Co-option of endogenous retroviruses through genetic escape from TRIM28 repression
Rocio Enriquez-Gasca,
Poppy A. Gould,
Hale Tunbak,
Lucia Conde,
Javier Herrero,
Alexandra Chittka,
Christine R. Beck,
Robert Gifford,
Helen M. Rowe
Affiliations
Rocio Enriquez-Gasca
Centre for Immunobiology, Blizard Institute, Queen Mary University of London, London E1 2AT, UK; Corresponding author
Poppy A. Gould
Centre for Immunobiology, Blizard Institute, Queen Mary University of London, London E1 2AT, UK
Hale Tunbak
Centre for Immunobiology, Blizard Institute, Queen Mary University of London, London E1 2AT, UK
Lucia Conde
Bill Lyons Informatics Centre, UCL Cancer Institute, London WC1E 6DD, UK
Javier Herrero
Bill Lyons Informatics Centre, UCL Cancer Institute, London WC1E 6DD, UK
Alexandra Chittka
Centre for Immunobiology, Blizard Institute, Queen Mary University of London, London E1 2AT, UK
Christine R. Beck
Department of Genetics and Genome Sciences, University of Connecticut Health Center, The Jackson Laboratory for Genomic Medicine, Connecticut, JAX CT, Farmington, CT 06032, USA
Robert Gifford
MRC-University of Glasgow Centre for Virus Research, Glasgow G611QH, UK
Helen M. Rowe
Centre for Immunobiology, Blizard Institute, Queen Mary University of London, London E1 2AT, UK; Corresponding author
Summary: Endogenous retroviruses (ERVs) have rewired host gene networks. To explore the origins of co-option, we employed an active murine ERV, IAPEz, and an embryonic stem cell (ESC) to neural progenitor cell (NPC) differentiation model. Transcriptional silencing via TRIM28 maps to a 190 bp sequence encoding the intracisternal A-type particle (IAP) signal peptide, which confers retrotransposition activity. A subset of “escapee” IAPs (∼15%) exhibits significant genetic divergence from this sequence. Canonical repressed IAPs succumb to a previously undocumented demarcation by H3K9me3 and H3K27me3 in NPCs. Escapee IAPs, in contrast, evade repression in both cell types, resulting in their transcriptional derepression, particularly in NPCs. We validate the enhancer function of a 47 bp sequence within the U3 region of the long terminal repeat (LTR) and show that escapee IAPs convey an activating effect on nearby neural genes. In sum, co-opted ERVs stem from genetic escapees that have lost vital sequences required for both TRIM28 restriction and autonomous retrotransposition.
