A GRHL3-regulated repair pathway suppresses immune-mediated epidermal hyperplasia

Gordon, William; Zeller, Michael; Klein, Rachel Herndon; Swindell, William R.; Ho, Hsiang‐Ling; Espetia, Francisco; Guðjónsson, Jóhann E.; Baldi, Pierre; Andersen, Bogi

doi:10.1172/jci77138

Cited by 50 publications

(69 citation statements)

References 77 publications

(79 reference statements)

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“…Primer sequences are listed in supplemental Table 4. Sequencing libraries were generated for two replicate Myc tag ChIP samples using the Illumina Tru-Seq kit according to the Illumina protocol for ChIP-Seq library preparation with some modification: following previously published protocols (23,24), after adaptor ligation, 14 cycles of PCR amplification were performed prior to size selection of the library. Clustering and 50-cycle single end sequencing were performed on the Illumina Hi-Seq 2000 Genome Analyzer.…”

Section: Methodsmentioning

confidence: 99%

Cofactors of LIM Domains Associate with Estrogen Receptor α to Regulate the Expression of Noncoding RNA H19 and Corneal Epithelial Progenitor Cell Function

Klein

Stephens

et al. 2016

Journal of Biological Chemistry

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Cofactors of LIM domain proteins, CLIM1 and CLIM2, are widely expressed transcriptional cofactors that are recruited to gene regulatory regions by DNA-binding proteins, including LIM domain transcription factors. In the cornea, epitheliumspecific expression of a dominant negative (DN) CLIM under the keratin 14 (K14) promoter causes blistering, wounding, inflammation, epithelial hyperplasia, and neovascularization followed by epithelial thinning and subsequent epidermallike differentiation of the corneal epithelium. The defects in corneal epithelial differentiation and cell fate determination suggest that CLIM may regulate corneal progenitor cells and the transition to differentiation. Consistent with this notion, the K14-DN-Clim corneal epithelium first exhibits increased proliferation followed by fewer progenitor cells with decreased proliferative potential. In vivo ChIP-sequencing experiments with corneal epithelium show that CLIM binds to and regulates numerous genes involved in cell adhesion and proliferation, including limbally enriched genes. Intriguingly, CLIM associates primarily with non-LIM homeodomain motifs in corneal epithelial cells, including that of estrogen receptor ␣. Among CLIM targets is the noncoding RNA H19 whose deregulation is associated with Silver-Russell and Beckwith-Wiedemann syndromes. We demonstrate here that H19 negatively regulates corneal epithelial proliferation. In addition to cell cycle regulators, H19 affects the expression of multiple cell adhesion genes. CLIM interacts with estrogen receptor ␣ at the H19 locus, potentially explaining the higher expression of H19 in female than male corneas. Together, our results demonstrate an important role for CLIM in regulating the proliferative potential of corneal epithelial progenitors and identify CLIM downstream target H19 as a regulator of corneal epithelial proliferation and adhesion.

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Section: Methodsmentioning

confidence: 99%

Cofactors of LIM Domains Associate with Estrogen Receptor α to Regulate the Expression of Noncoding RNA H19 and Corneal Epithelial Progenitor Cell Function

Klein

Stephens

et al. 2016

Journal of Biological Chemistry

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“…We recently established in PMA-stimulated OKF6 cells that IRF6 forms a hierarchal regulatory network with the GRHL3 and ELF3 transcription factors to promote IVL, TGM1, and SPRR1 gene expression downstream of RIPK4 signaling (7,29). Significantly, a role for GRHL3 in mediating the repair of epidermal lesions arising from immune-mediated barrier dysregulation has been demonstrated (30). Thus, the IRF6-dependent stimulation of GRHL3 gene expression in response to P. gingivalis may serve to promote the integrity of oral epithelia.…”

Section: Discussionmentioning

confidence: 99%

Interferon Regulatory Factor 6 Promotes Keratinocyte Differentiation in Response to Porphyromonas gingivalis

Huynh

Scholz

et al. 2017

Infect Immun

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We recently demonstrated that the expression of the interferon regulatory factor 6 (IRF6) transcription factor in oral keratinocytes was stimulated by the periodontal pathogen Porphyromonas gingivalis. Here, we have established that IRF6 promotes the differentiation of oral keratinocytes in response to P. gingivalis. This was evidenced by the IRF6-dependent upregulation of specific markers of keratinocyte terminal differentiation (e.g., involucrin [IVL] and keratin 13 [KRT13]), together with additional transcriptional regulators of keratinocyte differentiation, including Grainyheadlike 3 (GRHL3) and Ovo-like zinc finger 1 (OVOL1). We have previously established that the transactivator function of IRF6 is activated by receptor-interacting protein kinase 4 (RIPK4). Consistently, the silencing of RIPK4 inhibited the stimulation of IVL, KRT13, GRHL3, and OVOL1 gene expression. IRF6 was shown to also regulate the stimulation of transglutaminase-1 (TGM1) gene expression by P. gingivalis, as well as that of small proline-rich proteins (e.g., SPRR1), which are covalently cross-linked by TGM1 to other proteins, including IVL, during cornification. The expression of the tight junction protein occludin (OCLN) was found to also be upregulated in an IRF6-dependent manner. IRF6 was demonstrated to be important for the barrier function of oral keratinocytes; specifically, silencing of IRF6 increased P. gingivalis-induced intercellular permeability and cell invasion. Taken together, our findings potentially position IRF6 as an important mediator of barrier defense against P. gingivalis. KEYWORDS differentiation, GRHL3, IRF6, keratinocyte, Porphyromonas gingivalis, RIPK4, barrier function T he oral epithelium is an important physical and immunological barrier to pathogens (1). The integrity of the epithelium is maintained through continuous cycles of keratinocyte proliferation and differentiation, whereby basal keratinocytes intermittently exit the cell cycle and undergo terminal differentiation as they migrate toward the epithelium surface, concomitantly upregulating the expression of proteins that confer mechanical strength and elasticity to the epithelium (1-3). Depending on the anatomical location, terminally differentiated keratinocytes may also become cornified through the covalent cross-linking of IVL and other cornified envelope proteins by transglutaminases (e.g., TGM1) (1, 2).IRF6 is a critical transcriptional regulator of keratinocyte differentiation (4-7). IRF6 promotes keratinocyte differentiation in part by inducing the expression of additional transcriptional regulators of differentiation, including GRHL3 and OVOL1 (5-7). GRHL3 promotes keratinocyte differentiation through its interaction with other transcription factors (e.g., LMO4) (8, 9) and by recruiting the Trithorax complex to the promoters of differentiation-associated genes (10). OVOL1 can promote keratinocyte differentiation by repressing the transcription of target genes, including c-Myc (11).The transactivator function of IRF6 can be activated...

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“…∆/-/K14Cre+ cKO mice show mild hyperplasia and impaired terminal differentiation, although they lack defects in the homeostatic maintenance of the epidermal barrier seen in embryonic Grhl3 KO mice [54]. Interestingly, however, these cKO mice develop more pronounced epidermal hyperplasia in regions of chemical injury, which correlates with increased expression of keratin 6 (K6), a marker for both the injury response and aberrant differentiation of keratinocytes [54].…”

Section: The Grhl3mentioning

confidence: 99%

“…Interestingly, however, these cKO mice develop more pronounced epidermal hyperplasia in regions of chemical injury, which correlates with increased expression of keratin 6 (K6), a marker for both the injury response and aberrant differentiation of keratinocytes [54]. Direct mechanical injury to the epidermis also increases K6 expression, together with keratin 10 (K10) [35], [54], an early marker of terminal differentiation. In the normal response to injury, Grhl3 mRNA expression markedly increases together with increased Grhl3-expressing cells, indicating that Grhl3 is an important factor for the epithelial wound repair response [54].…”

Section: The Grhl3mentioning

confidence: 99%

“…Direct mechanical injury to the epidermis also increases K6 expression, together with keratin 10 (K10) [35], [54], an early marker of terminal differentiation. In the normal response to injury, Grhl3 mRNA expression markedly increases together with increased Grhl3-expressing cells, indicating that Grhl3 is an important factor for the epithelial wound repair response [54]. Taken together, these results suggest that although Grhl3 is not necessary for maintaining the skin barrier after birth, it is highly involved in postnatal epidermal repair, particularly following chemically-mediated damage that leads to an inflammatory response, thereby providing a link between repair mechanisms, inflammation and keratinocyte proliferation.…”

Section: The Grhl3mentioning

confidence: 99%

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Long-Lived Epidermal Cancer-Initiating Cells

Youssef

Cuddihy

Darido

2017

Preprint

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Non-melanomatous skin cancers (NMSCs), which include basal and squamous cell carcinoma (BCC and SCC respectively), represent a significant burden on the population as well as an economic load to the health care system, yet treatments of these preventable cancers remain ineffective. Although primary prevention is possible through minimising sunlight exposure, the World Health Organisation estimates that between 2 and 3 million new cases of NMSCs are diagnosed each year, accounting for 1 in 3 of all newly diagnosed cancers.Furthermore, studies have estimated there has been a 2-fold increase in the incidence of NMSCs between 1960s and 1980s. The increase in cases of NMSCs as well as the lack of effective treatments makes the need for novel therapeutic approaches all the more necessary.To rationally develop more targeted treatments for NMSCs, a better understanding of the cell of origin, in addition to the underlying pathophysiological mechanisms that govern the development of these cancers, is urgent. NMSCs are generally thought to arise from specific types of stem cells that become the source of clonal expansion of tumourigenic cells. Previous research on SCC has alluded to these stem cells being localised in the basal compartment of the skin, which ordinarily houses the progenitor cells that contribute towards wound healing and normal cell turnover of overlying epidermal skin layers. More recent research has Preprints (www.preprints.org) | NOT PEER-REVIEWED |

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A GRHL3-regulated repair pathway suppresses immune-mediated epidermal hyperplasia

Cited by 50 publications

References 77 publications

Cofactors of LIM Domains Associate with Estrogen Receptor α to Regulate the Expression of Noncoding RNA H19 and Corneal Epithelial Progenitor Cell Function

Cofactors of LIM Domains Associate with Estrogen Receptor α to Regulate the Expression of Noncoding RNA H19 and Corneal Epithelial Progenitor Cell Function

Interferon Regulatory Factor 6 Promotes Keratinocyte Differentiation in Response to Porphyromonas gingivalis

Long-Lived Epidermal Cancer-Initiating Cells

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