How Cells Implement Epigenetic Regulation of the Genome

How Cells Implement Epigenetic Regulation of the Genome

Chromatin—the complex of DNA and protein found in eukaryotic cells—is packaged in structures called nucleosomes. A nucleosome consists of a segment of DNA wound around eight histone proteins so that it resembles thread wrapped around a spool. Formation of nucleosomes depends on histone chaperone proteins that escort histones into and out of chromatin. Many chaperones contain so-called intrinsically disordered regions (IDRs) and use these unstructured regions to interact with histones. IDRs contain a post-translational modification called glutamylation, whose role in controlling chaperone function is not well understood. 

Counterintuitively, the tighter that a chaperone protein binds to histones, the more easily the chaperone can release the histone into chromatin. To explain this, studies by David Shechter, Ph.D., and his colleagues suggest that glutamylated chaperone IDRs mimic DNA in binding and organizing histones into a nucleosome-compatible conformation. Dr. Shechter has received a four-year, $1.4 million National Institutes of Health grant to study the role of glutamylated chaperone IDRs in assembling chromatin. Using nuclear magnetic resonance imaging and other technologies, the researchers will determine where molecules of glutamylated IDRs and histone interact with each other and how IDRs structurally stabilize histones.  In addition, they will measure the impact of chaperone glutamylation on chromatin assembly and use a cell-free extract from the frog Xenopus laevis to discover when and how chaperone glutamylation modulates chromatin assembly in a living organism.  

The findings could help in understanding normal cellular function and in diagnosing and treating diseases. Dr. Shechter is an associate professor of biochemistry at Einstein. (1R01GM135614) 

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