Genetic ablation of interacting with Spt6 (Iws1) causes early embryonic lethality

Orlacchio, Arturo; Stark, Aaron E.; Foray, Claudia; Amari, Foued; Sheetz, Tyler; Reese, Erika; Tessari, Anna; Perle, Krista La; Palmieri, Dario; Tsichlis, Philip N.; Coppola, Vincenzo

doi:10.1371/journal.pone.0201030

Cited by 10 publications

(9 citation statements)

References 22 publications

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“…After submission of our manuscript to this journal, a paper was published indicating the crucial role of Iws1 in mouse preimplantation embryo development 55 , supporting our findings in this study.…”

Section: Discussionsupporting

confidence: 87%

Iws1 and Spt6 Regulate Trimethylation of Histone H3 on Lysine 36 through Akt Signaling and are Essential for Mouse Embryonic Genome Activation

Oqani

Lin

Lee

et al. 2019

Sci Rep

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The mRNA processing and export factor, Iws1, interacts with the histone H3/H4 chaperone, Spt6 (Supt6 in mouse gene ontology) and recruits the lysine methyltransferase, Setd2, to chromatin to regulate H3K36me3. This recruitment is known to be crucial for pre-mRNA splicing and Iws1 has been shown to interact with REF1/Aly to mediate mRNA export. However, the role of this complex has not yet been examined in embryonic development. Here, we show that knockdown of either Iws1 or Supt6 blocked embryo development, primarily at the 8/16-cell stage, indicating that Iws1 and Supt6 are crucial for mouse preimplantation development. In the knockdown embryos, we observed decreases in pre-mRNA splicing, mRNA export and the expression of the lineage-specific transcription factor, Nanog. We found that either Iws1 or Supt6 are required for H3K36 trimethylation and that concurrent knockdown of both Iws1 and Supt6 blocks embryonic development at the 2-cell stage. We show that H3K36me3 is modulated by the Pi3k/Akt pathway, as inhibition of this pathway reduced the global level of H3K36me3 while activation of the pathway increased the level of this modification in 2-cell embryos. We observed that Iws1 interacts with nuclear Akt in early embryos, and herein propose that Akt modulates H3K36me3 through interaction with Iws1. Together, our results indicate that the Iws1 and Supt6 play crucial roles in embryonic genome activation, lineage specification, and histone modification during mouse early development.

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Section: Discussionsupporting

confidence: 87%

Iws1 and Spt6 Regulate Trimethylation of Histone H3 on Lysine 36 through Akt Signaling and are Essential for Mouse Embryonic Genome Activation

Oqani

Lin

Lee

et al. 2019

Sci Rep

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“…Mutation of SPT6 facilitates chromatin relaxation in specific genomic regions, which impacts the regulation of transcription, genomic stability and hyperrecombination 23 , 43 – 48 . Previous reports implicated SPT6’s chromatin remodeling activities to regulate zebrafish myogenesis 49 and mouse embryogenesis 50 . Here, we describe a pro-tumorigenic role for SPT6 in GBM and provide a mechanistic insight into its role in one of the deadliest of solid cancers.…”

Section: Discussionmentioning

confidence: 99%

SPT6-driven error-free DNA repair safeguards genomic stability of glioblastoma cancer stem-like cells

et al. 2020

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Glioblastoma cancer-stem like cells (GSCs) display marked resistance to ionizing radiation (IR), a standard of care for glioblastoma patients. Mechanisms underpinning radio-resistance of GSCs remain largely unknown. Chromatin state and the accessibility of DNA lesions to DNA repair machineries are crucial for the maintenance of genomic stability. Understanding the functional impact of chromatin remodeling on DNA repair in GSCs may lay the foundation for advancing the efficacy of radio-sensitizing therapies. Here, we present the results of a high-content siRNA microscopy screen, revealing the transcriptional elongation factor SPT6 to be critical for the genomic stability and self-renewal of GSCs. Mechanistically, SPT6 transcriptionally up-regulates BRCA1 and thereby drives an error-free DNA repair in GSCs. SPT6 loss impairs the self-renewal, genomic stability and tumor initiating capacity of GSCs. Collectively, our results provide mechanistic insights into how SPT6 regulates DNA repair and identify SPT6 as a putative therapeutic target in glioblastoma.

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“…Consistent with this idea, recent studies showed that Spn1 is required for normal transcript levels in both yeast and mammalian cells (REIM et al 2020;CERMAKOVA et al 2021), as well as for mRNA splicing and histone modifications (YOH et al 2007;YOH et al 2008;REIM et al 2020). Furthermore, in mammalian cells, Spn1 is essential for embryonic development and cell proliferation (LIU et al 2007;ORLACCHIO et al 2018;OQANI et al 2019), and it has been implicated in cancer (DAVOLI et al 2013;SANIDAS et al 2014).…”

Section: Introductionmentioning

confidence: 77%

Suppressor mutations that make the essential transcription factor Spn1/Iws1 dispensable in Saccharomyces cerevisiae

López-Rivera

Chuang

Spatt

et al. 2022

Preprint

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Spn1/Iws1 is an essential eukaryotic transcription elongation factor that is conserved from yeast to humans as an integral member of the RNA polymerase II elongation complex. Several studies have shown that Spn1 functions as a histone chaperone to control transcription, RNA splicing, genome stability, and histone modifications. However, the precise role of Spn1 is not understood, and there is little understanding of why it is essential for viability. To address these issues, we have isolated eight suppressor mutations that bypass the essential requirement for Spn1 in Saccharomyces cerevisiae. Unexpectedly, the suppressors identify several functionally distinct complexes and activities, including the histone chaperone FACT, the histone methyltransferase Set2, the Rpd3S histone deacetylase complex, the histone acetyltransferase Rtt109, the nucleosome remodeler Chd1, and a member of the SAGA co-activator complex, Sgf73. The identification of these distinct groups suggests that there are multiple ways in which Spn1 bypass can occur, including changes in histone acetylation and alterations of other histone chaperones. Thus, Spn1 may function to overcome repressive chromatin by multiple mechanisms during transcription. Our results suggest that bypassing a subset of these functions allows viability in the absence of Spn1.

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Genetic ablation of interacting with Spt6 (Iws1) causes early embryonic lethality

Cited by 10 publications

References 22 publications

Iws1 and Spt6 Regulate Trimethylation of Histone H3 on Lysine 36 through Akt Signaling and are Essential for Mouse Embryonic Genome Activation

Iws1 and Spt6 Regulate Trimethylation of Histone H3 on Lysine 36 through Akt Signaling and are Essential for Mouse Embryonic Genome Activation

SPT6-driven error-free DNA repair safeguards genomic stability of glioblastoma cancer stem-like cells

Suppressor mutations that make the essential transcription factor Spn1/Iws1 dispensable in Saccharomyces cerevisiae

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