Mosaic cis-regulatory evolution drives transcriptional partitioning of HERVH endogenous retrovirus in the human embryo

  1. Thomas Carter
  2. Manvendra Singh
  3. Gabrijela Dumbovic
  4. Jason D Chobirko
  5. John L Rinn
  6. Cédric Feschotte  Is a corresponding author
  1. Cornell University, United States [US]
  2. Cornell University, United States
  3. University of Colorado Boulder, United States

Abstract

The human endogenous retrovirus type-H (HERVH) family is expressed in the preimplantation embryo. A subset of these elements are specifically transcribed in pluripotent stem cells where they appear to exert regulatory activities promoting self-renewal and pluripotency. How HERVH elements achieve such transcriptional specificity remains poorly understood. To uncover the sequence features underlying HERVH transcriptional activity, we performed a phyloregulatory analysis of the long terminal repeats (LTR7) of the HERVH family, which harbor its promoter, using a wealth of regulatory genomics data. We found that the family includes at least 8 previously unrecognized subfamilies that have been active at different timepoints in primate evolution and display distinct expression patterns during human embryonic development. Notably, nearly all HERVH elements transcribed in ESCs belong to one of the youngest subfamilies we dubbed LTR7up. LTR7 sequence evolution was driven by a mixture of mutational processes, including point mutations, duplications, and multiple recombination events between subfamilies, that led to transcription factor binding motif modules characteristic of each subfamily. Using a reporter assay, we show that one such motif, a predicted SOX2/3 binding site unique to LTR7up, is essential for robust promoter activity in induced pluripotent stem cells. Together these findings illuminate the mechanisms by which HERVH diversified its expression pattern during evolution to colonize distinct cellular niches within the human embryo.

Data availability

Scripts, data tables, and notes for figures 1-4,6a and supplemental figures 1-1,2-1,3-1,4-1,5-1,6-2 by TAC and JDC - https://github.com/LumpLord/Mosaic-cis-regulatory-evolution-drives-transcriptional-partitioning-of-HERVH-endogenous-retrovirus..Scripts and data tables by MS for figures 5,6c and supplemental figures 6-1,6-3,5-2 - https://github.com/Manu-1512/LTR7-up

The following previously published data sets were used

Article and author information

Author details

  1. Thomas Carter

    Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States [US]
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7081-3259
  2. Manvendra Singh

    Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8626-5418
  3. Gabrijela Dumbovic

    Department of Biochemistry, University of Colorado Boulder, Boulder, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jason D Chobirko

    Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8495-9152
  5. John L Rinn

    Department of Biochemistry, University of Colorado Boulder, Boulder, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7231-7539
  6. Cédric Feschotte

    Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States
    For correspondence
    cf458@cornell.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8772-6976

Funding

National Institutes of Health (GM112972)

  • Cédric Feschotte

National Institutes of Health (HG009391)

  • Cédric Feschotte

National Institutes of Health (GM122550)

  • Cédric Feschotte

Cornell Center for Vertebrate Genomics

  • Thomas Carter

Howard Hughes Medical Institute

  • John L Rinn

National Institutes of Health (GM099117)

  • John L Rinn

Cornell Presidential Fellow Program

  • Manvendra Singh

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

Reviewing Editor

  1. Mia T Levine, University of Pennsylvania, United States

Publication history

  1. Preprint posted: July 8, 2021 (view preprint)
  2. Received: December 14, 2021
  3. Accepted: February 17, 2022
  4. Accepted Manuscript published: February 18, 2022 (version 1)
  5. Version of Record published: March 10, 2022 (version 2)

Copyright

© 2022, 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. Thomas Carter
  2. Manvendra Singh
  3. Gabrijela Dumbovic
  4. Jason D Chobirko
  5. John L Rinn
  6. Cédric Feschotte
(2022)
Mosaic cis-regulatory evolution drives transcriptional partitioning of HERVH endogenous retrovirus in the human embryo
eLife 11:e76257.
https://doi.org/10.7554/eLife.76257
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