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

在组织工程和开发干细胞驱动的器官再生新方法的时代，研究人员和医生必须了解多能干细胞如何分化为专门的细胞类型，以及为什么这些过程在衰老和年龄相关疾病（如癌症，组织再生受损，伤口愈合，脱发。皮肤是研究老化过程的重要和方便的模型，皮肤结构和功能在老化过程中发生变化。皮肤也作为成体干细胞的来源，并且从皮肤分离的几种不同的成体体细胞群被成功地用于重编程和诱导多能细胞的产生。过去二十年来对基因组和染色质生物学的研究已经揭示，除了遗传机制之外，谱系特异性基因表达程序也受到表观遗传学的调节，即，通过染色质结构的生化修饰。基因组组织者Satb 1蛋白在细胞核内不同基因之间建立特异性关联，从而调控细胞功能和基因表达程序，通过在细胞核内建立皮肤特异性基因组位点的特异性三维构象，调控皮肤上皮细胞中高表达基因的表达。然而，它在控制皮肤衰老中的作用仍不清楚。在这个项目中，我们提出了一个系统的研究，以1）了解皮肤特异性基因位点是如何在细胞核中空间组织的，2）定义形成其密切的基因组邻域的基因，3）了解Satb 1蛋白如何在皮肤发育和衰老过程中调节这些过程。本项目的成功实施将有助于更好地理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，并在临床年龄相关疾病中靶向干细胞，伴随着它们的不受控制的激活/扩增或耗尽/损失

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