HDAC functions in skin development, renewal and disease

描述(由申请人提供)：项目摘要：胚胎发育和出生后表皮和毛囊的更新需要基因表达的协调变化，而基因表达在肿瘤发生中往往是失调的。组蛋白脱乙酰酶(HDAC)通过抑制染色质的修饰来提供对基因表达程序的全局控制力，并形成几个类别，其中第一类成员显示出最高的组蛋白脱乙酰基酶活性。其中，HDACs 1和2与NuRD复合体中的Mi2β、MTA-2和MDB3结合，在Sin3复合体中与Sin3、SAP18和SAP30结合，而HDAC3与N-COR或SMRT结合。HDAC抑制剂(HDACi)是治疗多种肿瘤的很有前途的药物。然而，虽然各个HDACs的功能和靶点差异很大，但大多数HDACi广泛地抑制第一类HDACs，其确切的作用机制尚不清楚。该方案的目的是利用遗传学、生物化学和全球基因组学方法来描述和比较HDAC1、HDAC2和HDAC3在皮肤上皮细胞发育和再生中的功能，识别针对皮肤上皮细胞中特定启动子的转录因子，并确定HDAC1、2或3缺失对表皮肿瘤发生和发展的影响。这些实验的数据对于评估在表皮中靶向单个HDAC的潜在风险和好处以及开发更具体和有效的治疗方法至关重要。

DESCRIPTION (provided by applicant): Project summary Embryonic development and postnatal renewal of the epidermis and hair follicles require coordinated changes in gene expression that are often dysregulated in tumorigenesis. Histone deacetylases (HDACs) provide global control of gene expression programs by repressive modification of chromatin, and form several classes, of which Class 1 members display the highest histone deacetylase activity. Of these, HDACs 1 and 2 associate with Mi2?, MTA-2 and MDB3 in the NuRD complex and with Sin3, SAP18 and SAP30 in the Sin3 complex, while HDAC3 complexes with N-CoR or SMRT. HDAC inhibitors (HDACi) are promising therapeutic agents for multiple types of tumor. However, while the functions and targets of individual HDACs vary widely, most HDACi broadly inhibit Class 1 HDACs, and their precise mechanisms of action are poorly understood. The goals of this proposal are to use genetic, biochemical, and global genomic approaches to delineate and compare the functions of HDAC1, HDAC2 and HDAC3 in the development and regeneration of skin epithelia, to identify transcription factors that target individual HDACs to specific sets of promoters in skin epithelial cells, and to determine the consequences of deletion of Hdac1, 2 or 3 for the initiation and progression of epidermal tumors. Data from these experiments will be critical for evaluating the potential risks and benefits of targeting individual HDACs in the epidermis and for developing more specific and effective therapeutics.