Transcriptional control of parturition: insights from gene regulation studies in the myometrium

Abstract

The onset of labour is a culmination of a series of highly coordinated and preparatory physiological events that take place throughout the gestational period. In order to produce the associated contractions needed for fetal delivery, smooth muscle cells in the muscular layer of the uterus (i.e. myometrium) undergo a transition from quiescent to contractile phenotypes. Here, we present the current understanding of the roles transcription factors play in critical labour-associated gene expression changes as part of the molecular mechanistic basis for this transition. Consideration is given to both transcription factors that have been well-studied in a myometrial context, i.e. activator protein 1 (AP-1), progesterone receptors (PRs), estrogen receptors (ERs), and nuclear factor kappa B (NF-κB), as well as additional transcription factors whose gestational event-driving contributions have been demonstrated more recently. These transcription factors may form pregnancy- and labour- associated transcriptional regulatory networks in the myometrium to modulate the timing of labour onset. A more thorough understanding of the transcription factor-mediated, labour-promoting regulatory pathways holds promise for the development of new therapeutic treatments that can be used for the prevention of preterm labour in at-risk women.

MYB and ELF3 differentially modulate labor-inducing gene expression in myometrial cells

“…As they stand, our findings are important to consider in light of potential therapeutic applications that can be developed to address the critical health challenges associated with early labor onset. For instance, as we previously discussed [13], attempts to target MYB with different drugs or compounds to downregulate its activity in the context of treating acute myeloid leukemia have been met with some success [29][30][31]. Of course, therapeutic treatment of human extreme preterm birth may mandate somewhat different strategies than that of cancer.…”

“…More recent studies have shown preliminary evidence of co-operation between the more well-established transcription factor quartet and other candidate factors less well-known in this context, such as members of the KLF, SMAD, FOXO, IRF, and HOXA families (reviewed in [ 13 ]). Despite these initial advances in identifying putative members of gestational stage-specific transcription factor complexes, the full repertoire of proteins that contribute to the laboring phenotype in SMCs is not comprehensively characterized.…”

MYB and ELF3 differentially modulate labor-inducing gene expression in myometrial cells

“…However, as they stand, these findings are important to consider in light of potential therapeutic applications that can be developed to address the critical health challenges associated with early labour onset. For instance, as we previously discussed [9], attempts to target MYB with different drugs or compounds to down-regulate its activity in the context of treating acute myeloid leukemia have been met with some success [23][24][25]. Of course, therapeutic treatment of human extreme preterm birth may mandate somewhat different strategies than that of cancer.…”

“…Interestingly, many members of the highlighted transcription factor quartet exhibit consistent expression levels and alter their activity at labor onset due to a change in post-translational modifications. However, most of these novel candidate proteins are themselves differentially expressed between pre-laboring and active laboring time points in mouse and/or human term and preterm models (reviewed in [9]).…”

“…The control of patterns of transcriptional activation directly relies on the formation of complexes comprised of key transcription factor proteins, which operate in the same or co-existing regulatory circuitries. Some of the more extensively studied transcription factors that have been linked to the labor-driving transcriptional changes observed in SMCs include members of the Activator protein 1 (AP-1), Nuclear factor kappa beta (Nf-κβ), Estrogen receptor (ER), and Progesterone receptor (PR) families; more recent studies have shown preliminary evidence of co-operation with these four more well-established factors with other candidate factors lesser-known in this context, such as members of the KLF, SMAD, FOXO, IRF, and HOXA families (reviewed in [9]). Interestingly, many members of the highlighted transcription factor quartet exhibit consistent expression levels and alter their activity at labor onset due to a change in post-translational modifications.…”