DUX4 induces a transcriptome more characteristic of a less-differentiated cell state and inhibits myogenesis

TY - JOUR

T1 - DUX4 induces a transcriptome more characteristic of a less-differentiated cell state and inhibits myogenesis

AU - Knopp, Paul

AU - Krom, Yvonne D.

AU - Banerji, Christopher R S

AU - Panamarova, Maryna

AU - Moyle, Louise A.

AU - den Hamer, Bianca

AU - van der Maarel, Silvére M.

AU - Zammit, Peter S.

PY - 2016/10

Y1 - 2016/10

N2 - Skeletal muscle wasting in facioscapulohumeral muscular dystrophy (FSHD) results in substantial morbidity. On a disease-permissive chromosome 4qA haplotype, genomic and/or epigenetic changes at the D4Z4 macrosatellite repeat allows transcription of the DUX4 retrogene. Analysing transgenicmice carrying a human D4Z4 genomic locus from an FSHD-affected individual showed that DUX4 was transiently induced in myoblasts during skeletal muscle regeneration. Centromeric to the D4Z4 repeats is an inverted D4Z4 unit encoding DUX4c. Expression of DUX4, DUX4c and DUX4 constructs, including constitutively active, dominant-negative and truncated versions, revealed that DUX4 activates target genes to inhibit proliferation and differentiation of satellite cells, but that it also downregulates target genes to suppress myogenic differentiation. These transcriptional changes elicited by DUX4 in mouse have significant overlap with genes regulated by DUX4 in man. Comparison of DUX4 and DUX4c transcriptional perturbations revealed that DUX4 regulates genes involved in cell proliferation, whereas DUX4c regulates genes engaged in angiogenesis and muscle development, with both DUX4 and DUX4c modifing genes involved in urogenital development. Transcriptomic analysis showed that DUX4 operates through both target gene activation and repression to orchestrate a transcriptome characteristic of a less-differentiated cell state.

AB - Skeletal muscle wasting in facioscapulohumeral muscular dystrophy (FSHD) results in substantial morbidity. On a disease-permissive chromosome 4qA haplotype, genomic and/or epigenetic changes at the D4Z4 macrosatellite repeat allows transcription of the DUX4 retrogene. Analysing transgenicmice carrying a human D4Z4 genomic locus from an FSHD-affected individual showed that DUX4 was transiently induced in myoblasts during skeletal muscle regeneration. Centromeric to the D4Z4 repeats is an inverted D4Z4 unit encoding DUX4c. Expression of DUX4, DUX4c and DUX4 constructs, including constitutively active, dominant-negative and truncated versions, revealed that DUX4 activates target genes to inhibit proliferation and differentiation of satellite cells, but that it also downregulates target genes to suppress myogenic differentiation. These transcriptional changes elicited by DUX4 in mouse have significant overlap with genes regulated by DUX4 in man. Comparison of DUX4 and DUX4c transcriptional perturbations revealed that DUX4 regulates genes involved in cell proliferation, whereas DUX4c regulates genes engaged in angiogenesis and muscle development, with both DUX4 and DUX4c modifing genes involved in urogenital development. Transcriptomic analysis showed that DUX4 operates through both target gene activation and repression to orchestrate a transcriptome characteristic of a less-differentiated cell state.

KW - DUX4

KW - DUX4c

KW - FSHD

KW - Satellite cell

KW - Skeletal muscle

KW - Stem cells

KW - Transcriptome

UR - http://www.scopus.com/inward/record.url?scp=84995387826&partnerID=8YFLogxK

U2 - 10.1242/jcs.180372

DO - 10.1242/jcs.180372

M3 - Article

AN - SCOPUS:84995387826

SN - 0021-9533

VL - 129

SP - 3816

EP - 3831

JO - Journal of Cell Science

JF - Journal of Cell Science

IS - 20

ER -