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

Hui, Zhang; Zhu, Xudong; Chen, Jing; Zhang, Qun; Kong, Chengcai; Xing, Jinchun; Ding, Lijun; Diao, Zongli; Zhen, Xin; Sun, Haixiang; Yan, Guijun

doi:10.1186/s12958-015-0079-z

Cited by 30 publications

(24 citation statements)

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“…Interestingly, we have found the 9aaTAD activation domain in Crassostrea gigas, KLF1 ortholog (9aaTAD sequence ELL DYD FIL, gene ID; EKC39171), which closely resembles the first identified 9aaTAD in activator Oaf1 (9aaTAD sequence DLF DYD FLF) (12). Surprisingly, the 9aaTAD activation domains of KLF3 and KLF8 did not activate transcription, which correlated with their repressor function reported previously (52,(81)(82)(83)(84). The accumulation of valines has been shown here again to be associated with the 9aaTAD deactivation (Figures 7).…”

Section: Klf Homology With the Sp Family Revealed Their Activation Dosupporting

confidence: 76%

The evolution of the 9aaTAD domain in Sp2 proteins: inactivation with valines and intron reservoirs

Piskáček

Havelka

Jendruchova

et al. 2019

Preprint

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The Sp1 transcription factor has been defined as glutamine-rich activator. The Nine amino acid TransActivation Domains (9aaTAD) have been identified in numerous transcription activators. Here, we identified the conserved 9aaTAD motif in the Sp1 and in all nine members of SP family with broad natural 9aaTAD variations. We showed by the amino acid substitutions that the glutamine residues are completely dispensable for 9aaTADs function. We described the 9aaTAD domains' origin and evolutionary history. The ancestral Sp2 gene with inactive 9aaTAD has duplicated in early chordates and created new paralogs Sp1, Sp3 and Sp4. We discovered that the accumulation of valines in the 9aaTADs correlated with the domain inactivation. The Sp2 activation domain, whose dormancy have lasted over 100 million years during chordate evolution, enabled later diversification in the Sp1-4 clade, including both repressors and activators. The new paralogs Sp1 and Sp3 activation domains have regained their original activator function by loss of valines in their 9aaTADs.Keywords: activation domain, 9aaTAD, SP, Sp1, KLF, WT1, Gal4, Met4, Gcn4 and p53. demonstrated the importance of the hydrophobic amino acids for Gcn4 (30-33) and p53 activators (8,(34)(35)(36)(37)(38)(39)(40). Similarly, in the original report for the glutamine-rich activator Sp1(41), the importance of hydrophobic amino acids was already recognized, regardless of the overrepresented glutamines.Nevertheless, the designation as acidic or glutamine-rich activation domains persists to date (42-49).In the human genome, there are about 1,691 annotated transcription factors, divided into 68 groups according to their conserved DNA binding domain (50). The C2H2-type zinc finger is the largest group (682 members), which includes the evolutionally conserved family of KLF activators (Krüppel-like factors). The SP activators (Specificity proteins Sp1-9) belong to a new evolutional branch derived from the ancestral KLF family. The SP activators have been linked to cell proliferation, embryonic development, tissue differentiation, Wnt signaling pathway, metabolism, and their dysregulation has been implicated in a number of human diseases and cancers (51)(52)(53)(54)(55)(56). This report has focused on the SP family and followed the 9aaTAD domain's evolution. MATERIALS AND METHODSConstructs. The construct pBTM116-HA was generated by an insertion of the HA cassette into the EcoRI site of the vector pBTM116. The constructs G1-G45 and H1-H45 were generated by PCR and sub-cloned into pBTM116 EcoRI and BamHI sites. All constructs have a spacer of three amino acids inserted into the EcoRI site; peptide GSG. All constructs have been sequenced by Eurofins Genomics.Further detailed information about constructs and primer sequences are available on request.Assessment of enzyme activities. The β-galactosidase activity was determined in the yeast strain L40 (57,58). The strain L40 has a chromosomally integrated lacZ reporter driven by the lexA operator. In all hybrid assays, we used 2μ vector pBTM116 for...

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Section: Klf Homology With the Sp Family Revealed Their Activation Dosupporting

confidence: 76%

The evolution of the 9aaTAD domain in Sp2 proteins: inactivation with valines and intron reservoirs

Piskáček

Havelka

Jendruchova

et al. 2019

Preprint

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“…Furthermore, LIF is considered to be a direct downstream target gene of ATF3 23 . We have previously demonstrated that Krüppel-like factor 12 (KLF12) is expressed in the glandular epithelium (GE) and stromal cells of secretory-phase endometrial tissue and that KLF12 negatively regulates endometrial decidualization through the transcriptional repression of target genes both in vitro and in vivo 24 .…”

Section: Introductionmentioning

confidence: 99%

Increased Krüppel-like factor 12 impairs embryo attachment via downregulation of leukemia inhibitory factor in women with recurrent implantation failure

et al. 2018

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Recurrent implantation failure (RIF) caused by various etiological factors remains a challenge for fertility clinicians using assisted reproductive technology (ART) worldwide. Dysregulation of leukemia inhibitory factor (LIF) in the endometria of women with RIF is involved in impaired endometrial receptivity and embryo adhesion. However, the mechanism through which LIF expression is regulated in women with RIF is still poorly understood. Our previous study noted that the abnormally increased endometrial Krüppel-like factor 12 (KLF12) in RIF women led to impaired decidualization and embryo implantation. Here, we further found that KLF12 inhibited embryo adhesion in vivo and in vitro by repressing LIF expression. Mechanistically, KLF12 bound to conserved sites (CAGTGGG, −6771 to −6765 and −7115 to −7109) within the LIF promoter region and repressed LIF transcription directly. Exogenous LIF significantly reversed the KLF12-mediated repression of BeWo spheroid adhesion. KLF12 expression was reduced significantly in Ishikawa cells treated with progestogen, which was due to the activation of Akt signaling. These findings may provide novel potential therapeutic regimens for patients with RIF and disrupted endometrial receptivity.

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“…Several key factors, such as FOXO1A, Krüppel-like factor 12 (KLF12) and orphan nuclear receptor Nur77, have been implicated in regulation of the decidualization process [ 15 – 17 ]. We have previously demonstrated that KLF12, a progestogen target gene, is expressed in the glandular epithelium (GE) and in stromal cells of secretory phase endometrial tissue and that it negatively regulates endometrial decidualization through the transcriptional repression of target genes both in vitro and in vivo [ 18 ]. This study has revealed that the excessive expression of KLF12 and decreased expression of Nur77 in the endometrium of RIF patients.…”

Section: Introductionmentioning

confidence: 99%

Increased Krüppel-like factor 12 in recurrent implantation failure impairs endometrial decidualization by repressing Nur77 expression

Huang

Zhou

Yan

et al. 2017

Reprod Biol Endocrinol

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BackgroundDecidualization is a prerequisite for successful implantation and the establishment of pregnancy. A critical role of impaired decidualization in subfertility has been established. In human endometrial stromal cells (hESCs), Krüppel-like factor 12 (KLF12) and Nur77 are novel regulators of decidualization. We investigated whether KLF12 impaired the decidualization of hESCs in recurrent implantation failure (RIF) patients.MethodsEndometrial tissues and hESCs were collected from RIF patients (n = 34) and fertile controls (n = 30) for in vitro analysis. Primary hESCs isolated from RIF endometrial tissues were used to evaluate the biological functions of KLF12 and Nur77. In addition, their molecular mechanisms were investigated by adenovirus-mediated overexpression. Gene expression regulation was examined by real-time-quantitative PCR (qRT-PCR), immunostaining and luciferase reporter assay. Further, blastocyst-like spheroid (BLS) and blastocyst implantation models were performed to examine the roles of KLF12 and Nur77 during embryo expansion on hESCs.ResultshESCs from the RIF patients showed a poor decidual response, mainly characterized by decreased decidual prolactin (dPRL) secretion, impaired transformation and limited BLS expansion. In addition, KLF12 expression was increased in endometrial tissues from the RIF patients compared with those from the fertile controls, especially in stromal compartments. The opposite results were observed for Nur77 expression in these tissues. KLF12 repressed hESC decidualization by decreasing Nur77 expression. Mechanistically, KLF12 bound to a conserved site in the Nur77 promoter region. Nur77 overexpression significantly reversed the KLF12-mediated repression of dPRL expression, decidual transformation and BLS/blastocyst expansion.ConclusionsKLF12 impairs endometrial decidualization by transcriptionally repressing Nur77, and Nur77 overexpression reverses the poor decidual response of hESCs in RIF patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12958-017-0243-8) contains supplementary material, which is available to authorized users.

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

Cited by 30 publications

References 50 publications

The evolution of the 9aaTAD domain in Sp2 proteins: inactivation with valines and intron reservoirs

The evolution of the 9aaTAD domain in Sp2 proteins: inactivation with valines and intron reservoirs

Increased Krüppel-like factor 12 impairs embryo attachment via downregulation of leukemia inhibitory factor in women with recurrent implantation failure

Increased Krüppel-like factor 12 in recurrent implantation failure impairs endometrial decidualization by repressing Nur77 expression

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