Chunyuan Jin, MD, PhD

In eukaryotic cells, DNA is packaged into a DNA-protein complex called chromatin. The fundamental subunit of chromatin is the nucleosome core particle, which consists of 147 base pairs of DNA wrapped around a histone octamer. Chromatin structure regulates the access of regulatory factors to the genomic DNA, thereby exerting profound control over most DNA-templated processes such as transcription, DNA repair, and DNA replication. Chromatin structure can be altered by several epigenetic mechanisms, including DNA methylation, posttranslational histone modifications, and incorporation of histone variants. Among growing number of histone variants, we are particularly interested in histone H3 variant H3.3 due to its critical roles in development, aging, and cancer. H3.3 differs only five amino acid residues from canonical histone H3.1, yet it brings about distinctive properties to the chromatin. Moreover, H3.3 is localized at important genomic loci such as tissue-specific enhancers and pericentric heterochromatin regions. Thus, H3.3 must be maintained faithfully in these regions throughout cell divisions to ensure both cell identity and genome integrity. We conduct research to characterize factors that determine unique properties of nucleosomes containing different histone variants and that regulate the assembly and/disassembly of H3.3-containing nucleosomes. 

Epigenetic changes can be brought by environmental exposures, which may result in human disease such as cancer.  We focus on two types of chemicals – aldehydes and heavy metals. Aldehydes such as acrolein, formaldehyde and acetaldehyde are enriched in the environment and are carcinogenic. Contamination of carcinogenic heavy metals such as arsenic impacts hundreds of millions of people in the world. We recently found that chromatin assembly pathways are compromised by aldehyde exposures likely through forming lysine adducts on newly synthesized histones and the consequent reduction of N-terminal tail lysine acetylation. On the other hand, in collaboration with Dr. Costa’s laboratory, we demonstrated that arsenic exposure induces the loss of the stem-loop binding protein (SLBP) and the gain of  polyadenylation of canonical histone H3.1 mRNAs,  which stabilizes H3.1 mRNAs and could deregulate chromatin assembly by disrupting the balance between the amounts of different histone variants.   Mechanistic insight into dysregulation of chromatin assembly following environmental exposures and its roles in chemical carcinogenesis are under active investigation.