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A feedback loop between nonsense-mediated decay and the retrogene DUX4 in facioscapulohumeral muscular dystrophy.

Feng Q, Snider L, Jagannathan S, Tawil R, van der Maarel SM, Tapscott SJ, Bradley RK - Elife (2015)

Bottom Line: DUX4 is a double homeobox transcription factor that is normally expressed in the testis and causes apoptosis and FSHD when misexpressed in skeletal muscle.The mechanism(s) of DUX4 toxicity in muscle is incompletely understood.We report that DUX4-triggered proteolytic degradation of UPF1, a central component of the nonsense-mediated decay (NMD) machinery, is associated with profound NMD inhibition, resulting in global accumulation of RNAs normally degraded as NMD substrates.

View Article: PubMed Central - PubMed

Affiliation: Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States.

ABSTRACT
Facioscapulohumeral muscular dystrophy (FSHD) is a muscular dystrophy caused by inefficient epigenetic repression of the D4Z4 macrosatellite array and somatic expression of the DUX4 retrogene. DUX4 is a double homeobox transcription factor that is normally expressed in the testis and causes apoptosis and FSHD when misexpressed in skeletal muscle. The mechanism(s) of DUX4 toxicity in muscle is incompletely understood. We report that DUX4-triggered proteolytic degradation of UPF1, a central component of the nonsense-mediated decay (NMD) machinery, is associated with profound NMD inhibition, resulting in global accumulation of RNAs normally degraded as NMD substrates. DUX4 mRNA is itself degraded by NMD, such that inhibition of NMD by DUX4 protein stabilizes DUX4 mRNA through a double-negative feedback loop in FSHD muscle cells. This feedback loop illustrates an unexpected mode of autoregulatory behavior of a transcription factor, is consistent with 'bursts' of DUX4 expression in FSHD muscle, and has implications for FSHD pathogenesis.

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DUX4-induced NMD inhibition is not a side effect of DUX4toxicity.(A) Poly-caspase activity (red) following transfection with acontrol siRNA or siRNA against TP53 40 hr after lentiviralinfection. Box plot, percentage of nuclei with poly-caspase granules(estimated by ImageJ; n = 8 fields). Whiskers, max and min over thefields. (B) Isoform ratios of endogenously producedNMD-degraded isoforms of HNRNPD and SRSF2.Error bars, standard deviation.DOI:http://dx.doi.org/10.7554/eLife.04996.004
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fig1s1: DUX4-induced NMD inhibition is not a side effect of DUX4toxicity.(A) Poly-caspase activity (red) following transfection with acontrol siRNA or siRNA against TP53 40 hr after lentiviralinfection. Box plot, percentage of nuclei with poly-caspase granules(estimated by ImageJ; n = 8 fields). Whiskers, max and min over thefields. (B) Isoform ratios of endogenously producedNMD-degraded isoforms of HNRNPD and SRSF2.Error bars, standard deviation.DOI:http://dx.doi.org/10.7554/eLife.04996.004

Mentions: High levels of NMD substrates in DUX4-expressing cells were not simplya side effect of DUX4-induced apoptosis. TP53 knock-down (KD) preventedapoptosis following DUX4 expression in normal myoblasts, confirmingprevious reports that DUX4 toxicity is p53-dependent (Wallace et al., 2011). However, TP53 KD did not preventDUX4-induced NMD inhibition (Figure 1—figuresupplement 1).


A feedback loop between nonsense-mediated decay and the retrogene DUX4 in facioscapulohumeral muscular dystrophy.

Feng Q, Snider L, Jagannathan S, Tawil R, van der Maarel SM, Tapscott SJ, Bradley RK - Elife (2015)

DUX4-induced NMD inhibition is not a side effect of DUX4toxicity.(A) Poly-caspase activity (red) following transfection with acontrol siRNA or siRNA against TP53 40 hr after lentiviralinfection. Box plot, percentage of nuclei with poly-caspase granules(estimated by ImageJ; n = 8 fields). Whiskers, max and min over thefields. (B) Isoform ratios of endogenously producedNMD-degraded isoforms of HNRNPD and SRSF2.Error bars, standard deviation.DOI:http://dx.doi.org/10.7554/eLife.04996.004
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383350&req=5

fig1s1: DUX4-induced NMD inhibition is not a side effect of DUX4toxicity.(A) Poly-caspase activity (red) following transfection with acontrol siRNA or siRNA against TP53 40 hr after lentiviralinfection. Box plot, percentage of nuclei with poly-caspase granules(estimated by ImageJ; n = 8 fields). Whiskers, max and min over thefields. (B) Isoform ratios of endogenously producedNMD-degraded isoforms of HNRNPD and SRSF2.Error bars, standard deviation.DOI:http://dx.doi.org/10.7554/eLife.04996.004
Mentions: High levels of NMD substrates in DUX4-expressing cells were not simplya side effect of DUX4-induced apoptosis. TP53 knock-down (KD) preventedapoptosis following DUX4 expression in normal myoblasts, confirmingprevious reports that DUX4 toxicity is p53-dependent (Wallace et al., 2011). However, TP53 KD did not preventDUX4-induced NMD inhibition (Figure 1—figuresupplement 1).

Bottom Line: DUX4 is a double homeobox transcription factor that is normally expressed in the testis and causes apoptosis and FSHD when misexpressed in skeletal muscle.The mechanism(s) of DUX4 toxicity in muscle is incompletely understood.We report that DUX4-triggered proteolytic degradation of UPF1, a central component of the nonsense-mediated decay (NMD) machinery, is associated with profound NMD inhibition, resulting in global accumulation of RNAs normally degraded as NMD substrates.

View Article: PubMed Central - PubMed

Affiliation: Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States.

ABSTRACT
Facioscapulohumeral muscular dystrophy (FSHD) is a muscular dystrophy caused by inefficient epigenetic repression of the D4Z4 macrosatellite array and somatic expression of the DUX4 retrogene. DUX4 is a double homeobox transcription factor that is normally expressed in the testis and causes apoptosis and FSHD when misexpressed in skeletal muscle. The mechanism(s) of DUX4 toxicity in muscle is incompletely understood. We report that DUX4-triggered proteolytic degradation of UPF1, a central component of the nonsense-mediated decay (NMD) machinery, is associated with profound NMD inhibition, resulting in global accumulation of RNAs normally degraded as NMD substrates. DUX4 mRNA is itself degraded by NMD, such that inhibition of NMD by DUX4 protein stabilizes DUX4 mRNA through a double-negative feedback loop in FSHD muscle cells. This feedback loop illustrates an unexpected mode of autoregulatory behavior of a transcription factor, is consistent with 'bursts' of DUX4 expression in FSHD muscle, and has implications for FSHD pathogenesis.

Show MeSH
Related in: MedlinePlus