Epigenetic Regulation of Uterine Biology by Transcription Factor KLF11 via Posttranslational Histone Deacetylation of Cytochrome p450 Metabolic Enzymes

Abstract

Endocrine regulation of uterine biology is critical for embryo receptivity and human reproduction. Uterine endometrium depends on extrinsic sex steroid input and hence likely has mechanisms that enable adaptation to hormonal variation. Emerging evidence suggests that sex steroid bioavailability in the endometrium is determined by adjusting their metabolic rate and fate via regulation of cytochrome (CYP) p450 enzymes. The CYP enzymes are targeted by ubiquitously expressed Sp/Krüppel-like (Sp/KLF) transcription factors. Specifically, KLF11 is highly expressed in reproductive tissues, regulates an array of endocrine/metabolic pathways via epigenetic histone-based mechanisms and, when aberrantly expressed, is associated with diabetes and reproductive tract diseases, such as leiomyoma and endometriosis. Using KLF11 as a model to investigate epigenetic regulation of endometrial first-pass metabolism, we evaluated the expression of a comprehensive array of metabolic enzymes in Ishikawa cells. KLF11 repressed most endometrial CYP enzymes. To characterize KLF11-recruited epigenetic regulatory mechanisms, we focused on the estrogen-metabolizing enzyme CYP3A4. KLF11 expression declined in secretory phase endometrial epithelium associated with increased CYP3A4 expression. Additionally, KLF11 bound to CYP3A4 promoter GC elements and thereby repressed promoter, message, protein as well as enzymatic function. This repression was epigenetically mediated, because KLF11 colocalized with and recruited the corepressor SIN3A/histone deacetylase resulting in selective deacetylation of the CYP3A4 promoter. Repression was reversed by a mutation in KLF11 that abrogated cofactor recruitment and binding. This repression was also pharmacologically reversible with an histone deacetylase inhibitor. Pharmacological alteration of endometrial metabolism could have long-term translational implications on human reproduction and uterine disease.

Krüppel-like factor 12 is a novel negative regulator of forkhead box O1 expression: a potential role in impaired decidualization

“…This study has verified the important role of KLF12 in the induced decidualization in mice and is the first report of a putative molecular mechanism for the transcriptional repression of FOXO1 in hESCs. KLF12 belongs to the zinc finger-containing transcription factor family, which contains key mediators of endocrine/metabolic processes that play emerging key roles in human reproductive and uterine diseases [ 15 , 24 ]. For example, KLF11 is highly expressed in human urogenital tissues, and aberrant KLF11 expression has been linked to the pathogeneses of common uterine diseases, such as endometriosis and leiomyoma [ 25 , 26 ].…”

Krüppel-Like Factors

“…This interaction leads to acetylation of KLFs that stimulates their transcriptional activity 12 , 13 or acetylation of histones followed by chromatin remodeling that ignites transcription in regions that are targeted by KLFs 14 , 15 , 16 , 17 . Accordingly, binding of KLFs, such as KLF1, KLF4, KLF5, and KLF11, with histone deacetylases (HDACs) suppresses transcriptional activity due to deacetylation of either KLFs 18 , 19 or histones 20 , 21 . Another mechanism of transcriptional repression by KLFs involves interaction with the transcriptional repressors Sin3A (22) , C-terminal binding protein (CtBP)1, and CtBP2 23 , 24 , 25 , which in turn recruit HDACs (26) , methyltransferases (27) , and other silencing complexes such as polycomb proteins (28) and Ikaros (29) .…”

The Krüppel-like factors in female reproductive system pathologies

“…Additional pathways that have been linked to KLFs and which may underlie a number of uterine pathologies when these KLFs are aberrantly expressed include: KLF17 promotion of epithelial-mesenchymal transitions through induction of TWIST1 in endometrial cancer (Dong et al, 2014); KLF6-coactivation of NF-κB signaling via its induction of cytokines TNFα and IL-6 (Zhang et al ., 2014) in the pathogenesis of endometriosis; KLF5-mediated activation of the JAK-STAT signaling pathway (Tetrault et al ., 2012), the latter a key mediator of leukemia inhibitory factor control of embryo implantation and hence, successful pregnancy (Rosario et al, 2014); and KLF14- (de Assuncao et al, 2014) and KLF11-(Zheng et al, 2014) mediated activation of lipid and metabolic signaling, respectively, processes which when dysregulated can lead to abnormal metabolism and increased risk for endometrial cancer.…”