Interaction of the NRF2 and p63 transcription factors promotes keratinocyte proliferation in the epidermis

Kurinna, Svitlana; Seltmann, Kristin; Bachmann, Andreas L.; Schwendimann, Andreas; Thiagarajan, Lalitha; Hennig, Paulina; Beer, Hans‐Dietmar; Mollo, Maria Rosaria; Missero, Caterina; Werner, Sabine

doi:10.1093/nar/gkab167

Cited by 21 publications

(26 citation statements)

References 49 publications

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“…In this work, we used the data from the in vitro differential model of human keratinocytes analogous to the one utilised in previous studies of the role of TF and miR in differentiation (1,2,4). This is important because it provides the uniformity between the datasets obtained from ChIPseq and RNAseq analyses.…”

Section: Discussionmentioning

confidence: 99%

“…stage of keratinocytes in human epidermis (4,10). In this study, we hypothesised that miRs specifically expressed in keratinocytes will bind the target mRNAs during early stages of differentiation and thus contribute to the regulation of gene expression observed during this process.…”

Section: Page Of 3 15mentioning

confidence: 98%

“…factors (TF), including p63, RANX2, and NRF2(2)(3)(4). While TF-mediated, epigenetic mechanisms of basal-to-suprabasal transition and the skin barrier formation are extensively studied (5) much less is known about 1) mechanisms that maintain the basal, undifferentiated state of KSC and 2) the role of post-transcriptional mechanisms in differentiation of keratinocytes.…”

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confidence: 99%

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miR targetome of primary human keratinocytes reveals a function for non-conserved binding sites

Thiagarajan

Zhang

Griffiths‐Jones

et al. 2022

Preprint

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The homeostasis of the human body is protected by the skin, where the process of keratinocyte differentiation in outer layers has a crucial role. Cessation of proliferation in the basal layer of keratinocytes and initiation of their subrabasal functions are tightly controlled at the level of gene transcription and message translation. A subset of mRNAs has to be repressed during differentiation, and microRNAs are known to contribute to this by directly binding mRNAs at the 3UTRs. Using results of RNA sequencing from human primary keratinocytes during induced differentiation, we evaluated the predicted binding of highly, moderately, and lowly expressed miRs to their target mRNAs. We found that moderately expressed miRs can regulate more mRNAs, and that they do so using both conserved and non-conserved canonical binding. The cumulative score for the majority of repressed mRNAs revealed a surprisingly weak binding to miRs, and we found a significant contribution of non-conserved sites to the repression of the targets. While the presence of at least one conserved site was necessary for the miR function, its weak binding may be reinforced by a non-conserved site. Together, we found that the combination of conserved and non-conserved sites lower the binding threshold for miR-mRNA interactions to assume a tighter repression of the mRNA target during cell differentiation.

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Section: Discussionmentioning

confidence: 99%

Section: Page Of 3 15mentioning

confidence: 98%

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confidence: 99%

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miR targetome of primary human keratinocytes reveals a function for non-conserved binding sites

Thiagarajan

Zhang

Griffiths‐Jones

et al. 2022

Preprint

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“…To sustain proliferation and wound repair in keratinocytes, ΔNp63 interacts with nuclear factor erythroid 2-related factor 2 (NFE2L2; NRF2). Chromatin immunoprecipitation and sequencing data demonstrated the binding of human NRF2 and p63 at a genome-wide level to both enhancers and promoters of selected genes [ 97 ]. This opens the discussion on the epigenetic regulation of p63, see also below.…”

Section: Exploiting the P63 Interactome In Epithelial Development And...mentioning

confidence: 99%

“…This interaction causes a shift in the alternative splicing of FGFR-2, a gene implicated in epithelial differentiation. In AEC syndrome, mutations of p63 in the SAM domain affect the RNA processing, since p63 is enabled to bind ABBP1 [ 97 , 98 ].…”

Section: Exploiting the P63 Interactome In Epithelial Development And...mentioning

confidence: 99%

Distinct interactors define the p63 transcriptional signature in epithelial development or cancer

Pecorari

Bernassola

Melino

et al. 2022

Biochemical Journal

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The TP63 is an indispensable transcription factor for development and homeostasis of epithelia and its derived glandular tissue. It is also involved in female germline cell quality control, muscle and thymus development. It is expressed as multiple isoforms transcribed by two independent promoters, in addition to alternative splicing occurring at the mRNA 3′-UTR. Expression of the TP63 gene, specifically the amino-deleted p63 isoform, ΔNp63, is required to regulate numerous biological activities, including lineage specification, self-renewal capacity of epithelial stem cells, proliferation/expansion of basal keratinocytes, differentiation of stratified epithelia. In cancer, ΔNp63 is implicated in squamous cancers pathogenesis of different origin including skin, head and neck and lung and in sustaining self-renewal of cancer stem cells. How this transcription factor can control such a diverse set of biological pathways is central to the understanding of the molecular mechanisms through which p63 acquires oncogenic activity, profoundly changing its down-stream transcriptional signature. Here, we highlight how different proteins interacting with p63 allow it to regulate the transcription of several central genes. The interacting proteins include transcription factors/regulators, epigenetic modifiers, and post-transcriptional modifiers. Moreover, as p63 depends on its interactome, we discuss the hypothesis to target the protein interactors to directly affect p63 oncogenic activities and p63-related diseases.

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NRF2, a crucial modulator of skin cells protection against vitiligo, psoriasis, and cancer

2022

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The skin represents a physical barrier between the organism and the environment that has evolved to confer protection against biological, chemical, and physical insults. The inner layer, known as dermis, is constituted by connective tissue and different types of immune cells whereas the outer layer, the epidermis, is composed by different layers of keratinocytes and an abundant number of melanocytes, localized in the stratum basale of the epidermis. Oxidative stress is a common alteration of inflammatory skin disorders such as vitiligo, dermatitis, or psoriasis but can also play a causal role in skin carcinogenesis and tumor progression. Nuclear factor (erythroid‐derived 2)‐like 2 (NRF2) has emerged as a crucial regulator of cell defense mechanisms activating complex transcriptional programs that facilitate reactive oxygen species detoxification, repair oxidative damage and prevent xenobiotic‐induced toxicity. Accumulating evidence suggests that the keratinocytes, melanocytes, and other skin cell types express high levels of NRF2, which is known to play a pivotal role in the skin homeostasis, differentiation, and metabolism during normal and pathologic conditions. In the present review, we summarize the current evidence linking NRF2 to skin pathophysiology and we discuss some recent modulators of NRF2 activity that have shown a therapeutic efficacy in skin protection against tumor initiation and common inflammatory skin conditions such as vitiligo or psoriasis, with a particular emphasis on natural compounds.

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Interaction of the NRF2 and p63 transcription factors promotes keratinocyte proliferation in the epidermis

Cited by 21 publications

References 49 publications

miR targetome of primary human keratinocytes reveals a function for non-conserved binding sites

miR targetome of primary human keratinocytes reveals a function for non-conserved binding sites

Distinct interactors define the p63 transcriptional signature in epithelial development or cancer

NRF2, a crucial modulator of skin cells protection against vitiligo, psoriasis, and cancer

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