Xiaodong Cheng on the Regulatory Mechanism of Epigenetic Signaling
Fast Breaking Paper Commentary, December 2010
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Article: Enzymatic and structural insights for substrate specificity of a family of jumonji histone lysine demethylases
Authors: Horton, JR;Upadhyay, AK;Qi, HH;Zhang, X;Shi,
Y;Cheng, XD |
Xiaodong Cheng talks with ScienceWatch.com and answers a few questions about this month's Fast Breaking Paper paper in the field of Biology & Biochemistry.
Why do you think your paper is highly
cited?
Epigenetics is currently one of the hottest research topics in biology. Without changing the DNA sequence, changes in gene expression by epigenetic signaling could affect tumor formation, disease progression, aging-related mental retardation and autism, as well as intergenerational prenatal influences to offspring (imprinting). Our paper takes a small but important step towards understanding the regulatory mechanism of epigenetic signaling.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
In our bodies, all cells face the problem of controlling the amounts and timing of expression of their various genes. The reversible methylation of lysine residues within histones is a central regulatory mechanism for eukaryotic gene expression. Because histones often contain activating marks, along with repressive marks, it remains unclear how histone-modifying enzymes manage these conflicting signals. We described a fine-tuning mechanism in controlling these conflicting signals: just like traffic lights at intersections, when one side turns to green, the other side has to be red.
Would you summarize the significance of your paper
in layman's terms?
Left to right: Xiaodong Cheng, John Horton, Anup
Upadhyay, and Xing Zhang.
PhoTO by Jack Kearse of Emory’s Health Sciences
Photography.
Our DNA is covered by proteins called histones, and modifying either the DNA or the histones can turn genes on or off. In this paper, we studied two enzymes, called PHF8 and KIAA1718. They each include two attached modules. One module (called PHD) grabs onto a histone H3 tail with a methyl group on lysine 4 (which signals for genes to be turned on), while the other module (called Jumonji) removes a methyl group from somewhere else on the tail (such as lysine 9, which signals for genes to be turned off when it is methylated).
What these enzymes do is to make sure all the signs are consistent with each other. If a sign is out of place, they remove it, so that the reciprocal methylation of lysine 4 and lysine 9 is maintained.
Scientists previously knew the structures of the methyl-binding and methyl-removing modules in isolation. What is new is seeing how the modules are connected, and how one part controls the other.
How did you become involved in this research, and
how would you describe the particular challenges, setbacks, and
successes that you've encountered along the way?
I started to work on DNA methylation 20 years ago, right after receiving my Ph.D. in Physics. DNA and histones are two components of a nucleosome. Nucleosomes are the fundamental building blocks of eukaryotic genome. At that time, we knew that DNA methylation can influence gene expression. Only in the past decade or two have we really appreciated how much histone modifications can regulate gene expression.
However, these chemical modifications, on DNA and histones, are not independent events. They are intimately connected with one another. I want to decipher the underlying mechanisms controlling these chemical modifications.
It is important to know that some modifications are generally associated with gene silencing, whereas the others associated with gene activation. Thus we have a code—so-called epigenetic code (a combination of DNA and histone modifications)—to control gene expression.
In this particular case, the most challenging part was to get the paper published! Because the structures for the individual modules were already known, the significance and novelty of this study were not immediately realized until after a few rounds of explanation and revisions.
Where do you see your research leading in the
future?
We are continuing in our adventure to uncover the complex language of the histone code by understanding one methyl group at a time.
Do you foresee any social or political
implications for your research?
Mutations in the gene encoding one of the enzymes we studied, PHF8, cause a
type of inherited mental retardation. The mutants lost the ability to
remove the methyl group from histones. Understanding how PHF8 works may
help doctors better understand or even lead to treatment of such mental
retardation.
Xiaodong Cheng, Ph.D.
Professor of Biochemistry and Georgia Research Alliance Eminent
Scholar
Emory University School of Medicine
Atlanta, GA, USA
KEYWORDS: CLEFT LIP/CLEFT PALATE; DOMAIN-CONTAINING PROTEINS; LINKED MENTAL-RETARDATION; EMBRYONIC STEM-CELLS; GENE REPRESSION; PHD FINGER; PHF8 GENE; METHYLATION; RECOGNITION; JMJD2A.