Methylated cis-regulatory elements mediate KLF4-dependent gene transactivation and cell migration

Wan, Jun; Su, Yijing; Song, Qifeng; Tung, Brian; Oyinlade, Olutobi; Liu, Sheng; Ying, Mingyao; Guo, Ming; Song, Hongjun; Qian, Jiang; Zhu, Heng; Xia, Shuli

doi:10.7554/elife.20068

Cited by 45 publications

(78 citation statements)

References 51 publications

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“…The accessibility of TFs to regulatory DNA is closely related to the covalent modification of histones and DNA [1][2][3][4][5][6] .…”

Section: Introductionmentioning

confidence: 99%

Spatiotemporal DNA Methylome Dynamics of the Developing Mammalian Fetus

Hariharan

Gorkin

et al. 2017

Preprint

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SummaryGenetic studies have revealed an essential role for cytosine DNA methylation in mammalian development. However, its spatiotemporal distribution in the developing embryo remains obscure. Here, we profiled the methylome landscapes of 12 mouse tissues/organs at 8 developmental stages spanning from early embryogenesis to birth. Indepth analysis of these spatiotemporal epigenome maps systematically delineated ~2 million methylation variant regions and uncovered widespread methylation dynamics at nearly one-half million tissue-specific enhancers, whose human counterparts were enriched for variants involved in genetic diseases. Strikingly, these predicted regulatory elements predominantly lose CG methylation during fetal development, whereas the trend is reversed after birth. Accumulation of non-CG methylation within gene bodies of key developmental transcription factors coincided with their transcriptional repression during later stages of fetal development. These spatiotemporal epigenomic maps provide a valuable resource for studying gene regulation during mammalian tissue/organ progression and for pinpointing regulatory elements involved in human developmental diseases.

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“…The accessibility of TFs to regulatory DNA is closely related to the covalent modification of histones and DNA [1][2][3][4][5][6] .…”

Section: Introductionmentioning

confidence: 99%

Spatiotemporal DNA Methylome Dynamics of the Developing Mammalian Fetus

Hariharan

Gorkin

et al. 2017

Preprint

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“…The role of Klf4 as a pioneer factor might interfere in epigenetic modifications crucial to the progression of retinogenesis, which normally impedes the differentiation program of RGCs at late stages. For example, the ability to interact with methylated DNA was described as crucial for the function of Klf4 (Wan et al, 2017), and one possibility is that Klf4 remodels the chromatin enabling Atoh7 transcriptional activity. In addition, the analysis of histone modifications in retinal cells at various stages of development suggests that RGC genes are silenced by histone modifications as retinogenesis proceeds (Ueno et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

De novo genesis of retinal ganglion cells by targeted expression of Klf4 in vivo

et al. 2019

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Retinal ganglion cell (RGC) degeneration is a hallmark of glaucoma, the most prevalent cause of irreversible blindness. Thus, therapeutic strategies are needed to protect and replace these projection neurons. One innovative approach is to promote de novo genesis of RGCs via manipulation of endogenous cell sources. Here, we demonstrate that the pluripotency regulator gene Krüppel-like factor 4 (Klf4) is sufficient to change the potency of lineage-restricted retinal progenitor cells to generate RGCs in vivo. Transcriptome analysis disclosed that the overexpression of Klf4 induces crucial regulators of RGC competence and specification, including Atoh7 and Eya2. In contrast, loss-offunction studies in mice and zebrafish demonstrated that Klf4 is not essential for generation or differentiation of RGCs during retinogenesis. Nevertheless, induced RGCs (iRGCs) generated upon Klf4 overexpression migrate to the proper layer and project axons aligned with endogenous fascicles that reach the optic nerve head. Notably, iRGCs survive for up to 30 days after in vivo generation. We identified Klf4 as a promising candidate for reprogramming retinal cells and regenerating RGCs in the retina. This article has an associated 'The people behind the papers' interview.

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“…KLF4 was found to be hypermethylated in renal cell carcinomas [57] and endometrial cancers [58]. However, a surprising discovery was KLF4 can bind to methylated regions of chromatin to mediate activation of transcription without the need for demethylation of the DNA in some types of cancer cells [59,60]. These studies demonstrate a new role for some transcription factors as methylation readers in the transcription process.…”

Section: Krüppel-like Factormentioning

confidence: 99%

Transcriptional and Epigenetic Regulation of Krüppel-Like Transcription Factors

Salmon¹

2020

Gene Expression and Phenotypic Traits

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Krüppel-like factors (KLFs) are a family of zinc finger transcription factors (ZF-TF) that are now known to be involved in complex biological processes including cancer, proliferation, and cardiovascular disease as well as developmental processes. KLFs first gained notoriety when it became known that they are crucial for promoting and maintenance of stem cell pluripotency. Over the past 20 years since the discovery of Krüppel-like factor 1 (KLF1), this transcription factor family has grown to include 18 members and 7 closely related members of the specificity protein 1 (Sp1) family. In the present study, we review the mechanisms related to regulation of KLFs by direct promoter activation or repression. We will also review and discuss some mechanisms of posttranslational modifications that could affect KLF function. We seek to understand how these transcriptional regulators are themselves regulated and how that regulation could become aberrant during various disease processes.

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Methylated cis-regulatory elements mediate KLF4-dependent gene transactivation and cell migration

Cited by 45 publications

References 51 publications

Spatiotemporal DNA Methylome Dynamics of the Developing Mammalian Fetus

Spatiotemporal DNA Methylome Dynamics of the Developing Mammalian Fetus

De novo genesis of retinal ganglion cells by targeted expression of Klf4 in vivo

Transcriptional and Epigenetic Regulation of Krüppel-Like Transcription Factors

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