Role of Satb1 in the control of topological genome organization during skin development and ageing

在组织工程和干细胞驱动的器官再生新方法的开发时代，研究人员和医生必须了解多能干细胞是如何分化为特殊细胞类型的，以及为什么这些过程会在衰老和与衰老相关的疾病(如癌症、组织再生障碍、伤口愈合、脱发)中发生变化。皮肤是研究衰老过程生物学的重要和方便的模型，皮肤结构和功能在衰老过程中发生变化。皮肤也是成体干细胞的来源，从皮肤中分离出来的几个不同的成体体细胞群被成功地用于重新编程和产生诱导的多能细胞。过去二十年对基因组和染色质生物学的研究表明，除了遗传机制外，谱系特异的基因表达程序也受到表观遗传的调控，即通过染色质结构的生化修饰。基因组组织者Satb1蛋白在核内不同基因之间建立特定的联系中起着重要作用，这是适当控制细胞功能和基因表达程序所必需的。Satb1蛋白通过在核中建立皮肤特异性基因组位点的特定三维构象来调节在皮肤上皮细胞中高表达的基因的表达。然而，它在控制皮肤老化方面的作用尚不清楚。在这个项目中，我们建议进行一项系统的研究，以1)了解皮肤特定基因位点是如何在细胞核中空间组织的，2)定义形成其邻近基因组的基因，以及3)了解Satb1蛋白如何在皮肤发育和衰老过程中调节这些过程。该项目的成功实施将有助于更好地了解控制皮肤发育和衰老的调节机制的复杂性，并设计新的方法来调节衰老过程，并在临床年龄相关条件下靶向干细胞，同时伴随其不受控制的激活/扩张或耗尽/丢失。

In the era of tissue engineering and the development of novel approaches for stem cell-driven organ regeneration, it is important for researchers and physicians to understand how multi-potent stem cells differentiate into specialised cell types, and why these processes are altered during ageing and age-associated disorders, such as cancer, impaired tissue regeneration, wound healing, hair loss.Skin serves as an important and convenient model to study the biology of ageing process, and skin structure and functions are altered during ageing. Skin also serves as a source of adult stem cells, and several distinct adult somatic cell populations isolated from the skin were successfully employed for reprogramming and generation of induced pluripotent cells. Research into genome and chromatin biology over the last two decades has revealed that in addition to genetic mechanisms, lineage-specific gene expression programs are also regulated epigenetically, i.e., via biochemical modification of the chromatin structure. Genome organizer Satb1 protein plays an important role in establishing specific associations between different genes in the nucleus, which are required for proper control of cellular functions and gene expression programs.Satb1 protein regulates expression of the genes that are highly expressed in skin epithelial cells via establishing of specific three-dimensional conformation of the skin-specific genomic loci in the nucleus. However, its role in the control of skin ageing remains unclear. In this project, we propose a systematic study to 1) understand how skin-specific gene loci are spatially organised in the nucleus, 2) define genes that form their close genomic neighbourhood and 3) understand how Satb1 protein regulates these processes during skin development and ageing. Successful performance of this project will help in better understanding the complexity of regulatory mechanisms that control skin development and ageing and in designing new approaches for modulating ageing process and targeting stem cells in the clinical age-associated conditions accompanied by their un-controlled activation/expansion or exhausting/loss