DUX4 negatively regulates the activity of the human glucocorticoid nuclear receptor

ROSA, ALBERTO L; QUINTERO, JULIETA

Paraná

Congreso; Reunión Anual de la Sociedad Argentina de Bioquímica y Biología Molecular; 2018

Sociedad Argentina de Bioquímica y Biología Molecular

The retro-transposed gene DUX4, at the human chromosome 4q35, encodes a transcription factor that regulates the expression of zygote activated genes in placental mammals. Our laboratory showed that DUX4 is a toxic pro-apoptotic protein underlying the pathogenesis of facioscapulohumeral muscular dystrophy (FSHD), the second most common form of inherited myopathy in humans. We have demonstrated that DUX4 is a negative regulator of the progesterone nuclear receptor1. In this report we explored if DUX4 is a co-regulator of the glucocorticoid nuclear receptor (GNR). The activity of DUX4 on the GNR was studied in a reconstituted system on cultured T47D and HepG2 cells, which do not express endogenously GNR. In these studies, cells were co-transfected with a plasmid expressing the GNR plus a reporter plasmid MMTV-Luc and the potential co-repressor activity of DUX4 monitored using a plasmid expressing either wild-type or mutant versions of DUX4. Results of these studies showed that DUX4 dramatically inhibits the transcriptional activating function of GNR. DUX4 variants carrying mutations at the nuclear localization (NLS-1/2) or homeodomains (H1/H2-IWF) sequences lose their repressor activity on the GNR. Taken together, our results indicate that DUX4 is a strong co-repressor of the GNR and that its nuclear location and/or its N-terminal region contribute to this activity. Although DUX4 is mostly considered a transcriptional activator, our results show that this protein could indirectly modulate gene expression by repressing the activity of hormone NRs.1Quintero et al., 2017