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.

Metrics

  • 1,446
    Page views
  • 211
    Downloads
  • 1
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Computational and Systems Biology
    2. Genetics and Genomics
    Jayashree Kumar et al.
    Research Article Updated

    Splicing is highly regulated and is modulated by numerous factors. Quantitative predictions for how a mutation will affect precursor mRNA (pre-mRNA) structure and downstream function are particularly challenging. Here, we use a novel chemical probing strategy to visualize endogenous precursor and mature MAPT mRNA structures in cells. We used these data to estimate Boltzmann suboptimal structural ensembles, which were then analyzed to predict consequences of mutations on pre-mRNA structure. Further analysis of recent cryo-EM structures of the spliceosome at different stages of the splicing cycle revealed that the footprint of the Bact complex with pre-mRNA best predicted alternative splicing outcomes for exon 10 inclusion of the alternatively spliced MAPT gene, achieving 74% accuracy. We further developed a β-regression weighting framework that incorporates splice site strength, RNA structure, and exonic/intronic splicing regulatory elements capable of predicting, with 90% accuracy, the effects of 47 known and 6 newly discovered mutations on inclusion of exon 10 of MAPT. This combined experimental and computational framework represents a path forward for accurate prediction of splicing-related disease-causing variants.

    1. Cell Biology
    2. Genetics and Genomics
    Heyun Guo et al.
    Research Article

    In the first meiotic cell division, proper segregation of chromosomes in most organisms depends on chiasmata, exchanges of continuity between homologous chromosomes that originate from the repair of programmed double-strand breaks (DSBs) catalyzed by the Spo11 endonuclease. Since DSBs can lead to irreparable damage in germ cells, while chromosomes lacking DSBs also lack chiasmata, the number of DSBs must be carefully regulated to be neither too high nor too low. Here, we show that in Caenorhabditis elegans, meiotic DSB levels are controlled by the phosphoregulation of DSB-1, a homolog of the yeast Spo11 cofactor Rec114, by the opposing activities of PP4PPH-4.1 phosphatase and ATRATL-1 kinase. Increased DSB-1 phosphorylation in pph-4.1 mutants correlates with reduction in DSB formation, while prevention of DSB-1 phosphorylation drastically increases the number of meiotic DSBs both in pph-4.1 mutants as well as in the wild type background. C. elegans and its close relatives also possess a diverged paralog of DSB-1, called DSB-2, and loss of dsb-2 is known to reduce DSB formation in oocytes with increasing age. We show that the proportion of the phosphorylated, and thus inactivated, form of DSB-1 increases with age and upon loss of DSB-2, while non-phosphorylatable DSB-1 rescues the age-dependent decrease in DSBs in dsb-2 mutants. These results suggest that DSB-2 evolved in part to compensate for the inactivation of DSB-1 through phosphorylation, to maintain levels of DSBs in older animals. Our work shows that PP4PPH-4.1, ATRATL-1, and DSB-2 act in concert with DSB-1 to promote optimal DSB levels throughout the reproductive lifespan.