Regulation of the Melanocyte Lineage by the AP2 Transcription Factor Family
AP2 转录因子家族对黑素细胞谱系的调节
基本信息
- 批准号:10607024
- 负责人:
- 金额:$ 54.59万
- 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:2022-04-12 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:ATAC-seqAccelerationAddressAgingApoptosisBindingBiological AssayBranchio-Oculo-Facial SyndromesCell AgingCell Differentiation processCell LineCell MaintenanceCellsChIP-seqChromatinDataDefectDevelopmentDifferentiation and GrowthEmbryoEnhancersEnterobacteria phage P1 Cre recombinaseEpithelialEquilibriumExhibitsFamilyFeedbackGene ActivationGene ExpressionGenesGenetic EpistasisGenetic TranscriptionGrowthHairHair RemovalHair follicle structureHair shaft structureHomeostasisHumanImprove AccessIn VitroLigaseMEL GeneMaintenanceMalignant NeoplasmsMediatingMelanoma CellModelingMusMutationNatural regenerationNeural CrestNormal CellOutcomePathway interactionsPatientsPigmentsProliferatingProteinsRegulationRegulatory ElementRegulatory PathwayReporterResearchRoleSignal TransductionSkinStem Cell DevelopmentStudy modelsSumoylation PathwaySyndromeTFAP2A geneTestingTissuesTransactivationTranscription CoactivatorTranscription Factor AP-2 AlphaVariantZebrafishactivating transcription factoradult stem cellbasecell behaviorcell typeenhancer-binding protein AP-2experimental studygene regulatory networkin vitro Assayin vivoinhibitormelanoblastmelanocytemelanomamembermicrophthalmia-associated transcription factormutantoverexpressionparalogous genepluripotencyprematurepreventrecruitregenerativesenescencestem cell functionstem cell nichestem cellstranscription factortranscriptome sequencing
项目摘要
Defects in the maintenance of stem cells can result in loss of the ability of tissues to regenerate or, conversely,
in dysregulated growth and cancer. How the stem cell resists losing its regenerative qualities while retaining
control of proliferation remains poorly understood. The melanocyte stem cell (MSC) is an ideal model for the
study of adult stem cells in general. Either the apoptosis or differentiation of this cell type can cause hair
graying, and mutations in MITF, which encodes the master regulator of melanocyte development, have been
shown to cause hair graying in mice. Mutations in TFAP2A (Transcription Factor Activating-enhancer binding
Protein 2 alpha) cause branchio-oculo-facial syndrome (BOFS), which includes premature hair graying.
However, the mechanisms whereby TFAP2 proteins contribute to the relevant regulatory networks in MSCs
remain unclear. Based on extensive preliminary data from zebrafish, mice, and cultured human melanocytes,
our overall hypothesis is that AP-2 activity regulates pluripotency, growth and differentiation in melanocytes
and MSCs, working in parallel with MITF and regulated by KCTD15-mediated sumoylation. In Aim 1 we will
test the hypothesis that that cell-autonomous TFAP2 activity, provided redundantly by two paralogs, is
necessary for the maintenance of MSCs, and that BOFS-associated TFAP2A variants inhibit both paralogs,
leading to ectopic differentiation of MSCs and to hair graying. We will test this hypothesis in mice by deleting
the relevant Tfap2 paralogs in MSCs or in cells of the MSC niche, and examining hair graying and MSC status.
In Aim 2 we will test the hypothesis that TFAP2 paralogs serve as pioneer factors at a subset of the loci to
which MITF binds, facilitating MITF-mediated activation of genes that promote growth and differentiation. This
will entail deleting TFAP2 paralogs from a melanoma cell line and then assessing open chromatin using ATAC-
SEQ, and binding of MITF using ChIP-SEQ. We will carry out parallel experiments in primary melanoblasts
isolated from zebrafish embryos. In Aim 3 we will test the hypothesis that a negative feedback loop in TFAP2A
signaling is necessary for the correct balance of maintenance and recruitment of MSCs. We found that a
potent inhibitor of TFAP2-paralog transactivation activity, KCTD15, is expressed in melanocytes, and that
zebrafish kctd15a/b mutants exhibit supernumerary, ectopic melanocytes. We will test the model that Kctd15-
mediated sumoylation of Tfap2a blocks its transactivation activity, testing sumoylation in vitro. We will test
kctd15a for a role in controlling melanocyte differentiation by abrogating its expression in the melanocyte
lineage. We will also test the prediction that inhibition of TFAP2 mediates the effects of KCTD15 in the
melanocyte lineage. The expected outcome of the proposed research is a deeper understanding of pathways
that regulate the balance of growth and differentiation of MSCs. An understanding of the mechanisms whereby
MITF and TFAP2 proteins contribute to MSC maintenance, and of how these factors are regulated, will have a
broad impact as they participate in mechanisms of aging and in the initiation and progression of melanoma.
干细胞维持的缺陷会导致组织再生能力的丧失,或者相反,
在生长失调和癌症中的作用干细胞如何抵抗失去其再生品质,同时保留
对扩散控制的了解仍然很少。黑素细胞干细胞(MSC)是研究黑素细胞分化的理想模型。
成体干细胞的研究。这种细胞类型的凋亡或分化可以导致毛发
变灰和MITF突变,MITF编码黑素细胞发育的主要调节因子,
导致老鼠毛发变白。TFAP 2A(转录因子激活增强子结合)突变
蛋白2 α)引起鳃-眼-面综合征(BOFS),其中包括过早的头发变白。
然而,TFAP 2蛋白对MSC中相关调控网络的作用机制
仍然不清楚。基于斑马鱼、小鼠和培养的人类黑素细胞的大量初步数据,
我们的总体假设是AP-2活性调节黑素细胞的多能性、生长和分化
和MSC,与MITF平行工作并由KCTD 15介导的类小泛素化调节。在目标1中,
测试由两个旁系同源物冗余提供的细胞自主TFAP 2活性,
这是维持MSC所必需的,并且BOFS相关的TFAP 2A变体抑制这两种旁系同源物,
导致MSC的异位分化和头发变灰。我们将在小鼠中测试这一假设,
MSC或MSC龛的细胞中的相关Tfap 2旁系同源物,并检查毛发变灰和MSC状态。
在目的2中,我们将检验TFAP 2旁系同源物在基因座的子集处充当先锋因子以
MITF与之结合,促进MITF介导的促进生长和分化的基因活化。这
将需要从黑色素瘤细胞系中删除TFAP 2旁系同源物,然后使用ATAC-
SEQ的MITF的结合,以及使用ChIP-SEQ.我们将在原代成黑素细胞中进行平行实验
分离自斑马鱼胚胎。在目标3中,我们将检验TFAP 2A中的负反馈回路
信号传导对于MSC的维持和募集的正确平衡是必需的。我们发现一个
TFAP 2-parabolic反式激活活性的有效抑制剂KCTD 15在黑素细胞中表达,
斑马鱼kctd 15 a/B突变体表现出多余的异位黑素细胞。我们将测试Kctd 15-
介导的类小泛素化阻断了Tfap 2a的反式激活活性,在体外测试类小泛素化。我们将测试
kctd 15 a通过消除其在黑素细胞中的表达在控制黑素细胞分化中的作用
脉我们还将测试TFAP 2抑制介导KCTD 15在细胞中的作用的预测。
黑素细胞谱系拟议研究的预期成果是对途径有更深入的了解
调节MSC生长和分化的平衡。对这些机制的理解
MITF和TFAP 2蛋白有助于MSC的维持,以及这些因子是如何调节的,
广泛的影响,因为它们参与衰老机制和黑色素瘤的发生和发展。
项目成果
期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Transcription factor MITF and remodeller BRG1 define chromatin organisation at regulatory elements in melanoma cells.
- DOI:10.7554/elife.06857
- 发表时间:2015-03-24
- 期刊:
- 影响因子:7.7
- 作者:Laurette P;Strub T;Koludrovic D;Keime C;Le Gras S;Seberg H;Van Otterloo E;Imrichova H;Siddaway R;Aerts S;Cornell RA;Mengus G;Davidson I
- 通讯作者:Davidson I
Motility phenotype in a zebrafish vmat2 mutant.
- DOI:10.1371/journal.pone.0259753
- 发表时间:2022
- 期刊:
- 影响因子:3.7
- 作者:Sveinsdóttir HS;Decker A;Christensen C;Lucena PB;Þorsteinsson H;Richert E;Maier VH;Cornell R;Karlsson KÆ
- 通讯作者:Karlsson KÆ
MITF reprograms the extracellular matrix and focal adhesion in melanoma.
MITF在黑色素瘤中重新编程细胞外基质和局灶性粘附。
- DOI:10.7554/elife.63093
- 发表时间:2021-01-13
- 期刊:
- 影响因子:7.7
- 作者:Dilshat R;Fock V;Kenny C;Gerritsen I;Lasseur RMJ;Travnickova J;Eichhoff OM;Cerny P;Möller K;Sigurbjörnsdóttir S;Kirty K;Einarsdottir BÓ;Cheng PF;Levesque M;Cornell RA;Patton EE;Larue L;de Tayrac M;Magnúsdóttir E;Ögmundsdóttir MH;Steingrimsson E
- 通讯作者:Steingrimsson E
TFAP2 paralogs facilitate chromatin access for MITF at pigmentation and cell proliferation genes.
- DOI:10.1371/journal.pgen.1010207
- 发表时间:2022-05
- 期刊:
- 影响因子:4.5
- 作者:
- 通讯作者:
BRN2 is a non-canonical melanoma tumor-suppressor.
- DOI:10.1038/s41467-021-23973-5
- 发表时间:2021-06-17
- 期刊:
- 影响因子:16.6
- 作者:Hamm M;Sohier P;Petit V;Raymond JH;Delmas V;Le Coz M;Gesbert F;Kenny C;Aktary Z;Pouteaux M;Rambow F;Sarasin A;Charoenchon N;Bellacosa A;Sanchez-Del-Campo L;Mosteo L;Lauss M;Meijer D;Steingrimsson E;Jönsson GB;Cornell RA;Davidson I;Goding CR;Larue L
- 通讯作者:Larue L
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Robert Aaron Cornell其他文献
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{{ truncateString('Robert Aaron Cornell', 18)}}的其他基金
Genetic underpinnings of craniofacial disorders explored with spatial sequencing
通过空间测序探索颅面疾病的遗传基础
- 批准号:
10712635 - 财政年份:2023
- 资助金额:
$ 54.59万 - 项目类别:
Dissecting the transcriptional network governing differentiation of periderm
剖析控制周皮分化的转录网络
- 批准号:
10589307 - 财政年份:2022
- 资助金额:
$ 54.59万 - 项目类别:
Dissecting the transcriptional network governing differentiation of periderm
剖析控制周皮分化的转录网络
- 批准号:
10521268 - 财政年份:2022
- 资助金额:
$ 54.59万 - 项目类别:
Cornell- Common Fund Data Supplement Regulation of the Melanocyte Lineage by the AP2 Transcription Factor Family
康奈尔大学共同基金数据补充 AP2 转录因子家族对黑素细胞谱系的调节
- 批准号:
9985505 - 财政年份:2019
- 资助金额:
$ 54.59万 - 项目类别:
Dissecting the transcriptional network governing differentiation of periderm
剖析控制周皮分化的转录网络
- 批准号:
9900769 - 财政年份:2019
- 资助金额:
$ 54.59万 - 项目类别:
Dissecting the transcriptional network governing differentiation of periderm
剖析控制周皮分化的转录网络
- 批准号:
10058264 - 财政年份:2019
- 资助金额:
$ 54.59万 - 项目类别:
Functional tests of non-coding DNA variants associated with risk for orofacial clefting
与口面部裂风险相关的非编码 DNA 变异的功能测试
- 批准号:
9924262 - 财政年份:2018
- 资助金额:
$ 54.59万 - 项目类别:
Functional tests of non-coding DNA variants associated with risk for orofacial clefting.
与口面部裂风险相关的非编码 DNA 变异的功能测试。
- 批准号:
10614747 - 财政年份:2018
- 资助金额:
$ 54.59万 - 项目类别:
Regulation of the melanocyte lineage by the AP2 transcription factor family
AP2 转录因子家族对黑素细胞谱系的调节
- 批准号:
8832130 - 财政年份:2014
- 资助金额:
$ 54.59万 - 项目类别:
Regulation of the Melanocyte Lineage by the AP2 Transcription Factor Family
AP2 转录因子家族对黑素细胞谱系的调节
- 批准号:
10229547 - 财政年份:2013
- 资助金额:
$ 54.59万 - 项目类别:
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