Public release date: 23-Aug-2012 [ | E-mail | Share ]

Contact: Steve Graff stephen.graff@jefferson.edu 215-955-5291 Thomas Jefferson University

PHILADELPHIAIt's widely accepted that molecular mechanisms mediating epigenetics include DNA methylation and histone modifications, but a team from Thomas Jefferson University has evidence to the contrary regarding the role of histone modifications.

A study of Drosophila embryos from Jefferson's Department of Biochemistry and Molecular Biology published ahead of print in Cell August 23 found that parental methylated histones are not transferred to daughter DNA. Rather, after DNA replication, new nucleosomes are assembled from newly synthesized unmodified histones.

"Essentially, all histones are going away during DNA replication and new histones, which are not modified, are coming in," said Alexander M. Mazo, Ph.D., professor of Biochemistry and Molecular Biology at Jefferson, and a member of Jefferson's Kimmel Cancer Center. "In other words, what we found is that histone modifying proteins are hiding on the way over replicating DNA, instead of histones 'jumping' over as currently thought."

"What this paper tells us," he continues, "is that these histone modifying proteins somehow are able to withstand the passage of the DNA replication machinery. They remained seated on their responsive binding sites, and in all likelihood they will re-establish histone modification and finalize the chromatin structure that allows either activation or repression of the target gene."

The team suggests that since it appears these histone modifying proteinsthe Trithorax-group (TrxG), which maintain gene expression, and the Polycomb-group (PcG), which plays a role in epigenetic silencing of genesre-establish the histone code on newly assembled unmethylated histones, they may act as epigenetic marks.

Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequence. Epigenetic marks have become an important focus in recent years because they are thought to have the potential to explain mechanisms of aging, human development, and the origins of diseases, like cancer, heart disease, and mental illness.

According to widely-accepted models applied today, the tails of methylated histones turn genes in DNA "on" or "off" by loosening or tightening nucleosome structure, thus changing the accessibility of transcription factors and other proteins to DNA.

"People believe that everything gets worked off of DNA during the replication process and that these methylated histones act as epigenetic marks, since they are believed to rapidly jump from parental to daughter DNA" said Dr. Mazo. "But there is no experimental evidence to back this up."

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Histone-modifying proteins, not histones, remain associated with DNA through replication