Glucocorticoid receptor and Klf4 co-regulate anti-inflammatory genes in keratinocytes

Abstract

The glucocorticoid (GC) receptor (GR) and Kruppel-like factor Klf4 are transcription factors that play major roles in skin homeostasis. However, whether these transcription factors cooperate in binding genomic regulatory regions in epidermal keratinocytes was not known. Here, we show that in dexamethasone-treated keratinocytes GR and Klf4 are recruited to genomic regions containing adjacent GR and KLF binding motifs to control transcription of the anti-inflammatory genes Tsc22d3 and Zfp36. GR- and Klf4 loss of function experiments showed total GR but partial Klf4 requirement for full gene induction in response to dexamethasone. In wild type keratinocytes induced to differentiate, GR and Klf4 protein expression increased concomitant with Tsc22d3 and Zfp36 up-regulation. In contrast, GR-deficient cells failed to differentiate or fully induce Klf4, Tsc22d3 and Zfp36 correlating with increased expression of the epithelium-specific Trp63, a known transcriptional repressor of Klf4. The identified transcriptional cooperation between GR and Klf4 may determine cell-type specific regulation and have implications for developing therapies for skin diseases.

The Krüppel-like factor 9 cistrome in mouse hippocampal neurons reveals predominant transcriptional repression via proximal promoter binding

“…For example, Klf4 promotes differentiation of monocytes and directly upregulates transcription of the pro-inflammatory cytokine interleukin-6 [59–62]. It also cooperates with the glucocorticoid receptor to induce expression of anti-inflammatory genes in keratinocytes [63]. Klf13 regulates expression of IL-4 in CD4 (+) T cells [64].…”

Overexpression of Glucocorticoid-induced Leucine Zipper (GILZ) increases susceptibility to Imiquimod-induced psoriasis and involves cutaneous activation of TGF-β1

“…Keratinocytes were isolated from 8-week-old C57BL6/DBA female mouse dorsal skin and immortal keratinocyte cell lines were generated and cultured as previously described28. Keratinocytes were seeded in a 6-well plate to a confluence of about 80% 24 h prior to transfection.…”

“…We have previously reported that Tsc22d3 is transcriptionally up-regulated during the differentiation of keratinocytes in vitro 28; however, the role of GILZ in skin pathophysiology is largely unknown. Here, we aimed to evaluate the consequences of GILZ overexpression during the onset and progression of psoriasis by generating and characterizing a mouse model with generalized overexpression of this protein (GILZ-Tg mice).…”

Role of carbonic anhydrases in skin wound healing

“…30 MZF1 is involved in myeloid cell differentiation 31 and is a strong enhancer of cell migration and invasion, 32 thus potentially explaining the origin of the strong CA4 expression in neutrophils. KLF4, in turn, has been shown to be expressed during inflammation 33 and wound healing 34, 35, 36, 37 , and to facilitate cutaneous wound healing. 36 …”