A pinboard by
Danqi Chen

Ph.D. Candidate, New York University


Formaldehyde exposure and chromatin assembly

Formaldehyde (FA) is an environmental and occupational 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. We investigated the effects of FA on histone modifications, chromatin assembly transcription and cell transformation. We found that 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. 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, which mimics inhibition of chromatin assembly, facilitates FA-mediated cell transformation. We propose that inhibiting chromatin assembly represents a novel mechanism of cell transformation induced by environmental and occupational chemical carcinogen FA. Meanwhile, I also did some research on occupational carcinogen Hexavalent Chromium (Cr(VI)). The mechanisms of Cr(VI)-induced carcinogenesis remain largely unknown. Nupr1 (nuclear protein 1) could be induced by a variety of stressors. We report that the level of Nupr1 is significantly increased in human bronchial epithelial cells following exposure to Cr(VI) through epigenetic mechanisms. Interestingly, Cr(VI) exposure also results in the loss of acetylation at histone H4K16, which is considered a ‘hallmark’ of human cancer. This appears to be caused by the induction of Nupr1, since (a) overexpression of Nupr1 decreased the levels of both H4K16 acetylation and the histone acetyltransferase MOF; (b) the loss of acetylation of H4K16 upon Cr(VI) exposure is greatly compromised by knockdown of Nupr1. Moreover, Nupr1-induced reduction of H4K16 acetylation correlates with the transcriptional down-regulation at several genomic loci. Notably, overexpression of Nupr1 induces anchorage-independent cell growth. We propose that Cr(VI) induces Nupr1 and rapidly perturbs gene expression by downregulating H4K16 acetylation, thereby contributing to Cr(VI)-induced carcinogenesis. For this project, I did an oral presentation on 2016 Society of Toxicology. Through four years study, I have published many paper on EHP, JBC, MBC and Plos one