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.

The concept that disease rooted principally in chronic aberrant constitutive and reactive activation of mast cells (MCs), without the gross MC neoplasia in mastocytosis, first emerged in the 1980s, but only in the last decade has recognition of “mast cell activation syndrome” (MCAS) grown significantly. Two principal proposals for diagnostic criteria have emerged. One, originally published in 2012, is labeled by its authors as a “consensus” (re-termed here as “consensus-1”). Another sizable contingent of investigators and practitioners favor a different approach (originally published in 2011, newly termed here as “consensus-2”), resembling “consensus-1” in some respects but differing in others, leading to substantial differences between these proposals in the numbers of patients qualifying for diagnosis (and thus treatment). Overdiagnosis by “consensus-2” criteria has potential to be problematic, but underdiagnosis by “consensus-1” criteria seems the far larger problem given (1) increasing appreciation that MCAS is prevalent (up to 17% of the general population), and (2) most MCAS patients, regardless of illness duration prior to diagnosis, can eventually identify treatment yielding sustained improvement. We analyze these proposals (and others) and suggest that, until careful research provides more definitive answers, diagnosis by either proposal is valid, reasonable, and helpful.

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.