RESUMO
Cellular lineage determination is controlled by combinations of lineage-selective transcription factors (TFs) and associated coregulators that bind to cis-regulatory elements in DNA and regulate gene expression. The ability of these factors to regulate transcription is determined not only by their cooperativity, but also by biochemical and structural properties of the chromatin, sculpting higher-order genome organization. Here, we review recent advances in the understanding of the interplay between chromatin topology and transcription. Studies from many different fields, including adipocyte lineage determination, indicate that lineage determination and differentiation are dependent on elaborate crosstalk between cis-regulatory elements, leading to the formation of transcriptional hubs. Chromatin topology appears to provide a dynamic and supportive, rather than a deterministic, scaffold for this crosstalk.
Assuntos
Cromatina , Elementos Facilitadores Genéticos , Linhagem da Célula/genética , Cromatina/genética , DNA , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
The severity of Duchenne muscular dystrophy (DMD), an incurable disease caused by the lack of dystrophin, might be modulated by different factors, including miRNAs. Among them, miR-378 is considered of high importance for muscle biology, but intriguingly, its role in DMD and its murine model (mdx mice) has not been thoroughly addressed so far. Here, we demonstrate that dystrophic mice additionally globally lacking miR-378 (double-KO [dKO] animals) exhibited better physical performance and improved absolute muscle force compared with mdx mice. Accordingly, markers of muscle damage in serum were significantly decreased in dKO mice, accompanied by diminished inflammation, fibrosis, and reduced abundance of regenerating fibers within muscles. The lack of miR-378 also normalized the aggravated fusion of dystrophin-deficient muscle satellite cells (mSCs). RNA sequencing of gastrocnemius muscle transcriptome revealed fibroblast growth factor 1 (Fgf1) as one of the most significantly downregulated genes in mice devoid of miR-378, indicating FGF1 as one of the mediators of changes driven by the lack of miR-378. In conclusion, we suggest that targeting miR-378 has the potential to ameliorate DMD pathology.