Transposable elements in the keratinocyte genome and their regulation during skin development and epidermal differentiation

项目总结 除了信号/转录因子依赖的调节机制外，谱系特异性基因 干细胞及其后代的表达程序也受到表观遗传学的调节，即通过调节 共价DNA/组蛋白修饰和高阶染色质重塑。表观遗传调控机制 维持表皮角质形成细胞的祖细胞数量和上皮特性，并抑制早熟 在分化细胞中激活与末端分化相关的基因并平衡它们的转录。 转座元件(TES)构成了整个小鼠或人类的很大一部分(44%-55%) 基因组。大多数TES在生理条件下转录不活跃，而它们的不适当 激活与自身免疫性疾病的发病机制和肿瘤的发生有关。角质形成细胞中， 紫外线照射可激活多种内源性逆转录病毒序列的转录，这些序列与 红斑狼疮患者的序列被激活。此外，越来越多的数据证据表明， 内源性TES参与了促炎性皮肤疾病的发展，如牛皮癣。 然而，这个项目试图调查的一些关键问题仍然不清楚： 1)哪些TES在正常角质形成细胞中表达，在皮肤发育、出生后动态平衡和 终末分化，2)角质形成细胞中TE沉默的调节机制，以及3)TE沉默的时间 如果受损，角质形成细胞分化和表皮炎症反应是如何受到影响的？ 在这个多PI方案中，我们将解决不同类别的TE具有不同贡献的假设 表观遗传调节因子LSH和SetDB1对表皮角质形成细胞基因表达的调控 它们是介导TE沉默和预防促炎反应的关键决定因素 表皮。这一假设将通过三个具体目标加以阐述： 目的1.确定转座元件在正常小鼠和人中的表达情况 角质形成细胞在皮肤发育、出生后动态平衡和终末分化过程中的作用。 目的2.确定LSH和Setdb1在控制转座元件沉默中的作用 角质形成细胞。 目标3.定义与转座元件激活相关的影响和机制 角质形成细胞对表皮炎症反应的影响。 该应用程序生成的输出将提供对基本机制的新见解 在正常小鼠和人类皮肤中潜在的角质形成细胞分化，以及将促进发育 治疗表皮分化障碍和炎症反应的新范例 人类通过调节TE活动。

PROJECT SUMMARY In addition to signaling/transcription factor-dependent regulatory mechanisms, lineage-specific gene expression programs in stem cells and their progenies are also regulated epigenetically, i.e., via regulation of covalent DNA/histone modifications and higher-order chromatin remodeling. Epigenetic regulatory machinery maintain the progenitor population and epithelial identity in epidermal keratinocytes, as well as inhibit premature activation of terminal differentiation-associated genes and balance their transcription in differentiating cells. Transposable elements (TEs) constitute a large portion (44%-55%) of the entire mouse or human genomes. Most TEs are transcriptionally inactive under physiological conditions, while their inappropriate activation has been implicated in pathogenesis of autoimmune disorders and carcinogenesis. In keratinocytes, UV exposure activates transcription of various endogenous retroviral sequences which are closely related to the sequences activated in lupus erythematosus patients. Furthermore, increasing evidence of data suggest an involvement of endogenous TEs in the development of pro-inflammatory skin conditions, such as psoriasis. However, there is a number of critical questions that this project seeks to investigate, remain unclear: 1) Which TEs are expressed in normal keratinocytes during skin development, postnatal homeostasis and terminal differentiation, 2) Which mechanisms regulate TE silencing in keratinocytes, and 3) When TE silencing is compromised, how are keratinocyte differentiation and epidermal inflammatory response impacted? In this Multi-PI proposal, we will address the hypothesis that distinct classes of TEs differentially contribute to the control of gene expression in epidermal keratinocytes, mediated by epigenetic regulators Lsh and Setdb1 that serve as critical determinants mediating the TE silencing and preventing pro-inflammatory responses in the epidermis. This hypothesis will be addressed via three Specific Aims: Aim 1. Define the landscape of transposable element expression in normal mouse and human keratinocytes during skin development, postnatal homeostasis and terminal differentiation. Aim 2. Define the roles for Lsh and Setdb1 in the control of transposable element silencing in keratinocytes. Aim 3. Define the impact and mechanisms associated with the transposable element activation in keratinocytes on epidermal inflammatory response. The generated outputs from this application will provide novel insights into fundamental mechanisms underlying keratinocyte differentiation in normal mouse and human skin, as well as will promote the development of novel paradigms for management of disorders of epidermal differentiation and inflammatory responses in humans via modulation of TE activities.