Creative Minds: A New Mechanism for Epigenetics?

Posted on April 6, 2017 by Dr. Francis Collins

Keith Maggert

To learn more about how DNA and inheritance works, Keith Maggert has spent much of his nearly 30 years as a researcher studying what takes place not just within the DNA genome but also the subtle modifications of it. That’s where a stable of enzymes add chemical marks to DNA, turning individual genes on or off without changing their underlying sequence. What’s really intrigued Maggert is these “epigenetic” modifications are maintained through cell division and can even get passed down from parent to child over many generations. Like many researchers, he wants to know how it happens.

Maggert thinks there’s more to the story than scientists have realized. Now an associate professor at the University of Arizona College of Medicine, Tucson, he suspects that a prominent subcellular structure in the nucleus called the nucleolus also exerts powerful epigenetic effects. What’s different about the nucleolus, Maggert proposes, is it doesn’t affect genes one by one, a focal point of current epigenetic research. He thinks under some circumstances its epigenetic effects can activate many previously silenced, or “off” genes at once, sending cells and individuals on a different path toward health or disease.

Maggert has received a 2016 NIH Director’s Transformative Research Award to pursue this potentially new paradigm. If correct, it would transform current thinking in the field and provide an exciting new perspective to track epigenetics and its contributions to a wide range of human diseases, including cancer, cardiovascular disease, and neurodegenerative disorders.

The cells of all eukaryotic organisms, whether a fruit fly or human, must continuously produce lots of small subcellular structures called ribosomes, which build the proteins that are essential to life. The nucleolus is the cell’s factory for ribosomal production. As such, the nucleolus comes equipped with long clusters of ribosomal DNA genes, the blueprints from which ribosomes are made.

The nucleolus and its ribosomal DNA entered Maggert’s thinking about epigenetics several years ago while his lab worked on a line of fruit flies that had its genes for eye color silenced epigenetically to give its offspring white eyes. In one series of experiments, some ribosomal DNA accidentally was snipped away. To Maggert’s surprise, the next hatch of fruit flies was born with bright red eyes, even though the lost ribosomal DNA was on a completely different chromosome than the silenced genes. It wasn’t clear how the inadvertent mutation could turn a distant gene back on to produce the change of eye color [1].

Sipping a cup of coffee and puzzling over the results with his student, Maggert had his moment of clarity: ribosomal DNA might be a central regulator of epigenetic silencing for the entire genome. It was an idea that few, if any, had considered. Most researchers prefer to work on the protein-encoding parts of the human genome, which have lots of investigative resources, are easier to study, and directly relate to human health and disease. Ribosomal DNA remains much less well characterized. It is made up of long stretches of repeated genes that can run into the hundreds in a row for just one gene. It’s easy to get lost or tangled up.

Maggert does not reject current thinking about epigenetics, which he says is real but oftentimes the term is misapplied [2]. He also thinks that his nucleolus theory may apply specifically to epigenetic changes that get passed down from parent to progeny in times of cellular stress.

Maggert has experimental evidence indicating that cellular stress damages ribosomal DNA, causing blocks of genes to be lost [3]. As the ribosomal DNA grows shorter, Maggert thinks the whole nucleolus shrinks—along with its capacity to participate in fundamental cellular processes. This causes cells to malfunction as genes meant to be turned off switch on. He suspects this scrambling of a cell’s normal genomic program remains through cell division and can even be passed on to the next generation.

As Maggert is quick to point out, his ideas remain unproven. But with the Transformative Research Award, he hopes to change that. He and his colleagues have been meticulously building the needed tools to perform a series of genetic and epigenetic experiments in both fly and human cells. Maggert says the real make-or-break for his theory is still likely a year or more down the road. If it turns out as he thinks it might, it will mark an important advance in learning more about how DNA and inheritance works.

References:

[1] Ribosomal DNA contributes to global chromatin regulation. Paredes S, Maggert KA. Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17829-17834

[2] What do you mean, “epigenetic”? Deans C, Maggert KA. Genetics. 2015 Apr;199(4):887-896.

[3] Transgenerational inheritance of diet-induced genome rearrangements in Drosophila. Aldrich JC, Maggert KA. PLoS Genet. 2015 Apr 17;11(4):e1005148.

Links:

What is the Epigenome? (National Library of Medicine/NIH)

Maggert Laboratory (University of Arizona, Tucson)

Maggert Project Information (NIH RePorter)

NIH Director’s Transformative Research Program (Common Fund)

NIH Support: Common Fund; National Institute of General Medical Sciences