Abstract
In the last decade, the sequence-specific transcription factor double homeobox 4 (DUX4) has gone from being an obscure entity to being a key factor in important physiological and pathological processes. We now know that expression of DUX4 is highly regulated and restricted to the early steps of embryonic development, where DUX4 is involved in transcriptional activation of the zygotic genome. While DUX4 is epigenetically silenced in most somatic tissues of healthy humans, its aberrant reactivation is associated with several diseases, including cancer, viral infection and facioscapulohumeral muscular dystrophy (FSHD). DUX4 is also translocated, giving rise to chimeric oncogenic proteins at the basis of sarcoma and leukemia forms. Hence, understanding how DUX4 is regulated and performs its activity could provide relevant information, not only to further our knowledge of human embryonic development regulation, but also to develop therapeutic approaches for the diseases associated with DUX4. Here, we summarize current knowledge on the cellular and molecular processes regulated by DUX4 with a special emphasis on FSHD muscular dystrophy.
Highlights
Has gone from being an obscure entity to being a key factor in important physiological and pathological processes
Double homeobox 4 (DUX4) expression [95], quantitative mass spectrometry shows that many genes display discordant transcript and protein levels, with the highest divergence concerning genes downregulated by DUX4 [96]. These results suggest that post-transcriptional modulation by DUX4 occurs primarily at the level of protein stability and are in agreement with previous studies showing that about 30% of transcript-protein pairs display a varying degree of discordance between RNA and protein dynamics [97,98,99] and that the highest discrepancy frequently concerns downregulated transcripts [97]
The alteration of profibrotic/adipogenic physiological state associated with DUX4-induction was comparable to that caused by glycerol, which is characterized by an increased number of PDGFRα+ cells at the 10 day time point, rather than cardiotoxin-induced myofiber death, that did not show a significantly different number of fibroadipogenic progenitors (FAPs) infiltrates after 10 days of injury [80]
Summary
Double homeobox 4 (DUX4) encodes for a transcription factor with increasingly important roles in normal physiology and in disease. Crystallography studies structural studies elucidating how DUX4 binds to DNA and regulates its targets are exhave analyzed in detail the structure of the two DUX4 homeodomains in complex with tremely important, and could lead to the development of therapeutic strategies, such as DNA. DUX4 binding to its consensus target region, which is mediated by the DUX4 in Embryo folding of Activity the homeodomains covering three consecutive grooves and embracing the DNA, had never been observed before in othercell transcription with α-helical. RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) demonstrated that DUX4 directly activates the transcription of several protein-coding genes transiently expressed in cleavage stage embryos, including ZSCAN4, KDM4E, PRAMEF and ZFP352 [1]. Dux expression is tightly controlled at DNA, RNA and protein levels and its prolonged activation leads to developmental arrest and embryo death [30,35]
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