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

Abstract
Data availability
Article and author information

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

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Article and author information

Author details

Thomas Carter

Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States [US]

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7081-3259
Manvendra Singh

Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8626-5418
Gabrijela Dumbovic

Department of Biochemistry, University of Colorado Boulder, Boulder, United States

Competing interests
The authors declare that no competing interests exist.
Jason D Chobirko

Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-8495-9152
John L Rinn

Department of Biochemistry, University of Colorado Boulder, Boulder, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7231-7539
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.

"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.

Copyright

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.