Transcription Factor CTIP1/ BCL11A Regulates Epidermal Differentiation and Lipid Metabolism During Skin Development

Abstract

The epidermal permeability barrier (EPB) prevents organisms from dehydration and infection. The transcriptional regulation of EPB development is poorly understood. We demonstrate here that transcription factor COUP-TF-interacting protein 1 (CTIP1/BCL11A; hereafter CTIP1) is highly expressed in the developing murine epidermis. Germline deletion of Ctip1 (Ctip1 −/−) results in EPB defects accompanied by compromised epidermal differentiation, drastic reduction in profilaggrin processing, reduced lamellar bodies in granular layers and significantly altered lipid composition. Transcriptional profiling of Ctip1 −/− embryonic skin identified altered expression of genes encoding lipid-metabolism enzymes, skin barrier-associated transcription factors and junctional proteins. CTIP1 was observed to interact with genomic elements within the regulatory region of the gene encoding the differentiation-associated gene, Fos-related antigen2 (Fosl2) and lipid-metabolism-related gene, Fatty acid elongase 4 (Elvol4), and the expression of both was altered in Ctip1 −/− mice. CTIP1 appears to play a role in EPB establishment of via direct or indirect regulation of a subset of genes encoding proteins involved in epidermal differentiation and lipid metabolism. These results identify potential, CTIP1-regulated avenues for treatment of skin disorders involving EBP defects.

Whole-genome bisulfite sequencing of goat skins identifies signatures associated with hair cycling

“…These results are inconsistent with the notion that the methylation of promoter or gene body DNA is correlated with gene expression [ 27 , 28 ]. However, our results are consistent with the findings reported in other recent WGBS studies [ 29 , 42 ], in which the regulation of methylation and expression is diverse. This is likely due to the fact that the methylation differences observed were predominantly found in the introns of CGI in the present study (Additional file 2 : Table S3).…”

“…GREM1, an inhibitor of BMP, has been implicated as a key regulator during HF development [ 9 , 41 ]. The SPTLC3 gene encodes lipid-metabolizing enzymes in the ceramide biosynthesis pathway [ 42 ], and has been associated with lipid metabolism in epidermal tissue. The COL5A1 gene functions to orchestrate reorganization within the skin structure, and knockouts of COL5A1 resulted in an increased skin stretching phenotype in mice [ 43 ].…”

Detecting genome-wide directional effects of transcription factor binding on polygenic disease risk

“…Regarding the mTOR gene set, the MTOR gene is itself an intellectual disability gene that has been intimately linked to brain development 84,85 . Regarding the cholesterol metabolism gene set, the brain contains approximately 25% of the body's cholesterol (mostly as a component of the myelin sheaths that surround axons) 86,87 with defects in brain cholesterol metabolism being linked to central nervous system disease 88,89 , and BCL11A has recently been shown to influence (and be influenced by) lipid levels [90][91][92] . Furthermore, the cholesterol metabolism and mTOR gene-set enrichments may be related, as mTOR has been linked to cholesterol metabolism 93 , including in the developing brain 94 .…”

Photoprotective Properties of Isothiocyanate and Nitrile Glucosinolate Derivatives From Meadowfoam (Limnanthes alba) Against UVB Irradiation in Human Skin Equivalent

“…Immunohistochemical (IHC) analyses were performed as previously described ( Liang et al, 2012 ; Chagani et al, 2017 ; Li et al, 2017 ). Briefly, sections of 5 μm thickness were rehydrated and dissolved of paraffin with a graded xylene and ethanol series.…”