The Krüppel-like factors in female reproductive system pathologies

Abstract

Female reproductive tract pathologies arise largely from dysregulation of estrogen and progesterone receptor signaling leading to aberrant cell proliferation, survival and differentiation. The signaling pathways orchestrated by these nuclear receptors are complex, require the participation of many nuclear proteins serving as key binding partners or targets and involve a range of paracrine and autocrine regulatory circuits. Members of the Krüppel-like family of transcription factors are ubiquitously expressed in reproductive tissues and have been increasingly implicated as critical co-regulators and integrators of steroid hormone actions. Here we explore the involvement of KLF family members in uterine pathology, describe their currently known molecular mechanisms and discuss their potential as targets for therapeutic intervention.

The estrogen–macrophage interplay in the homeostasis of the female reproductive tract

“…In vivo studies using artificially induced menstruation in mice recently allowed to demonstrate that inflammatory monocytes and monocyte-derived macrophages are recruited during the simultaneous phases of tissue breakdown and repair to perform phagocytosis of apoptotic endothelial cells and tissue debris along with resident macrophages (Cominelli et al, 2014;Cousins et al, 2016). Transcription factors linked to phenotypic activation in macrophages, such as members of the KLF family, are highly expressed in reproductive tissues and have also been involved in endometrial and FRT pathologies (Daftary et al, 2013;Simmen et al, 2015). deposition, under the influence of the local inflammatory and hormonal environment, while the reduction in tissue factor and thrombin levels creates a pro-hemorrhagic and fibrinolytic milieu that is associated with endometrial sloughing (Davies and Kadir, 2012).…”

Chromatin accessibility dynamics ofChlamydia-infected epithelial cells

“…We also identify factors that have not been previously described in the context of chlamydial infection, notably the enrichment of the KLF family of transcription factor motifs within differential chromatin accessible regions in the latter stages of infection. Dysregulation of the biologically complex KLFs and their transcriptional networks is linked to several reproductive tract pathologies in both men and women [85], thus our discovery of enriched KLF binding motifs in response to chlamydial infection is compelling, given the scale and burden of chlamydial reproductive tract disease globally [3].…”

“…KLFs are zinc-finger TFs in the same family as Sp1, which is also enriched at 48 hours. The members of this large family orchestrate a range of paracrine and autocrine regulatory circuits and are ubiquitously expressed in reproductive tissues [84]. Dysregulation of KLFs and their dynamic transcriptional networks is associated with a variety of uterine pathologies [85].…”

“…The members of this large family orchestrate a range of paracrine and autocrine regulatory circuits and are ubiquitously expressed in reproductive tissues [84]. Dysregulation of KLFs and their dynamic transcriptional networks is associated with a variety of uterine pathologies [85]. We find motif enrichment for five distinct KLFs (KLF5, KLF6, KLF9, KLF10 and KLF14) at 48 hours, in addition to further KLFs at 12 and 48 hours (KLF 3 and KLF 4) without the initial filtering steps (Additional File 5).…”

Positive and negative effects of cellular senescence during female reproductive aging and pregnancy

“…A study on uterine fibroids reports that tissues from older patients (≥45 years old) have increased cellular senescence relative to those from younger patients (<45 years old) (Laser et al 2010). In mice, aged uteri are associated with the downregulation of several genes related to cell proliferation and stem cell renewal (Simmen et al 2015), suggesting the presence of cells with impaired proliferation during uterine aging. The impact of cellular senescence on uterine function is further implied from studies on telomerase activity.…”