Histone biotinylation represses retrotransposons in whole organisms, decreasing production of viral particles and retrotranspositions

Abstract

Repeat elements such as LTR retrotransposons constitute ~35% of the human genome. Transposition of these elements leads to genomic instability and may cause cancer. Previously, we have discovered an epigenetic mechanism that mediates LTR silencing: binding of biotin to lysine‐12 in histone H4 (K12BioH4), mediated by HCS. Here we provide novel evidence for a role of biotin in LTR silencing and genomic instability. First, we discovered that K9BioH2A is enriched at LTRs in Jurkat cells. The enrichment of K9BioH2A and K12BioH4 depended on biotin supply and was abolished by HCS knockdown. Decreased abundance of K9BioH2A and K12BioH4 in biotin‐deficient Jurkat cells increased LTR transcripts, increasing the risk for retrotranspositions. Second, we supplemented adults with 600 μg/d biotin for 4 wk. Biotin supplementation increased K12BioH4 at LTRs and decreased LTR transcripts in lymphocytes. Third, the production of MMTV particles increased in biotin‐deficient murine breast carcinoma cells compared with biotin‐normal controls. Fourth, the increased incidence of retrotranspositions was greater in HCS knockdown Drosophila compared with wild‐type controls. Our finding suggested that histone biotinylation plays a meaningful role in decreasing retrotranspositions and cancer risk. Support: University of Nebraska ARD, NIH DK063945 and ES015206, USDA 2006‐35200‐17138, NSF EPSCoR EPS‐0701892, and NSF MCB 0615831.