ATP酶依赖的染色质重塑复合体SWI/SNF介导“孕激素功能性撤退”的机制研究

Preterm is great harmful to newborns, functional progesterone withdrawal is a key mechanism for the onset of labor. Our previous studies have confirmed: before and after childbirth uterine smooth muscle PRA / PRB ratio change is the key reason functional progesterone withdrawal, PR promoter methylation plays an important role in the regulation of PRA / PRB ratio changes. Chromatin remodeling (histone acetylation and ATP-dependent SWI / SNF complex) loosen chromatin exposed gene promoter region, is closely related to DNA methylation. Accordingly group proposed "ATP-dependent SWI / SNF complex with histone acetylation involved in the regulation of uterine smooth PRA / PRB ratio, mediated functional progesterone withdrawal" hypothesis. The project is intended to people before and after childbirth for the study of uterine smooth muscle, tissues and cells from two levels, the use of genomics and proteomics to detect chromatin remodeling involved in regulating the expression of PRs; intervention in primary uterine smooth muscle cells PR promoter Histone acetylation and complex SWI / SNF complex expression, and molecular mechanisms between research in the regulation of expression of both PRs time. Provide a new theoretical basis for exploring the regulatory mechanisms of functional progesterone withdrawal, prevention and treatment of premature birth.

早产对新生儿危害极大，孕激素功能性撤退是分娩发动的关键机制。课题组前期研究证实：分娩前后子宫平滑肌PRA/PRB比例变化是孕激素功能性撤退的关键原因，PR启动子区甲基化在调控PRA/PRB比例变化中发挥重要作用。DNA甲基化需要染色质松解后的基因启动子区暴露，这一过程由染色质重塑（组蛋白乙酰化修饰和ATP依赖的SWI/SNF复合体）完成。据此课题组提出“ATP依赖的SWI/SNF复合体与组蛋白乙酰化修饰参与调控子宫平滑肌PRA/PRB比例，介导孕激素功能性撤退”假说。本项目拟以分娩前后人子宫平滑肌为研究对象，从组织和细胞两个层面，采用基因组学和蛋白组学方法检测染色质重塑参与调控PRs表达情况；干预原代子宫平滑肌细胞PR启动子区组蛋白乙酰化修饰复合体和SWI/SNF复合体表达后，研究二者在调控PRs表达时的相互作用及分子机制。为探索孕激素功能性撤退的调控机制，防治早产提供新理论依据。