Khader Nawrah, Dorogin Anna, Shynlova Oksana, Mitchell Jennifer A
Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada.
Lunenfeld Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.
PLoS Genet. 2025 Jun 2;21(6):e1011261. doi: 10.1371/journal.pgen.1011261. eCollection 2025 Jun.
The myometrium, the muscular layer of the uterus, undergoes crucial transitions during pregnancy, maintaining quiescence throughout gestation, and generating coordinated contractions during labor. Dysregulation of this transition can lead to premature labor with serious complications for the infant. Despite extensive gene expression data available for varying myometrial states, the molecular mechanisms governing the increase in contraction-associated gene expression at labor onset remain unclear. Transcription factors, such as JUND and progesterone receptor (PR), play essential roles in regulating transcription of select myometrial contraction-associated genes, however, a broader understanding of their involvement in transcriptional regulation at a genome-wide scale is lacking. This study examines changes in transcription and JUND binding within human myometrial tissue during the transition from quiescence (term-not-in labor/TNIL) to contractility (term labor/TL). Total RNA-sequencing reveals a global increase in primary transcript levels at TL, with AP-1/JUND binding motifs overrepresented in the promoters of upregulated transcripts. Interestingly, ChIP-seq analysis demonstrates higher JUND enrichment in TNIL compared to TL tissues, suggesting its role in preparing the myometrium for labor onset. Integration of JUND and PR ChIP-seq data identifies over 10,000 gene promoters bound by both factors at TNIL and TL, including genes involved in labor-driving processes. Additionally, the study uncovers elevated levels of enhancer RNAs (eRNAs) at intergenic JUND peaks in laboring myometrial tissues, and implicates additional transcription factors, such as NFKB and ETS, in the regulatory switch from quiescence to contractility. In summary, this research enhances our understanding of the myometrial molecular regulatory network during pregnancy and labor, shedding light on the roles of JUND and PR in gene expression regulation genome-wide. These findings open avenues for further exploration, potentially leading to improved interventions for preventing premature labor and the associated complications.
子宫肌层是子宫的肌肉层，在孕期经历关键转变，在整个妊娠期保持静息状态，并在分娩时产生协调收缩。这种转变的失调可导致早产，给婴儿带来严重并发症。尽管有大量关于不同子宫肌层状态的基因表达数据，但分娩开始时控制收缩相关基因表达增加的分子机制仍不清楚。转录因子，如JUND和孕激素受体（PR），在调节某些子宫肌层收缩相关基因的转录中起重要作用，然而，目前缺乏对它们在全基因组范围内参与转录调控的更广泛了解。本研究考察了人类子宫肌层组织从静息状态（足月未临产/TNIL）到收缩状态（足月临产/TL）转变过程中的转录变化和JUND结合情况。全RNA测序显示TL时初级转录本水平整体增加，上调转录本的启动子中AP-1/JUND结合基序过度富集。有趣的是，ChIP-seq分析表明，与TL组织相比，TNIL组织中JUND富集程度更高，表明其在为子宫肌层分娩开始做准备中发挥作用。JUND和PR ChIP-seq数据整合鉴定出在TNIL和TL时由这两种因子结合的超过10000个基因启动子，包括参与分娩驱动过程的基因。此外，该研究发现临产子宫肌层组织基因间JUND峰处增强子RNA（eRNA）水平升高，并表明其他转录因子，如NFKB和ETS，参与从静息到收缩的调控转换。总之，本研究增进了我们对孕期和分娩期间子宫肌层分子调控网络的理解，阐明了JUND和PR在全基因组基因表达调控中的作用。这些发现为进一步探索开辟了道路，可能会带来预防早产及相关并发症的改进干预措施。
