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Oral FABAC therapy decreased liver fat in preestablished NAFLD in mice and rats. Inhibition of stearoyl CoA desaturase activity and fatty acid synthesis are mechanisms that may contribute to this decrease. FABACs may be potential therapeutic agents for human NAFLD.
The threshold of 200 nucleotides (nt) conventionally divides non-coding RNAs (ncRNA) into long ncRNA (lincRNA, that have more than 200 nt in length) and the remaining ones which are grouped as “small” RNAs (microRNAs, small nucleolar RNAs and piwiRNAs). Promoter-associated RNAs (paRNAs) are generally 200–500 nt long and are transcribed from sequences positioned in the promoter regions of genes. Growing evidence suggests that paRNAs play a crucial role in controlling gene transcription. Here, we used deep sequencing to identify paRNA sequences that show altered expression in a melanoma cell line compared to normal melanocytes. Thousands of reads were mapped to transcription start site (TSS) regions. We limited our search to paRNAs adjacent to genes with an expression that differed between melanoma and normal melanocytes and a length of 200–500 nt that did not overlap the gene mRNA by more than 300 nt, ultimately leaving us with 11 such transcripts. Using quantitative real-time PCR (qRT-PCR), we found a significant correlation between the expression of the mRNA and its corresponding paRNA for two studied genes: TYR and HSPC152. Ectopic overexpression of the paRNA of HSPC152 (designated paHSPC) enhanced the expression of the HSPC152 mRNA, and an siRNA targeting the paHSPC152 decreased the expression of the HSPC152 mRNA. Overexpression of paHSPC also affected the epigenetic structure of its putative promoter region along with effects on several biologic features of melanoma cells. The ectopic expression of the paRNA to TYR did not have any effect. Overall, our work indicates that paRNAs may serve as an additional layer in the regulation of gene expression in melanoma, thus meriting further investigation.
and 7 Tel Aviv Med Ctr, Tel Aviv, Israel Peeling skin syndromes form a large and heterogeneous group of inherited disorders characterized by superficial epidermal detachment, often associated with inflammatory features. We studied a consanguineous family featuring non-inflammatory peeling of the skin exacerbated by exposure to heat and mechanical stress. Whole exome sequencing revealed a homozygous nonsense mutation in FLG2, encoding filaggrin 2, which co-segregated with the disease phenotype in the family. The mutation resulted in decreased FLG2 RNA and filaggrin 2 protein in the patient's epidermis. Filaggrin 2 deficiency was shown to prevent epidermal differentiation in skin equivalents. Moreover, Filaggrin 2 was found to co-localize with corneodesmosin which plays a crucial role in maintaining cell-cell adhesion in the uppermost epidermal layers. Absence of filaggrin 2 in the patient's skin was associated with markedly decreased corneodesmosin expression. Accordingly, we showed that FLG2 down-regulation leads to reduced corneodesmosin expression and disrupts keratinocyte cell-cell adhesion in the dispase dissociation assay. This effect was aggravated by temperature elevation, corroborating the clinical phenotype. Taken together, the present data suggest that filaggrin 2 is essential for normal differentiation and cell-cell adhesion in the cornified cell layers.
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