The histone acetyltransferase inhibitor Nir regulates epidermis development

Duteil, Delphine; Tourrette, Yves; Eberlin, Adrien; Willmann, Dominica; Patel, Dharmeshkumar; Friedrichs, Nicolaus; Müller, Judith; Schüle, Roland

doi:10.1242/dev.158543

Cited by 7 publications

(15 citation statements)

References 59 publications

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“…In addition to C40, TFAP2C binds within the first intron of TP63 , creating genome accessibility at these sites during epidermal commitment [83]. The histone acetyltransferase (HAT) inhibitor NOCL2 binds to P1 and P2 in keratinocytes and epidermal‐specific Nocl2 depletion increased H3K18 acetylation (H3K18Ac) and reduced ΔNp63 [97], contradicting the association of increased H3K18Ac levels with higher ΔNp63 in lung disease [98]. A role for histone methylation has also been reported, where loss of histone demethylase KMD6A activates a TP63 enhancer [99], related to monomethylation of H3K4 as a delimiter of super enhancer activity rather than to its role as a demethylase.…”

Section: Transcriptional Control Of P63mentioning

confidence: 99%

“…Indirect roles of acetylation have also been reported. NIR (NOC2L) was initially reported to bind TAp63 but not ΔNp63 [238], but subsequent work showed that it is associated with the TP63 locus and deletion reduces both histone acetylation and ΔNp63α levels [97]. In contrast, HDAC1/2 knockout did not alter ΔNp63α levels or ΔNp63α‐activated genes but induced ΔNp63‐repressed genes, associated with p63‐mediated targeting of HDAC1/2 to repressed gene promoters [239].…”

Section: Post‐translational Modifications That Influence P63 Protein Stability And/or Activitymentioning

confidence: 99%

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The foggy world(s) of p63 isoform regulation in normal cells and cancer

Pokorná

Vysloužil

Hrabal

et al. 2021

The Journal of Pathology

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The p53 family member p63 exists as two major protein variants (TAp63 and ΔNp63) with distinct expression patterns and functional properties. Whilst downstream target genes of p63 have been studied intensively, how p63 variants are themselves controlled has been relatively neglected. Here, we review advances in understanding ΔNp63 and TAp63 regulation, highlighting their distinct pathways. TAp63 has roles in senescence and metabolism, and in germ cell genome maintenance, where it is activated post‐transcriptionally by phosphorylation cascades after DNA damage. The function and regulation of TAp63 in mesenchymal and haematopoietic cells is less clear but may involve epigenetic control through DNA methylation. ΔNp63 functions to maintain stem/progenitor cells in various epithelia and is overexpressed in squamous and certain other cancers. ΔNp63 is transcriptionally regulated through multiple enhancers in concert with chromatin modifying proteins. Many signalling pathways including growth factors, morphogens, inflammation, and the extracellular matrix influence ΔNp63 levels, with inconsistent results reported. There is also evidence for reciprocal regulation, including ΔNp63 activating its own transcription. ΔNp63 is downregulated during cell differentiation through transcriptional regulation, while post‐transcriptional events cause proteasomal degradation. Throughout the review, we identify knowledge gaps and highlight discordances, providing potential explanations including cell‐context and cell–matrix interactions. Identifying individual p63 variants has roles in differential diagnosis and prognosis, and understanding their regulation suggests clinically approved agents for targeting p63 that may be useful combination therapies for selected cancer patients. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Transcriptional Control Of P63mentioning

confidence: 99%

Section: Post‐translational Modifications That Influence P63 Protein Stability And/or Activitymentioning

confidence: 99%

The foggy world(s) of p63 isoform regulation in normal cells and cancer

Pokorná

Vysloužil

Hrabal

et al. 2021

The Journal of Pathology

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“…However, epidermal ablation of either Hdac1 or Hdac2 did not affect epidermal development, suggesting these HDACs have redundant and compensatory functions. Similarly, epidermal deletion of HAT inhibitor Nir/Noc2l at E12.5 resulted in a single‐layered epidermis without stratification and impaired HF development in embryogenesis . Moreover, in vitro HDAC inhibition in human foreskin organ culture led to abnormal epidermal architecture, proliferation arrest, and premature terminal differentiation .…”

Section: Histone Acetylation In Skin Development and Homeostasismentioning

confidence: 99%

Epigenetic control in skin development, homeostasis and injury repair

Kang

Chovatiya

Tumbar

2019

Experimental Dermatology

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Cell‐type‐ and cell‐state‐specific patterns of covalent modifications on DNA and histone tails form global epigenetic profiles that enable spatiotemporal regulation of gene expression. These epigenetic profiles arise from coordinated activities of transcription factors and epigenetic modifiers, which result in cell‐type‐specific outputs in response to dynamic environmental conditions and signalling pathways. Recent mouse genetic and functional studies have highlighted the physiological significance of global DNA and histone epigenetic modifications in skin. Importantly, specific epigenetic profiles are emerging for adult skin stem cells that are associated with their cell fate plasticity and proper activity in tissue regeneration. We can now begin to draw a more comprehensive picture of how epigenetic modifiers orchestrate their cell‐intrinsic role with microenvironmental cues for proper skin development, homeostasis and wound repair. The field is ripe to begin to implement these findings from the laboratory into skin therapies.

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“…Moreover, NIR functions as a key regulator of skin development via controlling the expression of essential factors in epidermis development. 5 Previous studies have shown that NIR functions as a negative regulator of p53-dependent transcription by the direct interaction with p53. 4 NIR has also been shown to repress the expression of p63 by restricting H3K18ac at the p63 promoter.…”

Section: Introductionmentioning

confidence: 99%

Knockdown of NIR Suppresses Breast Cancer Cell Proliferation via Promoting FOXO3

Chen¹,

Dong²,

Wang³

et al. 2021

OTT

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Background: Novel inhibitor of histone acetyltransferase repressor (NIR), a corepressor with a novel inhibitor of histone acetyltransferase (INHAT) activity, has been reported to be a negative modulator of p53 and a regulator of the cell cycle in cancer cells. However, the role of NIR in the progression of breast cancer remains elusive. Materials and Methods: Oncomine database was used to analyze the mRNA levels and prognosis value of NIR in breast cancer. We performed loss-of-function and gain-of-function studies using lentivirus expressing shRNA targeting NIR, enhancer of zeste homolog 2 (EZH2) and forkhead box O3 (FOXO3) or lentivirus expressing NIR or FOXO3, respectively. Cell proliferation and colony formation assays were performed. Coimmunoprecipitation (Co-IP) and immunoprecipitation (IP) were performed to identify the interaction between NIR and polycomb repressive complex 2 (PRC2) subunits. ChIP assay was used to identify the enrichment of NIR, EZH2, H3K27ac and H3K27me3 at the FOXO3 promoter region and the regulation of H3K27 modification at the FOXO3 promoter by NIR. Results: High levels of NIR expression were correlated with poor prognosis in breast cancer patients. Knockdown of NIR suppressed the proliferation of breast cancer cells. Mechanically, NIR was recruited by EZH2 to the promoter vicinity of FOXO3 via direct protein-protein interaction. Silencing NIR increased H3K27ac and decreased H3K27me3 levels at the FOXO3 promoter, resulting in enhancing FOXO3 expression. In accordance with this, growth inhibition of breast cancer cells caused by silencing of NIR could be reversed by FOXO3 knockdown. Conclusion: NIR knockdown inhibited proliferation by switching the H3K27me3 and H3K27ac marks at the FOXO3 promoter to promote FOXO3 transcription, and this effect depends on the physical interaction between NIR and PRC2 in breast cancer cells. Our results suggest that NIR might be a potential target for breast cancer treatment.

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The histone acetyltransferase inhibitor Nir regulates epidermis development

Cited by 7 publications

References 59 publications

The foggy world(s) of p63 isoform regulation in normal cells and cancer

The foggy world(s) of p63 isoform regulation in normal cells and cancer

Epigenetic control in skin development, homeostasis and injury repair

Knockdown of NIR Suppresses Breast Cancer Cell Proliferation via Promoting FOXO3

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