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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Macfarlan, Todd S. Gifford, Wesley D. Agarwal, Saurabh Driscoll, Shawn Lettieri, Karen Wang, Jianxun Andrews, Shane E. Franco, Laura Rosenfeld, Michael G. Ren, Bing Pfaff, Samuel L. |
| Description | Country affiliation: United States Author Affiliation: Macfarlan TS ( Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, California, 92037, USA.) |
| Abstract | Endogenous retroviruses (ERVs) constitute a substantial portion of mammalian genomes, and their retrotransposition activity helped to drive genetic variation, yet their expression is tightly regulated to prevent unchecked amplification. We generated a series of mouse mutants and embryonic stem (ES) cell lines carrying 'deletable' and 'rescuable' alleles of the lysine-specific demethylase LSD1/KDM1A. In the absence of KDM1A, the murine endogenous retrovirus MuERV-L/MERVL becomes overexpressed and embryonic development arrests at gastrulation. A number of cellular genes normally restricted to the zygotic genome activation (ZGA) period also become up-regulated in Kdm1a mutants. Strikingly, many of these cellular genes are flanked by MERVL sequences or have cryptic LTRs as promoters that are targets of KDM1A repression. Using genome-wide epigenetic profiling of Kdm1a mutant ES cells, we demonstrate that this subset of ZGA genes and MERVL elements displays increased methylation of histone H3K4, increased acetylation of H3K27, and decreased methylation of H3K9. As a consequence, Kdm1a mutant ES cells exhibit an unusual propensity to generate extraembryonic tissues. Our findings suggest that ancient retroviral insertions were used to co-opt regulatory sequences targeted by KDM1A for epigenetic silencing of cell fate genes during early mammalian embryonic development. |
| File Format | HTM / HTML |
| ISSN | 08909369 |
| e-ISSN | 15495477 |
| DOI | 10.1101/gad.2008511 |
| Journal | Genes & Development |
| Issue Number | 6 |
| Volume Number | 25 |
| Language | English |
| Publisher | Cold Spring Harbor Laboratory Press |
| Publisher Date | 2011-03-15 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Discipline Molecular Discipline Biology__semicolon__developmental Discipline Biology__semicolon__genetics__semicolon__cell Discipline Biology Embryonic Stem Cells Metabolism Virology Gene Expression Regulation, Developmental Oxidoreductases, N-demethylating Animals Cell Line Cells, Cultured Histone Deacetylases Histone Demethylases Histones Mice Mice, Inbred C57bl Mice, Nude Mutation Nuclear Proteins Genetics Promoter Regions, Genetic Repressor Proteins Retroviridae Virus Activation Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't |
| Content Type | Text |
| Resource Type | Article |
| Subject | Genetics Developmental Biology |
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