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The transcription factor DUX4 orchestrates translational reprogramming by broadly suppressing translation efficiency and promoting expression of DUX4-induced mRNAs

ABSTRACT: The transcription factor DUX4 orchestrates translational reprogramming by broadly suppressing translation efficiency and promoting expression of DUX4-induced mRNAs

PROVIDER: PRJNA850793 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19749634_1.fastq.gz	Fastqsanger.gz
	SRR19749634_2.fastq.gz	Fastqsanger.gz
	SRR19749635_1.fastq.gz	Fastqsanger.gz
	SRR19749635_2.fastq.gz	Fastqsanger.gz
	SRR19749636_1.fastq.gz	Fastqsanger.gz

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DUX4 orchestrates translational reprograming by broadly suppressing translation efficiency [polysome-seq]

Project description:DUX4 orchestrates translational reprograming by broadly suppressing translation efficiency [polysome-seq]

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DUX4 orchestrates translational reprograming by broadly suppressing translation efficiency [RNA-seq]

Project description:DUX4 orchestrates translational reprograming by broadly suppressing translation efficiency [RNA-seq]

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DUX4 orchestrates translational reprograming by broadly suppressing translation efficiency [Ribo-seq]

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DUX4 orchestrates translational reprograming by broadly suppressing translation efficiency [polysome-seq]

Project description:DUX4, an embryonic transcription factor normally silenced in somatic tissues, was recently shown to reduce major histocompatibility complex I (MHC-I) and promote immune evasion in numerous cancer types. We report that transient expression of DUX4 results in the long-term suppression of interferon-gamma induction of MHC-I and the immunoproteasome. Brief expression of transcriptionally active DUX4 leads to a prolonged decrease in protein synthesis, altering the activity of translation initiation regulators eIF2a, eIF4E, 4EBP1, and translation elongation factor eEF2. Translational profiling identified mRNAs susceptible to DUX4-induced inhibition of translation initiation and elongation, including mRNAs encoding antigen presentation factors. We show that DUX4 orchestrates translational reprogramming by broadly attenuating protein synthesis while inducing the expression of RNAs encoding early embryonic proteins that are translationally up regulated and predicted to be less vulnerable to translational inhibition. Endogenous expression of DUX4 and its target genes in FSHD muscle cells and SuSa germinoma cells also correlates with suppression of protein synthesis and reduced MHC-I presentation. Our findings reveal a novel role of DUX4 in modulating translational control to reshape the cellular translatome with important implications for development and disease.

2023-04-11 | GSE206436 | GEO

DUX4 orchestrates translational reprograming by broadly suppressing translation efficiency [RNA-seq]

2023-02-01 | GSE206438 | GEO

DUX4 orchestrates translational reprograming by broadly suppressing translation efficiency [Ribo-seq]

2023-02-01 | GSE206437 | GEO

The transcription factor DUX4 orchestrates translational reprogramming by broadly suppressing translation efficiency and promoting expression of DUX4-induced mRNAs.

Project description:Translational control is critical for cell fate transitions during development, lineage specification, and tumorigenesis. Here, we show that the transcription factor double homeobox protein 4 (DUX4), and its previously characterized transcriptional program, broadly regulates translation to change the cellular proteome. DUX4 is a key regulator of zygotic genome activation in human embryos, whereas misexpression of DUX4 causes facioscapulohumeral muscular dystrophy (FSHD) and is associated with MHC-I suppression and immune evasion in cancer. We report that translation initiation and elongation factors are disrupted downstream of DUX4 expression in human myoblasts. Genome-wide translation profiling identified mRNAs susceptible to DUX4-induced translation inhibition, including those encoding antigen presentation factors and muscle lineage proteins, while DUX4-induced mRNAs were robustly translated. Endogenous expression of DUX4 in human FSHD myotubes and cancer cell lines also correlated with reduced protein synthesis and MHC-I presentation. Our findings reveal that DUX4 orchestrates cell state conversion by suppressing the cellular proteome while maintaining translation of DUX4-induced mRNAs to promote an early developmental program.

| S-EPMC10553841 | biostudies-literature

The transcription factor DUX4 orchestrates translational reprogramming by broadly suppressing translation efficiency and promoting expression of DUX4-induced mRNAs

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-02-01 | GSE206439 | GEO

Human DUX4 and mouse Dux interact with STAT1 and broadly inhibit interferon-stimulated gene induction

Project description:DUX4 activates the first wave of zygotic gene expression in the early embryo. Mis-expression of DUX4 in skeletal muscle causes facioscapulohumeral dystrophy (FSHD), whereas expression in cancers suppresses IFNg-induction of MHC Class I and contributes to immune evasion. We show that the DUX4 protein broadly suppresses immune signaling pathways—including IFNg, IFNb, DDX58, IFIH1 and cGAS mediated pathways. A conserved region containing (L)LxxL(L) motifs in the DUX4 carboxyterminal domain (CTD) was necessary to suppress interferon stimulated genes (ISGs). Co-immunoprecipitation identified DUX4-CTD interaction with multiple immune signaling factors, including STAT1. The DUX4-CTD (L)LxxL(L) region interacts with phosphorylated STAT1, sequesters it in the nucleus, modestly reduces its DNA binding, and prevents STAT1 from inducing ISG transcription. Mouse Dux similarly interacted with STAT1 and suppressed IFNg induction of ISGs. These findings identify an evolved role of the DUXC family in modulating immune signaling pathways with implications for development, cancers, and FSHD.

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Human DUX4 and mouse Dux interact with STAT1 and broadly inhibit interferon-stimulated gene induction [CUT&TAG]

2023-05-09 | GSE209785 | GEO