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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：
Robert Aaron Cornell
金额：
$ 54.59万
依托单位：
UNIVERSITY OF WASHINGTON
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：
https://reporter.nih.gov/project-details/10607024
关键词：
ATAC-seq Acceleration Address Aging Apoptosis Binding Biological Assay Branchio-Oculo-Facial Syndromes Cell Aging Cell Differentiation process Cell Line Cell Maintenance Cells ChIP-seq Chromatin Data Defect Development Differentiation and Growth Embryo Enhancers Enterobacteria phage P1 Cre recombinase Epithelial Equilibrium Exhibits Family Feedback Gene Activation Gene Expression Genes Genetic Epistasis Genetic Transcription Growth Hair Hair Removal Hair follicle structure Hair shaft structure Homeostasis Human Improve Access In Vitro Ligase MEL Gene Maintenance Malignant Neoplasms Mediating Melanoma Cell Modeling Mus Mutation Natural regeneration Neural Crest Normal Cell Outcome Pathway interactions Patients Pigments Proliferating Proteins Regulation Regulatory Element Regulatory Pathway Reporter Research Role Signal Transduction Skin Stem Cell Development Study models Sumoylation Pathway Syndrome TFAP2A gene Testing Tissues Transactivation Transcription Coactivator Transcription Factor AP-2 Alpha Variant Zebrafish activating transcription factor adult stem cell base cell behavior cell type enhancer-binding protein AP-2 experimental study gene regulatory network in vitro Assay in vivo inhibitor melanoblast melanocyte melanoma member microphthalmia-associated transcription factor mutant overexpression paralogous gene pluripotency premature prevent recruit regenerative senescence stem cell function stem cell niche stem cells transcription factor transcriptome 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.

干细胞的维护缺陷会导致组织再生能力的丧失，或者相反，

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：
eLife
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：
PloS one
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：
eLife
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.