Transposon expression and repression in skeletal muscle

Abstract

Transposons and their derivatives make up a major proportion of the human genome, but they are not just relics of ancient genomes. They can still be expressed, potentially affecting the transcription of adjacent genes, and can sometimes even contribute to their coding sequence. Active transposons can integrate into new sites in the genome, potentially modifying the expression of nearby loci and leading to genetic disorders. In this review, we highlight work exploring the expression of transposons in skeletal muscles and transcriptional regulation by the KRAB-ZFP/KAP1/SETDB1 complex. We next focus on specific cases of transposon insertion causing phenotypic variation and distinct muscular dystrophies, as well as the implication of transposon expression in immune myopathies. Finally, we discuss the dysregulation of transposons in facioscapulohumeral dystrophy and aging.

Keywords: Muscular dystrophy; Skeletal muscle; Transposable elements.

Fig. 1

Transposon insertion effects on coding genes. Examples from muscle studies are given. Left: TE insertions can affect transcription of nearby genes, possibly as carriers of binding sites for transcription factors like KRAB-ZFPs. Middle: The insertion of a TE inside a gene can lead to inclusion of the TE sequence inside a coding transcript, leading to frameshifts, early stop codons or nonsense-mediated decay. Right: TE insertions can generate novel protein isoforms with new functional domains

Fig. 2

Roles of KAP1/TRIM28 and SETDB1 in muscle physiology and regeneration. Top: In myogenic cells KAP1 associates with KRAB-ZFPs and SETDB1 to silence TEs through H3K9me3, but also forms a distinct repressive complex at the Myog promoter, a gene essential for differentiation. Phosphorylation of KAP1 leads to dissociation of specific corepressors, allowing Myogenin transcription and differentiation. However, it is possible that a KAP1-KZFP complex and myogenic transcription factors bind to nearby sequences in the promoter, without directly interacting. Phosphorylation of KAP1 is also associated with exercise-induced hypertrophy. Bottom: Consequences of KAP1 or SETDB1 loss in muscle stem cells on muscle regeneration. Normally, satellite cells activate 3–4 days after injury, myotubes fuse between 7 and 10 days post-injury, and regeneration is complete between 21 and 28 days post-injury. When KAP1 is absent from the satellite cells, myotubes do not fuse and excessive fibrosis persists during regeneration. When Setdb1 is knocked out in satellite cells, the CGAS-STING pathway is activated, leading to elimination of satellite cells by the immune system. The early loss of the critical satellite cells abrogates muscle regeneration