1. Chromosomes and Gene Expression

Spen links RNA-mediated endogenous retrovirus silencing and X chromosome inactivation

  1. Ava C Carter
  2. Jin Xu
  3. Meagan Y Nakamoto
  4. Yuning Wei
  5. Brian J Zarnegar
  6. Quanming Shi
  7. James P Broughton
  8. Ryan C Ransom
  9. Ankit Salhotra
  10. Surya D Nagaraja
  11. Rui Li
  12. Diana R Dou
  13. Kathryn E Yost
  14. Seung-Woo Cho
  15. Anil Mistry
  16. Michael T Longaker
  17. Paul A Khavari
  18. Robert T Batey
  19. Deborah S Wuttke
  20. Howard Y Chang  Is a corresponding author
  1. Stanford University, United States
  2. University of Colorado, Boulder, United States
  3. Novartis Institute of Biomedical Research, United States
https://doi.org/10.7554/eLife.54508
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  1. Ava C Carter
  2. Jin Xu
  3. Meagan Y Nakamoto
  4. Yuning Wei
  5. Brian J Zarnegar
  6. Quanming Shi
  7. James P Broughton
  8. Ryan C Ransom
  9. Ankit Salhotra
  10. Surya D Nagaraja
  11. Rui Li
  12. Diana R Dou
  13. Kathryn E Yost
  14. Seung-Woo Cho
  15. Anil Mistry
  16. Michael T Longaker
  17. Paul A Khavari
  18. Robert T Batey
  19. Deborah S Wuttke
  20. Howard Y Chang
(2020)
Spen links RNA-mediated endogenous retrovirus silencing and X chromosome inactivation
eLife 9:e54508.
https://doi.org/10.7554/eLife.54508
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Abstract

The Xist lncRNA mediates X chromosome inactivation (XCI)1,2. Here we show that Spen, an Xist-binding repressor protein essential for XCI3-9, binds to ancient retroviral RNA, performing a surveillance role to recruit chromatin silencing machinery to these parasitic loci. Spen inactivation activates a subset of endogenous retroviral (ERV) elements in mouse embryonic stem cells, with gain of chromatin accessibility, active histone modifications, and ERV RNA transcription. Spen binds directly to ERV RNAs that show structural similarity to the A-repeat of Xist, a region critical for Xist-mediated gene silencing10-11. ERV RNA and Xist A-repeat bind the RRM domains of Spen in a competitive manner. Insertion of an ERV into an A-repeat deficient Xist rescues binding of Xist RNA to Spen and results in strictly local gene silencing in cis. These results suggest that Xist may coopt transposable element RNA-protein interactions to repurpose powerful antiviral chromatin silencing machinery for sex chromosome dosage compensation.

Data availability

All raw and processed sequencing data have been deposited in GEO under accession number GSE131413.

The following data sets were generated

Article and author information

Author details

  1. Ava C Carter

    Center for Personal Dynamic Regulomes and Program in Epithelial Biology, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  2. Jin Xu

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0944-9835

  3. Meagan Y Nakamoto

    Biochemistry, University of Colorado, Boulder, Boulder, United States
    Competing interests
    No competing interests declared.

  4. Yuning Wei

    Dermatology, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  5. Brian J Zarnegar

    Dermatology, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  6. Quanming Shi

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  7. James P Broughton

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  8. Ryan C Ransom

    Dept of Surgery, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  9. Ankit Salhotra

    Dept of Surgery, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  10. Surya D Nagaraja

    Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  11. Rui Li

    Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  12. Diana R Dou

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6269-9636

  13. Kathryn E Yost

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  14. Seung-Woo Cho

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  15. Anil Mistry

    Novartis Institute of Biomedical Research, Cambridge, United States
    Competing interests
    Anil Mistry, is an employee of Novartis.

  16. Michael T Longaker

    Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  17. Paul A Khavari

    Department of Dermatology, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  18. Robert T Batey

    Department of Biochemistry, University of Colorado, Boulder, Boulder, United States
    Competing interests
    No competing interests declared.

  19. Deborah S Wuttke

    Department of Biochemistry, University of Colorado, Boulder, Boulder, United States
    Competing interests
    No competing interests declared.

  20. Howard Y Chang

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    For correspondence
    howchang@stanford.edu
    Competing interests
    Howard Y Chang, Reviewing editor, eLifeis a co-founder of Accent Therapeutics, Boundless Bio, and an advisor to 10x Genomics, Arsenal Biosciences, and Spring Discovery.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9459-4393

Funding

National Human Genome Research Institute (HG007735)

  • Howard Y Chang

National Human Genome Research Institute (HG004361)

  • Howard Y Chang

Scleroderma Research Foundation

  • Howard Y Chang

Howard Hughes Medical Institute

  • Howard Y Chang

National Institute of General Medical Sciences (GM120347)

  • Robert T Batey
  • Deborah S Wuttke

National Institute of Dental and Craniofacial Research (DEO26730)

  • Michael T Longaker

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Gene W Yeo, University of California, San Diego, United States

Version history

  1. Received: December 17, 2019
  2. Accepted: May 5, 2020
  3. Accepted Manuscript published: May 7, 2020 (version 1)
  4. Version of Record published: June 9, 2020 (version 2)

Copyright

© 2020, Carter et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ava C Carter
  2. Jin Xu
  3. Meagan Y Nakamoto
  4. Yuning Wei
  5. Brian J Zarnegar
  6. Quanming Shi
  7. James P Broughton
  8. Ryan C Ransom
  9. Ankit Salhotra
  10. Surya D Nagaraja
  11. Rui Li
  12. Diana R Dou
  13. Kathryn E Yost
  14. Seung-Woo Cho
  15. Anil Mistry
  16. Michael T Longaker
  17. Paul A Khavari
  18. Robert T Batey
  19. Deborah S Wuttke
  20. Howard Y Chang
(2020)
Spen links RNA-mediated endogenous retrovirus silencing and X chromosome inactivation
eLife 9:e54508.
https://doi.org/10.7554/eLife.54508

Share this article

https://doi.org/10.7554/eLife.54508

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