{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n DUX4 is a double homeobox transcription factor with context‐dependent functions that span early embryonic development, muscle homeostasis, and even hematologic malignancy. In the preimplantation embryo, DUX4 (and its mouse homolog Dux) is expressed transiently just before or at zygotic genome activation, where it binds directly to promoters of a broad set of genes—including those normally active only in the cleavage stage as well as endogenous retroviral elements—to “kick‐start” embryonic transcriptional programs."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In skeletal muscle, inappropriate de‐repression and expression of DUX4 underlie the pathogenic cascade of facioscapulohumeral muscular dystrophy (FSHD). In this disease context, DUX4 misexpression leads to the activation of non‐muscle and embryonic gene programs and disrupts normal myogenic differentiation by modulating key targets such as PITX1 and by repressing muscle regulators like MyoD. Its activity is amplified through interactions with coactivators (e.g., p300/CBP) that remodel local chromatin, while DUX4‐triggered perturbation of RNA processing—including the destabilization of the nonsense‐mediated decay machinery—further exacerbates cell toxicity. Together, these mechanisms account for the differentiation defects, heightened sensitivity to stress, and cell death observed in FSHD muscle."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, in certain hematologic malignancies such as B‐progenitor acute lymphoblastic leukemia, chromosomal rearrangements and fusion events involving DUX4 result in its aberrant overexpression. In these settings, the deregulated DUX4 promotes an oncogenic transcriptional program that interferes with normal hematopoietic differentiation—mediated in part by disruption of critical factors like ERG—thereby contributing to leukemogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, DUX4 functions as an essential developmental activator during early embryogenesis and, when misexpressed in somatic tissues, drives pathological cascades that lead to muscle degeneration in FSHD and contribute to malignant transformation in select leukemias. This multifaceted role highlights DUX4 as both a critical regulator of cell fate and a potential therapeutic target in diverse human diseases.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Peter G Hendrickson, Jessie A Doráis, Edward J Grow, et al. 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