thông tin chi tiết - Computational Biology - # Epigenomic and Transcriptomic Regulation of Myometrial Gene Expression

Comprehensive Epigenomic and Transcriptomic Profiling of Human Myometrium at Term Pregnancy

Q: How do other transcription factors and signaling pathways, in addition to PGR, regulate the expression of contractility-associated genes in the myometrium, and how do they interact to fine-tune myometrial function?

In addition to PGR, several other transcription factors and signaling pathways play crucial roles in regulating the expression of contractility-associated genes in the myometrium. These factors interact in a complex network to fine-tune myometrial function and prepare the uterus for labor. Activator Protein 1 (AP-1): AP-1 complex subunits act as coregulators of PGR and have dynamic expression patterns throughout gestation. FOS:JUN heterodimers are implicated in the initiation of labor through the transcriptional regulation of genes like Cx43, which are essential for myometrial contractility. STAT and NFkB: Signal Transducer and Activator of Transcription (STAT) proteins and Nuclear Factor-kappa B (NFkB) are involved in inflammatory and immune responses in the myometrium. They regulate the expression of genes associated with myometrial contractility and inflammation, contributing to the remodeling of the myometrium during pregnancy. Smooth Muscle Transcription Regulators (SRF and ELK1): These regulators play a role in coordinating smooth muscle gene expression in the myometrium. They interact with hormone receptors like PGR to modulate the expression of genes involved in uterine contractility. The interaction between these transcription factors and signaling pathways is essential for the precise regulation of contractility-associated genes in the myometrium. Cross-talk between PGR, AP-1, STAT, NFkB, and other factors ensures the coordinated expression of genes involved in myometrial function. Dysregulation of these interactions can lead to aberrant myometrial activity and may contribute to pregnancy-related disorders such as preterm birth.

Q: Given the significant variations observed in the epigenomic and transcriptomic profiles across individual myometrial specimens, how do factors like genetic background, environmental exposures, and underlying health conditions influence the molecular regulation of myometrial activity, and what are the implications for personalized approaches to managing pregnancy-related disorders?

The variations in epigenomic and transcriptomic profiles across individual myometrial specimens can be influenced by a combination of genetic background, environmental exposures, and underlying health conditions. These factors can impact the molecular regulation of myometrial activity and have implications for personalized approaches to managing pregnancy-related disorders. Genetic Background: Genetic variations among individuals can lead to differences in gene expression patterns and epigenetic modifications in the myometrium. Polymorphisms in genes encoding for transcription factors, hormone receptors, and signaling molecules can affect the regulatory networks that control myometrial function. Environmental Exposures: Environmental factors such as diet, stress, and exposure to toxins can influence the epigenetic landscape of the myometrium. Epigenetic modifications induced by environmental exposures can alter gene expression patterns and contribute to the risk of pregnancy-related disorders. Underlying Health Conditions: Pre-existing health conditions like obesity, diabetes, and hypertension can impact the molecular regulation of myometrial activity. These conditions can lead to chronic inflammation, hormonal imbalances, and metabolic dysregulation, all of which can affect gene expression in the myometrium. Personalized approaches to managing pregnancy-related disorders should take into account the individual variations in epigenomic and transcriptomic profiles. By considering the genetic background, environmental exposures, and health conditions of each patient, healthcare providers can tailor treatment strategies to address specific molecular pathways that may be dysregulated in the myometrium. Precision medicine techniques, such as genomic sequencing, epigenetic profiling, and transcriptomic analysis, can help identify personalized targets for intervention and improve outcomes for women at risk of pregnancy complications.

Khái niệm cốt lõi

The human myometrium undergoes extensive epigenomic and transcriptomic remodeling during pregnancy to prepare for parturition, which is critical for understanding the molecular mechanisms underlying myometrial quiescence and contractility.

Tóm tắt

The study investigated the epigenomic landscape and transcriptome of human term pregnant, non-labor myometrial tissues to understand the gene regulatory mechanisms that maintain myometrial quiescence and prepare the uterus for parturition.

Key highlights:

Identified over 30,000 putative enhancers marked by H3K27ac and H3K4me1 in the myometrium, with enrichment of binding motifs for known myometrial regulators like AP-1, STAT, NFκB, and PGR.
Detected 540 putative super enhancers, 76% of which co-localized with PGR binding sites and were associated with highly expressed genes involved in myometrial function.
Functionally screened a 35-kb upstream region of the contractile-suppressing gene PLCL2 and identified it as a cis-acting element regulated by the progesterone receptor (PGR).
Demonstrated that PGR overexpression can increase PLCL2 expression in myometrial cells, and the inferred PGR activity positively correlates with PLCL2 mRNA levels in human myometrial specimens.

These findings provide a comprehensive resource to study gene regulatory mechanisms in the human myometrium and identify PGR as a key regulator of the contractile machinery, which could inform the development of novel interventions for parturition disorders like preterm birth.

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biorxiv.org

Thống kê

The myometrium contains an average of 44,238 H3K27ac-positive and 74,325 H3K4me1-positive genomic regions.
The myometrium expresses an average of 12,157 active genes (FPKM ≥ 1).
A total of 27,162 chromatin loops were identified in the myometrium.

Trích dẫn

"Results of this study serve as a resource to study gene regulatory mechanisms in the human myometrium at the term pregnancy stage for further advancing women's health research."
"These findings build upon our understanding of myometrial remodeling throughout gestation and will be pertinent for the development of medical interventions aiming to address pre-term birth."

Thông tin chi tiết chính được chắt lọc từ

Assessment of the Epigenomic Landscape in Human Myometrium at Term Pregnancy

by Wu,S. P. S.,... lúc www.biorxiv.org 02-21-2024

https://www.biorxiv.org/content/10.1101/2024.02.19.581035v1

Yêu cầu sâu hơn

How do the epigenomic and transcriptomic profiles of the myometrium change across different stages of pregnancy, and how do these changes contribute to the maintenance of uterine quiescence and the initiation of labor?

The epigenomic and transcriptomic profiles of the myometrium undergo significant changes throughout pregnancy to prepare for labor and parturition. During early pregnancy, the myometrium remains quiescent to support the developing fetus. This quiescent state is maintained by the expression of specific genes and the activity of regulatory elements. As pregnancy progresses towards term, there is a dynamic shift in the epigenomic landscape, characterized by changes in histone modifications and chromatin structure. These changes lead to the activation of genes involved in uterine contractility and the initiation of labor.
One key player in this process is the progesterone receptor (PGR), which plays a crucial role in regulating myometrial gene expression. At term pregnancy, there is a stoichiometric increase in the PGR A to B isoform ratio, leading to the withdrawal of functional progesterone signaling and the activation of estrogen receptor alpha. This shift in hormone signaling contributes to the reprogramming of the myometrium towards a contractile phenotype. Additionally, transcription factors like AP-1, STAT, NFkB, and others are involved in the regulation of genes associated with myometrial contractility.
The epigenetic marks, such as H3K27ac and H3K4me1, serve as enhancers for gene regulation in the myometrium. Putative enhancers and super enhancers are identified in the myometrium, which are associated with highly expressing genes and play a role in coordinating smooth muscle and hormonal control programs. These enhancers are co-localized with transcription factor binding motifs, indicating a complex regulatory network that fine-tunes gene expression in the myometrium.
Overall, the changes in the epigenomic and transcriptomic profiles of the myometrium across different stages of pregnancy reflect the transition from a quiescent state to an active contractile state in preparation for labor. These changes are orchestrated by a network of transcription factors, signaling pathways, and regulatory elements that work together to ensure the timely onset of parturition.

How do other transcription factors and signaling pathways, in addition to PGR, regulate the expression of contractility-associated genes in the myometrium, and how do they interact to fine-tune myometrial function?

In addition to PGR, several other transcription factors and signaling pathways play crucial roles in regulating the expression of contractility-associated genes in the myometrium. These factors interact in a complex network to fine-tune myometrial function and prepare the uterus for labor.

Activator Protein 1 (AP-1): AP-1 complex subunits act as coregulators of PGR and have dynamic expression patterns throughout gestation. FOS:JUN heterodimers are implicated in the initiation of labor through the transcriptional regulation of genes like Cx43, which are essential for myometrial contractility.

STAT and NFkB: Signal Transducer and Activator of Transcription (STAT) proteins and Nuclear Factor-kappa B (NFkB) are involved in inflammatory and immune responses in the myometrium. They regulate the expression of genes associated with myometrial contractility and inflammation, contributing to the remodeling of the myometrium during pregnancy.

Smooth Muscle Transcription Regulators (SRF and ELK1): These regulators play a role in coordinating smooth muscle gene expression in the myometrium. They interact with hormone receptors like PGR to modulate the expression of genes involved in uterine contractility.

The interaction between these transcription factors and signaling pathways is essential for the precise regulation of contractility-associated genes in the myometrium. Cross-talk between PGR, AP-1, STAT, NFkB, and other factors ensures the coordinated expression of genes involved in myometrial function. Dysregulation of these interactions can lead to aberrant myometrial activity and may contribute to pregnancy-related disorders such as preterm birth.

Given the significant variations observed in the epigenomic and transcriptomic profiles across individual myometrial specimens, how do factors like genetic background, environmental exposures, and underlying health conditions influence the molecular regulation of myometrial activity, and what are the implications for personalized approaches to managing pregnancy-related disorders?

The variations in epigenomic and transcriptomic profiles across individual myometrial specimens can be influenced by a combination of genetic background, environmental exposures, and underlying health conditions. These factors can impact the molecular regulation of myometrial activity and have implications for personalized approaches to managing pregnancy-related disorders.

Genetic Background: Genetic variations among individuals can lead to differences in gene expression patterns and epigenetic modifications in the myometrium. Polymorphisms in genes encoding for transcription factors, hormone receptors, and signaling molecules can affect the regulatory networks that control myometrial function.

Environmental Exposures: Environmental factors such as diet, stress, and exposure to toxins can influence the epigenetic landscape of the myometrium. Epigenetic modifications induced by environmental exposures can alter gene expression patterns and contribute to the risk of pregnancy-related disorders.

Underlying Health Conditions: Pre-existing health conditions like obesity, diabetes, and hypertension can impact the molecular regulation of myometrial activity. These conditions can lead to chronic inflammation, hormonal imbalances, and metabolic dysregulation, all of which can affect gene expression in the myometrium.

Personalized approaches to managing pregnancy-related disorders should take into account the individual variations in epigenomic and transcriptomic profiles. By considering the genetic background, environmental exposures, and health conditions of each patient, healthcare providers can tailor treatment strategies to address specific molecular pathways that may be dysregulated in the myometrium. Precision medicine techniques, such as genomic sequencing, epigenetic profiling, and transcriptomic analysis, can help identify personalized targets for intervention and improve outcomes for women at risk of pregnancy complications.