Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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DNA virus infections shape transposable element activity in vitro and in vivo (HCMV,KSHV,DUX4) - Cut&Run of H3K9me3, H3K14ac and H3K27me3

ABSTRACT: We show strong activation of TEs in the context of DNA virus infection and investigate the molecular mechanisms of how TEs are induced. We demonstrate that herpesvirus infection leads to a robust expression of the MLT and THE1-class of LTR containing retrotransposons as well as a subset of long-interspersed nuclear elements-1 (LINEs), Alu-elements and some HERVs. Mechanistically we demonstrate that this TEs upregulation is induced by two pathways that act synergistically: de-repression of KAP1/TRIM28 mediated by phosphorylation and expression of the pioneer factor double-homeobox 4 (DUX4). Here, we show changes in H3K9me3, H3K14ac and H3K27me3 during two HSV-1 infection timepoints (6h and 14h).

INSTRUMENT(S): Illumina NovaSeq 6000, NEBNext Ultra II DNA Library Prep Kit, None, snakePipes 3.4

ORGANISM(S): Homo sapiens

SUBMITTER: Mirko Schmitz

PROVIDER: E-MTAB-17158 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:DUX4 is a double homeodomain transcription factor whose misexpression in the muscle causes facioscapulohumeral muscular dystrophy (FSHD). The transcriptional activity of DUX4 has been extensively characterized, and is thought to be the primary driver of FSHD pathogenesis. Yet, DUX4 expression lowers the protein level of an RNA quality control factor, UPF1, without affecting its transcript level, hinting at post-transcriptional regulatory activity downstream of DUX4 expression. How extensive the post-transcriptional activity of DUX4 is, and how relevant it is to FSHD pathogenesis, is unknown. In order to gain insight into DUX4-induced post-transcriptional gene regulation, we measured transcript and protein levels in DUX4 expressing cells via RNA-seq and SILAC-based quantitative mass spectrometry, respectively. We show that DUX4 transcriptional targets are robustly translated, including those genes previously identified as potential FSHD biomarkers. However, comparing the overall pattern of gene expression changes for RNA versus protein reveals striking differences in the most highly activated pathways, with the former showing changes in RNA processing and splicing, and the latter affecting the humoral immune response, proteolysis and exocytosis, among other pathways. Consistent with a misregulation of exocytosis, fluorescence imaging shows fragmented golgi apparatus in DUX4-expressing cells. Of the genes that showed discordant RNA and protein expression levels, post-transcriptional buffering was particularly evident for genes involved in stress response and may explain why DUX4-expressing cells succumb to toxicity despite robust transcriptional activation of stress response genes. Moreover, several genes involved in RNA decay including UPF1, UPF3B, SMG6 and XRN1 showed downregulation at the protein level, which may explain the massive inhibition of RNA quality control in DUX4-expressing cells. These results highlight the importance of considering post-transcriptional gene regulation in DUX4-expressing cells in order to fully understand the FSHD disease process.

Dataset Information

DNA virus infections shape transposable element activity in vitro and in vivo (HCMV,KSHV,DUX4) - Cut&Run of H3K9me3, H3K14ac and H3K27me3

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