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

项目摘要 除了信号传导/转录因子依赖的调控机制，谱系特异性基因 干细胞及其后代中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。表观遗传调节机制 维持表皮角质形成细胞中的祖细胞群和上皮身份，以及抑制过早的 激活终末分化相关基因并平衡其在分化细胞中的转录。 转座因子（Transposable elements，TE）占整个小鼠或人类基因组的很大一部分（44%-55 基因组大多数TE在生理条件下是转录失活的，而它们的不适当的表达是不稳定的。 激活与自身免疫性疾病和癌发生的发病机制有关。在角质形成细胞中， 紫外线照射可激活多种内源性逆转录病毒序列的转录， 在红斑狼疮患者中激活的序列。此外，越来越多的数据表明， 内源性TE参与促炎性皮肤病如银屑病的发展。 然而，该项目寻求调查的一些关键问题仍然不清楚： 1)哪些TE在皮肤发育、出生后体内平衡和发育过程中在正常角质形成细胞中表达， 终末分化，2）哪些机制调节角质形成细胞中的TE沉默，以及3）当TE沉默时， 受到影响时，角质形成细胞分化和表皮炎症反应如何受到影响？ 在这个多PI的建议，我们将解决的假设，不同类别的TE差异贡献 通过表观遗传调节因子Lsh和Setdb 1介导的表皮角质形成细胞中基因表达的控制 作为介导TE沉默和防止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来解决： 目标1.定义转座因子在正常小鼠和人类中的表达情况 角质形成细胞在皮肤发育、出生后体内平衡和终末分化过程中的作用。 目标二。定义Lsh和Setdb 1在控制转座因子沉默中的作用， 角质形成细胞 目标3：定义转座因子激活的影响和机制， 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为基本机制提供新的见解 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 新的范例，用于管理疾病的表皮分化和炎症反应， 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.