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Transcriptional landscape of NFIX defines developmental and regenerative programs in skeletal muscle

ABSTRACT: Skeletal muscle is the most widespread tissue of the body, covering 40% of the total body weight. This remarkable tissue exhibits extraordinary regenerative potential, sustained by muscle stem cells, termed satellite cells. Among key players governing muscular homeostasis, Nuclear Factor I X (NFIX) is a transcription factor that plays fundamental roles during myogenesis as well as in adult muscle regeneration. However, molecular mechanisms involving NFIX expression are nowadays mostly undiscovered. Here, combining multi-omic data analysis and in-vitro validation, we resolved the Nfix transcriptional landscape in skeletal muscle tissue. Our results indicate that epigenetic alterations and intragenic enhancers strongly control Nfix promoters’ activity, that together with alternative splicing processes affects Nfix isoforms’ expression. Specifically, during myogenic development, changes in DNA methylation within the Nfix gene are related to alterations in Nfix gene expression. In adult muscle, differential usage of Nfix promoters defines distinct regenerative programs, with promoter 2 acting as a stem Nfix promoter while promoter 1 drives Nfix expression during muscle regeneration. Consequently, differential Nfix promoters’ activity encodes Nfix-specific isoforms with distinct roles in skeletal muscle. Overall, these data unravel transcriptional mechanisms affecting the Nfix gene expression in skeletal muscle, providing molecular basis for translational approaches targeting Nfix-related pathologies.

ORGANISM(S): Mus musculus

PROVIDER: GSE333416 | GEO | 2026/09/02

REPOSITORIES: GEO

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