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

Autor:	Carter TA; Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States., Singh M; Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States., Dumbović G; BioFrontiers Institute, University of Colorado Boulder, Boulder, United States.; Institute for Cardiovascular Regeneration, Goethe University Frankfurt, Frankfurt am Main, Germany., Chobirko JD; Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States., Rinn JL; BioFrontiers Institute, University of Colorado Boulder, Boulder, United States.; Department of Biochemistry, University of Colorado Boulder, Boulder, United States., Feschotte C; Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2022 Feb 18; Vol. 11. Date of Electronic Publication: 2022 Feb 18.
DOI:	10.7554/eLife.76257
Abstrakt:	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 eight 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. Competing Interests: TC, MS, GD, JC, JR, CF No competing interests declared (© 2022, Carter et al.)
Databáze:	MEDLINE
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