Epigenetic control of mammalian LINE-1 retrotransposon by retinoblastoma proteins

Abstract

Long interspersed nuclear elements (LINEs or L1 elements) are targeted for epigenetic silencing during early embryonic development and remain inactive in most cells and tissues. Here we show that E2F-Rb family complexes participate in L1 elements epigenetic regulation via nucleosomal histone modifications and recruitment of histone deacetylases (HDACs) HDAC1 and HDAC2. ChIP experiments demonstrated that (i) Rb and E2F interact with human and mouse L1 elements, (ii) L1 elements are deficient in both heterochromatin-associated histone marks H3 tri methyl K9 and H4 tri methyl K20 in Rb family triple knock out (Rb, p107, p130) fibroblasts (TKO), (iii) L1 promoter exhibits increased histone H3 acetylation in the absence of HDAC1 and HDAC2 recruitment, (iv) L1 expression in TKO fibroblasts is upregulated compared to wild type counterparts, (v) L1 expression increases in the presence of the HDAC inhibitor TSA. On the basis of these findings we propose a model in which L1 sequences throughout the genome serve as centers for heterochromatin formation in an Rb family-dependent manner. As such, Rb proteins and L1 elements may play key roles in heterochromatin formation beyond pericentromeric chromosomal regions. These findings describe a novel mechanism of L1 reactivation in mammalian cells mediated by failure of co-repressor protein recruitment by Rb, loss of histone epigenetic marks, heterochromatin formation, and increased histone H3 acetylation.

Transposable elements in the mammalian germline: a comfortable niche or a deadly trap?

“…Reduction in H4K20 methylation through Suv420h1 and Suv420h2 deficiency does not affect TE expression in ES cells (Matsui et al, 2010). Combined loss of H3K9 and H4K20 trimethylation can induce the reactivation of L1 elements, as was observed in mouse fibroblasts lacking the heterochromatin-associated retinoblastoma protein (Montoya-Durango et al, 2009). Finally, the repressive mark H3K27 trimethylation probably has a role in silencing TEs, as combined inactivation of the polycomb complexes PRC1 and PRC2 leads to an upregulation of LTR-sequences in ES cells (Leeb et al, 2010).…”

Simultaneous Knockdown of Mutant BRAF and Expression of INK4A in Melanoma Cells Leads to Potent Growth Inhibition and Apoptosis

“…It has been shown that HERV-K sequences, as other host genes, are regulated by DNA methylation in the promoter/enhancer sequences located in the 5'-LTR regions (Lavie et al, 2005). Since RB protein, a downstream mediator of BRAF-MEK-ERK and p16-CDK4 signaling pathways, is a key regulator of DNA methylation (Montoya-Durango et al, 2009), it is conceivable that the observed association between HERV-K, p-ERK, and p16-CDK4 may act through RB, a notion that will surely prompt further investigation. It is worth noting that the four melanoma cell lines examined, 624Mel, A375, A101D, and OM431, all have BRAF T1799A mutation, constitutive activation of ERK, loss of wild-type p16, over-expression of phospho-RB protein (Rotolo et al, 2005), and have comparable levels of HERV-K RNA transcripts (not shown).…”

Consequences of ongoing retrotransposition in mammalian genomes

“…142,144 L1 promoters are silenced by H3K9me3 and H4K20me3 in MEFs dependent on binding of retinoblastoma protein family members to L1. 145 However, L1 promoters in mouse fibroblast cell lines are enriched for H3K9me3, but not H4K20me3. 144 Different histone marks may therefore be more or less important at different points in development to initiate silencing, direct DNA methylation, and/or maintain silencing of particular types of retrotransposons.…”