982783 - 财政年份:2019
- 资助金额:
$ 55.37万 - 项目类别:
DNA hydroxymethylation and Tet-enzymes in the control of the skin development and hair growth
DNA 羟甲基化和 Tet 酶在控制皮肤发育和毛发生长中的作用
- 批准号:
10186705 - 财政年份:2019
- 资助金额:
$ 55.37万 - 项目类别:
Chromatin architectural protein CTCF and regulation of skin development and tumorigenesis
染色质结构蛋白 CTCF 与皮肤发育和肿瘤发生的调节
- 批准号:
9910061 - 财政年份:2017
- 资助金额:
$ 55.37万 - 项目类别:
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