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在近期怀孕的宫内膜中,核心压缩器CNOT1的下降会损害孕激素受体的功能,并增加收缩性基因表达

Youn-Tae Kwak¹, Alina P Montalbano², Andrew M Kelleher³

¹Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.

The Journal of biological chemistry

|June 19, 2024

概括

孕激素 (P4) 和它的受体 (PR) 通常会抑制子宫收缩. 一个核心压缩器,CNOT1,在临近产期时减少,允许收缩基因激活,导致分娩.

科学领域:

生殖生物学生殖生物学
分子内分泌学分子内分泌学
基因调节基因调节

背景情况:

孕激素 (P4) 通过抑制子宫收缩性来维持怀孕至关重要.
P4/PR信号抑制了肌肉膜中的促炎和收缩相关蛋白 (CAP) 基因,部分是通过与NF-κB的相互作用.
通过P4/PR阻断这些基因的精确机制尚未完全阐明.

研究的目的:

调查CCR-NOT转录复合体子单元1 (CNOT1) 在P4/PR介导的肌肉收缩抑制中作为核心抑制剂的作用.
了解在怀孕晚期期间链接P4/PR信号,CNOT1和CAP基因 (OXTR,CX43) 调节的分子机制.

主要方法:

描述CNOT1作为一个与肌肉膜中的PR-B相互作用的核心压缩剂.
分析CNOT1表达和结合NF-κB响应元素在术后小鼠肌胎中的分析.
在OXTR和CX43促进体中评估基因组修饰和基因组修饰酶的表达.
用P4治疗怀孕小鼠和细胞培养物以评估CNOT1表达和招募.
敲除CNOT1以评估其对收缩基因表达的影响.

主要成果:

鉴定出CNOT1是一种核心压缩剂,与肌肉膜中的PR-B相关.
在预产期,小鼠肌子膜表现出CNOT1表达和结合OXTR和CX43促进体的减少,与增加的CAP基因表达相吻合.
这些变化与这些基因位置的基因突变变化 (抑制性减少,活性标记增加) 相关.
在细胞和体内,P4治疗增加了CNOT1的表达,并将其招募到PR-bound元素中.
CNOT1的淘汰导致收缩基因的表达增加.

结论:

近期P4/PR调节的核心压缩器CNOT1的表达和DNA结合减少,有助于诱导肌体收缩性.
在OXTR和CX43促进体中,相关的基因组修饰变化促进了过渡到分娩的过程.
CNOT1是P4/PR调节肌膜静止和激活的关键调解者.

关键词:

在 NF-κBB 中.基因调节基因调节基因调节这是一种炎症炎症炎症炎症.肌肉膜静止的时间这种表达方式是myometrium myometrium 怀孕怀孕怀孕怀孕怀孕孕激素是孕激素的一种.转录核心压缩机子宫收缩子宫收缩

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