C. David Allis, Ph.D., of the Rockefeller University will be awarded the 2014 Japan Prize in Life Sciences for the pioneering work of his lab in discovering that chemical modifications of DNA-packaging proteins play a key role in regulating the activity of individual genes.
Those proteins or “histones” have been thought to actively regulate gene expression through methylation or acetylation since both processes were discovered in the mid-1960s by Rockefeller researcher Vincent Allfrey. Later research, some of it by Dr. Allis, suggested that histone hyperacetylation correlated strongly with active genes, and hypoacetylation with silent genes.
However, researchers lacked direct causal proof of the relationship until 1996, when Dr. Allis and several lab colleagues discovered that the first transcription histone acetyltransferase (HAT) was a known transcription regulator in yeast. A month later, Harvard researcher Stuart Schreiber and colleagues published a study showing the first known histone deacetylase was a transcription corepressor, again in yeast.
“This one-two punch almost demanded that histone proteins were playing an active role in the transcription process, not just passive participants serving to package the DNA,” Dr. Allis told GEN.
Evidence to that effect emerged around the same time in studies by Michael Grunstein, Ph.D., M. Mitchell Smith, Ph.D., of the University of Virginia, and others focused more on DNA methylation than acetylation.
“For a while, these camps were pretty separate. Now it’s clear that these marks on histones and DNA work together in a concerted fashion to create the epigenetics tapestry,” said Dr. Allis, who is Joy and Jack Fishman professor and head of the Laboratory of Chromatin Biology and Epigenetics at Rockefeller U. “This began the modern era of chromatin biology, a very exciting time for us and the histone modification field.”
In humans, larger gene families encode the histone proteins, likely for dosage reasons. In 2012, two research teams—a McGill University-led consortium, and the St. Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project—independently found histone mutations in pediatric gliomas. Last year a postdoc in Dr. Allis’ lab, Peter Lewis, Ph.D., now at the University of Wisconsin-Madison, published findings revealing that mutated histone H3 comprised anywhere from 3.6% to 17.6% of total H3 in samples of DIPG, a rare brain stem cancer in children. The histone mutation—often but not always a change of a lysine to methionine residue—“poisons” the enzyme system responsible for modifying it. However, when small amounts of mutant H3 were added to normal human cells, a global reduction in the levels of methylation of normal H3 histones resulted.
“Surprising to us was that this mutation has now appeared at other histone residues in other tumors, often with a specific age and tumor type. Thus, human mutations may be guiding us toward pathways that alter the epigenetic landscape that we never thought possible before,” Dr. Allis said.
Alterations in epigenetic landscapes—from DNA and histone modifications to histone variances and noncoding RNAs—have been found in multiple cancer types. Histone modifications, for example, are visible with remarkably high frequency in brain, bone, and blood cancers. “More will be found, and interestingly, many of these are in pediatric cases,” Dr. Allis said.
Several large-scale efforts are underway to find drugs to treat not only “writers and erasers” of the modifications, but also “readers”—proteins that dock on the histone modification in a precise way to bring about disease. Just last month, a study by Jörn Lötsch, M.D., Ph.D., and colleagues in Trends in Molecular Medicine found up to 5% of nonepigenetic drugs had epigenetic effects beyond cancer that have recently been discovered: Anamdamide, for example, yields effects associated with HIV/AIDS and multiple sclerosis; Valproate, with epilepsy and bipolar disorder.
Histone modifications have also been found to play a key role in cell reprogramming. Transcription factors—such as those identified by Shinya Yamanaka, M.D., Ph.D., who with Sir John B. Gurdon, Ph.D. won the 2012 Nobel Prize in physiology or medicine—can induce pluripotency in somatic cells committed to a specific lineage. But the process is inefficient, Dr. Allis said.
“One of the barriers that might be at play here is chromatin, and here work has emerged that some of the chromatin marks that fall more into the repressive or silent area may be responsible. If drugs or siRNAs are used to inhibit the responsible writers of these marks, the efficiency of reprogramming increases,” Dr. Allis added.
The Japan Foundation awards the approximately half-million-dollar Japan Prize every year to scientists and researchers deemed to have made substantial contributions to their fields, as well as to peace and prosperity of mankind. Since its inception in 1985 the Japan Prize has been awarded to 81 people from 13 countries.
Dr. Allis joined Rockefeller in 2003 after holding academic positions at Baylor College of Medicine and University of Virginia. He received his Ph.D. in 1978 from Indiana University and performed postdoctoral work at the University of Rochester.
“Our major challenge, hopefully one taken up by the next generation of young scientists who are intrigued with epigenetics, will be to learn how to better harness the potential of the epigenetic mechanisms to bring about better health and living for many,” Dr. Allis said. “I look forward to that in the years ahead, and I am pleased that some of our work has contributed to this worthwhile goal.”