Krüppel-like factors in mammalian stem cells and development

Bialkowska, Agnieszka B.; Yang, Vincent W.; Mallipattu, Sandeep K.

doi:10.1242/dev.145441

Cited by 123 publications

(107 citation statements)

References 272 publications

(263 reference statements)

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“…To find out which of the expression changes in RNA‐Seq experiments are the most important causes of podocyte dysfunction, we focused our attention on transcriptional factors involved in the regulation of nephrin expression and found that KLF10 is a candidate target. There are currently a total of 27 SP/KLF family members identified in mouse or human, which include nine members of the SP subfamily (SP1–SP9) and 18 members of the KLF subfamily (KLF1–KLF18; McConnell & Yang, ; Bialkowska et al , ; Memon & Lee, ). Due to the structural similarities in the SP/KLF DNA‐binding domains at their C‐terminal regions and the diverse functional (transactivation/repression) domains at their N‐terminal regions, the SP/KLF members may have overlapping sets of target genes but display diverse influences on target gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…Kruppel‐like factors (KLFs) are evolutionarily conserved and structurally related zinc finger‐containing transcription factors, which also share sequence homology with specificity proteins such as SP1 and SP3 (McConnell & Yang, ; Bialkowska et al , ). Like SP subfamily members, KLFs mediate transcriptional activation and/or repression by recognizing similar GC‐rich consensus sequences in target DNA, along with the recruitment of specific co‐activators, co‐repressors, or other chromatin remodeling proteins (McConnell & Yang, ; Bialkowska et al , ). Accumulating evidence has implicated that KLFs play a vital role in multiple biological processes and diseases.…”

Section: Introductionmentioning

confidence: 99%

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A KDM6A–KLF10 reinforcing feedback mechanism aggravates diabetic podocyte dysfunction

et al. 2019

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Diabetic nephropathy is the leading cause of end‐stage renal disease. Although dysfunction of podocytes, also termed glomerular visceral epithelial cells, is critically associated with diabetic nephropathy, the mechanism underlying podocyte dysfunction still remains obscure. Here, we identify that KDM 6A, a histone lysine demethylase, reinforces diabetic podocyte dysfunction by creating a positive feedback loop through up‐regulation of its downstream target KLF 10. Overexpression of KLF 10 in podocytes not only represses multiple podocyte‐specific markers including nephrin, but also conversely increases KDM 6A expression. We further show that KLF 10 inhibits nephrin expression by directly binding to the gene promoter together with the recruitment of methyltransferase Dnmt1. Importantly, inactivation or knockout of either KDM 6A or KLF 10 in mice significantly suppresses diabetes‐induced proteinuria and kidney injury. Consistent with the notion, we also show that levels of both KDM 6A and KLF 10 proteins or mRNA s are substantially elevated in kidney tissues or in urinary exosomes of human diabetic nephropathy patients as compared with control subjects. Our findings therefore suggest that targeting the KDM 6A– KLF 10 feedback loop may be beneficial to attenuate diabetes‐induced kidney injury.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A KDM6A–KLF10 reinforcing feedback mechanism aggravates diabetic podocyte dysfunction

et al. 2019

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“…During the first three cell cycles, we detected expression of a single Sox gene, MleSox2 (contig22607, contig22608), a member of the SoxC group (Schnitzler, Simmons, Pang, Martindale, & Baxevanis, 2014). Members of the Krüppel-like factor and specificity protein (KLF/SP) gene family are characterized by the presence of a highly conserved triple C2H2 zinc finger DNA-binding domain and play key roles in essential biological processes, including balancing stem cell proliferation and differentiation (Bialkowska, Yang, & Mallipattu, 2017;Presnell, Schnitzler, & Browne, 2015). We detected significant expression for both MleKlf5a (contig2761, contig16159, contig16164, contig26148) and MleKlf5b (contig4663, contig27551) (Presnell et al, 2015).…”

Section: Annotation Of Assembled Reference Contigsmentioning

confidence: 99%

The maternal‐zygotic transition and zygotic activation of the Mnemiopsis leidyi genome occurs within the first three cleavage cycles

Davidson¹,

Koch

Schnitzler

et al. 2017

Molecular Reproduction Devel

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The maternal-zygotic transition (MZT) describes the developmental reprogramming of gene expression marked by the degradation of maternally supplied gene products and activation of the zygotic genome. While the timing and duration of the MZT vary among taxa, little is known about early stage transcriptional dynamics in the non-bilaterian phylum Ctenophora. We sought to better understand the extent of maternal mRNA loading and subsequent differential transcript abundance during the earliest stages of development by performing comprehensive RNA-sequencing-based analyses of mRNA abundance in single- and eight-cell-stage embryos in the lobate ctenophore Mnemiopsis leidyi. We found 1,908 contigs with significant differential abundance between single- and eight-cell stages, of which 1,208 contigs were more abundant at the single-cell stage and 700 contigs were more abundant at the eight-cell stage. Of the differentially abundant contigs, 267 were exclusively present in the eight-cell samples, providing strong evidence that both the MZT and zygotic genome activation (ZGA) have commenced by the eight-cell stage. Many highly abundant transcripts encode genes involved in molecular mechanisms critical to the MZT, such as maternal transcript degradation, serine/threonine kinase activity, and chromatin remodeling. Our results suggest that chromosomal restructuring, which is critical to ZGA and the initiation of transcriptional regulation necessary for normal development, begins by the third cleavage within 1.5 hours post-fertilization in Mnemiopsis leidyi.

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“…cell differentiation, angiogenesis, erythropoiesis) 11–13 . Recent studies demonstrate that KLFs play a vital role in cardiac, liver, and kidney fibrosis 11–13 .…”

Section: Introductionmentioning

confidence: 99%

“…cell differentiation, angiogenesis, erythropoiesis) 11–13 . Recent studies demonstrate that KLFs play a vital role in cardiac, liver, and kidney fibrosis 11–13 . Specifically, the global loss of KLF15 exacerbated interstitial fibrosis in 5/6 nephrectomized rats 14, 15 .…”

Section: Introductionmentioning

confidence: 99%

The loss of Krüppel-like factor 15 in Foxd1+ stromal cells exacerbates kidney fibrosis

Mallipattu

Guo

et al. 2017

Kidney International

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Large epidemiological studies clearly demonstrate that multiple episodes of acute kidney injury contribute to the development and progression of kidney fibrosis. Although our understanding of kidney fibrosis has improved in the past two decades, we have limited therapeutic strategies to halt its progression. Myofibroblast differentiation and proliferation remain critical to progression of kidney fibrosis. Although canonical Wnt signaling can trigger activation of myofibroblasts in the kidney, mediators of Wnt inhibition in the resident progenitor cells are unclear. Recent studies demonstrate that the loss of a Kruppel-Like Factor 15 (KLF15), a kidney-enriched zinc-finger transcription factor, exacerbates kidney fibrosis in murine models. Here, we tested whether Klf15 mRNA and protein expression is reduced in late stages of fibrosis in mice that underwent unilateral ureteric obstruction, a model of progressive renal fibrosis Knockdown of Klf15 in Foxd1-expressing cells (Foxd1-Cre Klf15fl/fl) increased extracellular matrix deposition and myofibroblast proliferation as compared to wildtype (Foxd1-Cre Klf15+/+) mice after three and seven days of ureteral obstruction. This was validated in mice receiving angiotensin II treatment for six weeks. In both these murine models, the increase in renal fibrosis was found in Foxd1-Cre Klf15fl/fl mice and accompanied by activation of Wnt/β-catenin signaling. Furthermore, knockdown of Klf15 in cultured mouse embryonic fibroblasts activated canonical Wnt/β-catenin signaling, increased profibrotic transcripts, and increased proliferation after treatment with a Wnt1 ligand. Conversely, overexpression of KLF15 inhibited phospho-β-catenin (Ser552) expression in Wnt1-treated cells. Thus, KLF15 has a critical role in attenuating kidney fibrosis by inhibiting the canonical Wnt/β-catenin pathway.

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Krüppel-like factors in mammalian stem cells and development

Cited by 123 publications

References 272 publications

A KDM6A–KLF10 reinforcing feedback mechanism aggravates diabetic podocyte dysfunction

A KDM6A–KLF10 reinforcing feedback mechanism aggravates diabetic podocyte dysfunction

The maternal‐zygotic transition and zygotic activation of the Mnemiopsis leidyi genome occurs within the first three cleavage cycles

The loss of Krüppel-like factor 15 in Foxd1+ stromal cells exacerbates kidney fibrosis

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