HMBOX1在干细胞端粒功能和多能性调控中的作用和机制研究

Genome stability and pluripotency maintenance of stem cells are not only relied on the regulation of some important endogenous transcription factors and the modulation of different signaling pathways but also depended on functional telomeres, which protect the integrity end of chromosome. HMBOX1 is a DNA-binding protein and a potential transcription factor. We found that HMBOX1 is a novel telomere-associated protein and it could directly bind to telomeric DNA in embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) specifically. Our preliminary results indicate that HMBOX1 plays an important role in the maintenance of telomere integrity and stem cell pluripotency. Our project will systematically study HMBOX1 characterizations on regulation of telomere functions by using two types of cell models, which maintain their telomeres through a telomerase dependent mechanism or a telomerase independent mechanism termed alternative lengthening of telomeres (ALT). And then, we will focus on how HMBOX1 affects telomere functions and pluripotency in ESCs and iPSCs. Furthermore, we plan to product HMBOX1 conditional knockout mice and will use this mice model to figure out how HMBOX1 regulate telomere functions in totipotent zygotes during preimplantation embryo development and how HMBOX1 affects telomere functions and pluripotency in adult stem cells, such as spermatogonial stem cells (SSCs). This study will discover the novel functions of HMBOX1 functions in telomere biology、stem cells growth and ontogenesis.

干细胞基因组的稳定性及其多能性的维持不仅依赖于一些重要内源因子的调控和不同信号通路的调节，也有赖于端粒功能的正常实现。HMBOX1是一种DNA结合蛋白，也是一种潜在的转录调控因子。我们发现HMBOX1特异地结合在胚胎干细胞和诱导多能性干细胞的端粒DNA上，是一种新的端粒调控蛋白。初步的研究结果显示，HMBOX1在调控端粒稳定性和干细胞多能性中扮演着重要的角色。本项目将利用端粒酶依赖和端粒延长替代机制的细胞，首次系统地研究HMBOX1对端粒功能的调控作用，继而重点研究HMBOX1对干细胞端粒稳定性和多能性的影响，最后制作HMBOX1的条件性敲除小鼠模型，研究它对全能性的受精卵发育过程中端粒正常延伸的影响以及对成体干细胞中的精原干细胞端粒稳定性和多能性的调节作用。通过课题研究，我们将阐明HMBOX1的端粒调控机制与网络，解析HMBOX1是如何参与端粒调控、干细胞生长和个体发育等重要过程。

干细胞基因组的稳定性及其多能性的维持不仅依赖于一些重要内源因子的调控和不同信号通路的调节，也有赖于端粒功能的正常实现。HMBOX1是一种DNA结合蛋白，也是一种潜在的转录调控因子。我们发现HMBOX1特异地结合在胚胎干细胞和诱导多能性干细胞的端粒DNA上，是一种新的端粒调控蛋白。初步的研究结果显示，HMBOX1在调控端粒稳定性和干细胞多能性中扮演着重要的角色。本项目将利用端粒酶依赖和端粒延长替代机制的细胞，首次系统地研究HMBOX1对端粒功能的调控作用，继而重点研究HMBOX1对干细胞端粒稳定性和多能性的影响，最后制作HMBOX1的条件性敲除小鼠模型，研究它对全能性的受精卵发育过程中端粒正常延伸的影响以及对成体干细胞中的精原干细胞端粒稳定性和多能性的调节作用。通过课题研究，我们将阐明HMBOX1的端粒调控机制与网络，解析HMBOX1是如何参与端粒调控、干细胞生长和个体发育等重要过程。