Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 27, Pages 8367-8372Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1422187112
Keywords
epigenetics; histone methylation; repression; transposable elements; retroviruses
Categories
Funding
- National Cancer Institute Cancer Center [P30 CA91842]
- Institute of Clinical and Translational Sciences (ICTS/CTSA) from the National Center for Research Resources [UL1TR000448]
- National Institutes of Health (NIH) [AI 079732, AI 118852, AI 097244]
- Ministry of Education, Culture, Sports, Science and Technology of Japan [20062005]
- NIH [T32 AI 7163-34]
- Grants-in-Aid for Scientific Research [20062005] Funding Source: KAKEN
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Genome stability relies on epigenetic mechanisms that enforce repression of endogenous retroviruses (ERVs). Current evidence suggests that distinct chromatin-based mechanisms repress ERVs in cells of embryonic origin (histone methylation dominant) vs. more differentiated cells (DNA methylation dominant). However, the latter aspect of this model has not been tested. Remarkably, and in contrast to the prevailing model, we find that repressive histone methylation catalyzed by the enzyme SETDB1 is critical for suppression of specific ERV families and exogenous retroviruses in committed B-lineage cells from adult mice. The profile of ERV activation in SETDB1-deficient B cells is distinct from that observed in corresponding embryonic tissues, despite the loss of repressive chromatin modifications at all ERVs. We provide evidence that, on loss of SETDB1, ERVs are activated in a lineage-specific manner depending on the set of transcription factors available to target proviral regulatory elements. These findings have important implications for genome stability in somatic cells, as well as the interface between epigenetic repression and viral latency.
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