Endogenous retroviruses and neighboring genes are coordinately repressed by LSD1/KDM1A

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.

Lysine-specific demethylase 1 regulates differentiation onset and migration of trophoblast stem cells

“…1b for schematic of the different embryonic cell types). Consistent with previous reports [19][20][21][22] , we find that Lsd1 À / À embryos are significantly reduced in size but possess cells of the three early embryonic lineages, namely epiblast, extraembryonic ectoderm and primitive endoderm/visceral endoderm as shown by haematoxylin and eosin (HE) staining (Fig. 1b).…”

“…To specifically dissect Lsd1 functions in the different cell lineages of the pregastrula stage mouse embryo, we engineered a novel conditional Lsd1 allele by flanking exon 1 with loxP sites. In agreement with earlier reports [19][20][21][22] , ubiquitous deletion of the conditional Lsd1 allele (Lsd1 À / À ) leads to early embryonic lethality, and only resorbed embryos are detected by E7.5 (Fig. 1a).…”

“…Several studies have reported functions of Lsd1 in ESCs and in the early epiblast [19][20][21][22][23][24] . Whether or not absence of Lsd1 in the epiblast indeed accounts for the early embryonic lethality of Lsd1-deficient embryos preceding E7.5 has not been conclusively addressed.…”

“…5 (refs 19-22) proposing predominant functions in pluripotent cells of the epiblast. Analysis of Lsd1-deficient mouse embryonic stem cells in culture suggested a progressive loss of DNA methylation 19 , altered expression of genes crucial for ES cell differentiation 21 or a bias towards extraembryonic lineage differentiation 20 . Furthermore, Adamo et al 23 reported that LSD1 regulates the balance between self-renewal and differentiation of human ESCs (hESCs).…”

Interplay of TRIM28 and DNA methylation in controlling human endogenous retroelements

“…ERV-contained sequences regulate vertebrate development (Wang et al 2007;Bourque et al 2008;Kunarso et al 2010;Mey et al 2012;Schmidt et al 2012) and contributed, for instance, to the evolutionary diversification of the placenta (Chuong et al 2013). Moreover, ERVs can serve as tissuespecific promoters or enhancers for cellular genes, and control of some ERV-cellular gene pairs is coordinated notably in ES cells (Buzdin et al 2006;Karimi et al 2011;Macfarlan et al 2011Macfarlan et al , 2012Rebollo et al 2011). However, most EREs are silenced by histone methylation, histone deacetylation, and DNA methylation in early embryos (Rowe and Trono 2011).…”