Biotinylation of Histones Represses Transposable Elements in Human and Mouse Cells and Cell Lines and in Drosophila melanogaster3

Abstract

Transposable elements such as long terminal repeats (LTR) constitute about 45% of the human genome; transposition events impair genome stability. Fifty-four promoter-active retrotransposons have been identified in humans. Epigenetic mechanisms are important for transcriptional repression of retrotransposons, preventing transposition events and abnormal regulation of genes. Here, we demonstrate that the covalent binding of the vitamin biotin to lysine-12 in histone H4 (H4K12bio) and lysine-9 in histone H2A (H2AK9bio), mediated by holocarboxylase synthetase (HCS), is an epigenetic mechanism to repress retrotransposon transcription in human and mouse cell lines and in primary cells from a human supplementation study. Abundance of H4K12bio and H2AK9bio at intact retrotransposons and a solitary LTR depended on biotin supply and HCS activity, and was inversely linked with the abundance of LTR transcripts. Knockdown of HCS in Drosophila enhances retrotransposition in the germline. Importantly, we demonstrated that depletion of H4K12bio and H2AK9bio in biotin-deficient cells correlates with increased production of viral particles, transposition events, and ultimately decreases chromosomal stability. Collectively, this study reveals a novel diet-dependent epigenetic mechanism that could affect cancer risk.

Nutrition, Histone Epigenetic Marks, and Disease

“…When DNMT1 is knocked down by using siRNA, both cytosine and H3K9 methylation on chromatin are impaired, confirming DNMT1 as the primary loading factor. Consistent with this notion, aberrant cytosine methylation impairs both histone methylation and histone biotinylation (Chew et al 2008).…”

“…Finally, the flow of information among marks in the epigenome is immense and goes far beyond a cross talk among methylation marks. Epigenomic synergies have been documented for H3K4acme3 and H3K9ac in gene activation (Kouzarides and Berger 2007) and for cytosine methylation, H3K9me2, and H4K12bio in the repression of retrotransposons (Chew et al 2008). Despite these limitations, the following themes have emerged in the field of diet-dependent changes in the histone methylome and their consequences for human health.…”

“…Consistent with the important roles of HLCS in epigenomics, no living HLCS null individual has ever been reported, indicating this condition may cause embryonic lethality. HLCS knockdown studies (~30 % residual activity) produced phenotypes such as decreased life span and heat resistance in Drosophila melanogaster , and aberrant gene regulation in human cell lines (Chew et al 2008;Gralla et al 2008;Pestinger et al 2011). Mutations have been identified and characterized in the human HLCS gene.…”

“…To date, 12 distinct biotinylation sites have been identified in histones (Figure 2), and all known species of biotinylated histones are gene repression marks (Camporeale et al 2007a;Chew et al 2008;Gralla et al 2008;. Biotinylation marks appear to be more abundant in histones H3 and H4 than in other histones.…”

“…Evidence that epigenetic mechanisms are important in retroelement control and cancer prevention are as follows (Chen et al 1997;Chen and Townes 2000;Chew et al 2008;Jahner et al 1982;Slotkin and Martienssen 2007;Walsh et al 1998;Yoder et al 1997): Firstly, the human genome contains at least 54 transcriptionally active LTRs (Buzdin et al 2006). Retrotransposons and any integrating virus produces DNA breaks during integration (Gasior et al 2006) that may directly or indirectly lead to tumorigenesis (Fan 2007).…”