Genetic Regulation

Medicine
C. David Allis
Tri-Institutional Professor and Joy and Jack Fishman Professor, Head, Laboratory of Chromatin Biology and Epigenetics, Rockefeller University, NY USA
Michael Grunstein
Distinguished Professor of Biological Chemistry, Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA USA

Allis and Grunstein are suggested as possible Nobel Prize winners “for fundamental discoveries concerning histone modifications and their role in Histone Regulation”

Allis and Grunstein achieved distinction for research that extends our understanding of how genes are controlled. Together, they ushered in an experimental approach to epigenetics, identifying ways in which the expression of genes is controlled by processes that are “above” or “in addition to” genetics itself.

We are used to the idea that DNA contains a sequence of genes that are, in the familiar metaphor, a blueprint for life. But if DNA is a blueprint, how is it that of two genetically identical twins, one may suffer autism or schizophrenia, for example, while the other does not? How does a single set of genetic instructions produce both a caterpillar and a butterfly?

The answers start with the packaging of DNA. A medium-sized chromosome contains a molecule of DNA about 3.2 cm long, stretched out. In total, between 2 and 3 meters of DNA are packed into each cell nucleus, which is about 6 micrometers in diameter. The very tight packing is achieved by winding the DNA around proteins called histones to form bead-like structures called nucleosomes. The packed molecule is about 40,000 times shorter than the stretched-out DNA. For most of their scientific history — they were discovered in the 1880s — histones were considered essentially inert packing material.

In the late 1980s Grunstein and his colleagues showed that part of one of the histones of yeast is essential for the control of specific genes in yeast. Without the histone, the yeast could live, but it could not reproduce sexually. This was the first demonstration of a direct interaction between histones and DNA. Soon after, Allis and his colleagues discovered an enzyme that added an acetyl chemical group to a specific exposed amino acid on the tail end of a histone molecule, which sticks out from the bead-like nucleosome. A month or so later, they found an enzyme that removes the acetyl. Essentially, the two enzymes write and erase marks not on the DNA itself, but on the histones, and those marks enable, and prevent, the genes on that piece of DNA being read. Other enzymes apply and remove methyl groups, which serve a similar regulatory function.

This marked the start of the experimental phase of epigenetics, which found rapid applications in medicine. Inhibitors of histone deacetylase are being used to treat rare forms of lymphoma, and epigenetic modifications are being found now in many types of cancer. The possibility of selectively adding or removing these chemical marks has made histone regulation an exciting field for drug discovery. Histone regulation is also implicated in aging, in some of the complications arising from animal cloning, and in the transgenerational effects of poor maternal nutrition, so the fundamental research of Allis and of Grunstein has far-reaching impact.

Commentary on the Medicine Laureates by Jeremy Cherfas, Biology correspondent, ScienceWatch