Formaldehyde facilitates cell transformation by compromising chromatin assembly

Formaldehyde (FA) is an environmental and occupational chemical carcinogen. Recent studies demonstrated that exogenous FA caused only a modest increase in DNA adducts above levels caused by endogenous FA. This raised a possibility that epigenetic mechanisms might contribute to FA-mediated carcinogenicity. Here we report a drastic decrease of acetylation of N-terminal tails of the cytosolic histones following FA exposure, the modifications important for histone nuclear import and assembly into chromatin. In fact, the amount of histone proteins in chromatin fraction decreases following FA exposure. Moreover, the histone depletions are evident at most of the genomic loci we tested, suggesting that FA compromises chromatin assembly. Notably, FA increases chromatin accessibility and changes expression of hundreds of cancer-related genes. Importantly, the knockdown of histone H3.3 (a H3 variant), which mimics inhibition of chromatin assembly, facilitates FA-mediated cell transformation. We propose that inhibiting chromatin assembly represents a novel mechanism for FA carcinogenesis. Overall design: mRNA profiles of formaldehyde-responsive genes in BEAS-2B cells were generated by deep sequencing in duplicates using Ilumina HiSeq