HDAC functions in skin development, renewal and disease

描述（由申请人提供）：项目总结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，这些变化通常在肿瘤发生中失调。组蛋白去乙酰化酶（HDAC）通过染色质的抑制性修饰提供基因表达程序的全局控制，并形成几个类别，其中第1类成员显示出最高的组蛋白去乙酰化酶活性。其中，HDAC 1和2与NuRD复合物中的Mi2 β、MTA-2和MDB 3缔合，并且与Sin 3复合物中的Sin 3、SAP 18和SAP 30缔合，而HDAC 3与N-CoR或SMRT复合。HDAC抑制剂（HDACi）是治疗多种肿瘤的有效药物。然而，虽然个体HDAC的功能和靶点差异很大，但大多数HDACi广泛抑制1类HDAC，并且对其确切的作用机制知之甚少。该提案的目标是使用遗传、生物化学和全局基因组方法来描绘和比较HDAC 1、HDAC 2和HDAC 3在皮肤上皮细胞的发育和再生中的功能，以鉴定将个体HDAC靶向皮肤上皮细胞中的特定启动子组的转录因子，并确定Hdac 1缺失的后果，2或3用于表皮肿瘤的起始和进展。来自这些实验的数据对于评估靶向表皮中个体HDAC的潜在风险和益处以及开发更特异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 Mi2ß, 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.