Multiple Epigenetic Modifiers Induce Aggressive Viral Extinction in Extraembryonic Endoderm Stem Cells

• Published in: Cell stem cell 2010-05, Vol.6 (5), p.457-467
• Main Authors: Golding, Michael C., Zhang, Liyue, Mann, Mellissa R.W.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell differentiation, maturation, development, hematopoiesis; Cell Lineage - genetics; Cell physiology; Chromatin - metabolism; Ectoderm - cytology; Ectoderm - metabolism; Ectoderm - virology; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Embryonic Stem Cells - virology; Endoderm - cytology; Endoderm - metabolism; Endoderm - virology; Epigenesis, Genetic; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Developmental; Gene Silencing; Genes, Reporter; Mice; Mice, Inbred C57BL; Molecular and cellular biology; Reproducibility of Results; Retroviridae - genetics; Retrovirus; RNA Interference; RNA, Messenger - genetics; RNA, Messenger - metabolism; STEMCELL; Terminal Repeat Sequences - genetics; Transcription, Genetic; Virus Inactivation
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2010.03.014

To prevent insertional mutagenesis arising from retroviral reactivation, cells of embryonic origin possess a unique capacity to silence retroviruses. Given the distinct modes of X chromosome inactivation between embryonic and extraembryonic lineages, we investigated paradigms of viral extinction. We show that trophectoderm stem cells do not silence retroviral transcription, whereas extraembryonic endoderm stem cells aggressively extinguish proviral transcription, even more rapidly than do embryonic stem cells. By using a short hairpin RNA library, we identified epigenetic modifiers of retroviral extinction in extraembryonic endoderm stem cells. Multiple chromatin remodeling and polycomb repressor complex proteins act to modulate integrated, as well as endogenous, retroviral element silencing, with a subset of factors displaying differential effects between stem cell types. Furthermore, our data suggest that small RNAs play a role in this process through interactions with the Argonaute family. Our results further the understanding of mechanisms regulating retroviral transcription in different stem cell lineages. [Display omitted] ► Mouse ESCs, TSCs, and XEN cells have different capacities to suppress retroviral activity ► RNAi screens identified epigenetic factors that mediate silencing of retroviruses ► Candidates modulate integrated, as well as endogenous, retroviral element silencing ► An Argonaute protein binds integrated provirus and may mediate retroviral extinction