Exploring the Roles of Progesterone and Estrogen Receptors in Human Labor


Preterm birth (PTB) is the leading cause of infant morbidity worldwide. Approximately 380,000 babies are born prematurely in the USA every year. Estrogen (E2) and progesterone (P4) play essential roles during pregnancy and labor; a clear understanding of their action mechanisms, however, is lacking. E2 and P4 function by activating their cognate nuclear receptors ESR1 and PGR, respectively, to affect their binding to regulatory regions of target genes and control their transcription and function. In this study, I sought to identify steroid hormone target genes and pathways critical for myometrium quiescence and contraction. Elucidating molecular mechanisms whereby the myometrium transforms from a quiescent to a contractile state would fill a vital evidence gap and be beneficial in advancing treatment for the prevention of PTB. Via bioinformatic analysis of RNA-sequencing (RNA-seq), PGR Chromatin Immunoprecipitation-sequencing (ChIP-seq), ESR1 ChIP-seq, and histone modification ChIP-seq using human myometrial tissues from pregnant women at term who were not in labor (TNIL) and women at term who were in labor (TIL), I discovered differentially expressed genes that were bound differentially by ESR1, PGR, and histone modifications, H3K4me3 and H3K27ac. Gene Ontology analysis uncovered that genes found highly expressed in TIL were highly enriched for pathways associated with acute inflammatory response and positive regulation of cytokine-mediated signaling pathways, whereas genes found highly expressed in TNIL were highly enriched for pathways related to muscle structure, muscle contraction, and cell junction assembly. These transcriptional differences led to distinct clustering between TIL and TNIL samples when subjected to Principal Component Analysis. Because signal transduction leads to transcriptional changes, these transcriptional differences between labor status led to ChIP-seq experiments with two crucial pregnancy steroid receptors, ESR1 and PGR. ChIP-seq revealed that genomic regions differentially occupied by each transcription factor between TIL and TNIL were enriched in pathways like those identified in RNA-seq analysis, suggesting that ESR1 and PGR, via interaction with genomic loci, directly mediate the expression of genes associated with labor status. Integrative analysis of RNA-seq and ChIP-seq data of hormone receptors and histone marks uncovered ESR1/PGR downstream target genes potentially regulating labor status.

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