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

Thomas A. Carter, View ORCID ProfileManvendra Singh, Gabrijela Dumbović, Jason D. Chobirko, View ORCID ProfileJohn L. Rinn, Cédric Feschotte
doi: https://doi.org/10.1101/2021.07.08.451617
Thomas A. Carter
1Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14850, USA
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Manvendra Singh
1Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14850, USA
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Gabrijela Dumbović
2Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80309, USA
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Jason D. Chobirko
1Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14850, USA
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John L. Rinn
2Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80309, USA
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Cédric Feschotte
1Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14850, USA
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  • For correspondence: cf458@cornell.edu
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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 complex mutational processes, including 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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted July 08, 2021.
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Mosaic cis-regulatory evolution drives transcriptional partitioning of HERVH endogenous retrovirus in the human embryo
Thomas A. Carter, Manvendra Singh, Gabrijela Dumbović, Jason D. Chobirko, John L. Rinn, Cédric Feschotte
bioRxiv 2021.07.08.451617; doi: https://doi.org/10.1101/2021.07.08.451617
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Mosaic cis-regulatory evolution drives transcriptional partitioning of HERVH endogenous retrovirus in the human embryo
Thomas A. Carter, Manvendra Singh, Gabrijela Dumbović, Jason D. Chobirko, John L. Rinn, Cédric Feschotte
bioRxiv 2021.07.08.451617; doi: https://doi.org/10.1101/2021.07.08.451617

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