Many hematological malignancies are associated with a genetic error in which a portion of one chromosome has broken and fused with another chromosome. This inappropriate fusion of chromosomal DNA is referred to as chromosomal translocation.
A large proportion of infant leukemias are the result of chromosomal translocations in the Mixed Lineage Leukemia (MLL) gene. Children suffering from these chromosomal translocations have low survival rates and face treatment options that have devastating side effects.
The Stowers Institute's Shilatifard Lab studies chromosomal translocations related to the MLL gene. Several years ago, they identified a molecular complex – COMPASS – containing the yeast homologue of the human MLL. COMPASS was the first H3K4 methylase to be identified, and human MLL is also found in COMPASS-like complexes capable of methylating H3K4, a posttranslational modification marking chromosomes for transcription.
"We observed that the addition of three methyl groups (a process known as trimethylation) on the fourth lysine of H3K4 is regulated by the active site of the yeast equivalent of the MLL protein complex, COMPASS," said Yoh-hei Takahashi, Ph.D., Postdoctoral Research Associate and first author on the publication in Molecular and Cellular Biology. "We also demonstrated that a single residue (Tyr1052) functions with a known subunit of COMPASS (Cps40) to regulate the trimethylation of H3K4."
"These are exciting findings because each of these are significant steps that lead to unraveling how translocations cause leukemia and how we can develop treatments that better target and cure leukemia," said Ali Shilatifard, Ph.D., Investigator and senior author on the publication.
Additional contributing authors to the study published in Molecular and Cellular Biology from the Stowers Institute include Jung Shin Lee, Ph.D., Postdoctoral Research Associate; Selene Swanson, Research Specialist II; Anita Saraf, M.D., Ph.D., Senior Proteomics Scientist; Laurence Florens, Ph.D., Managing Director of Proteomics; and Michael Washburn, Ph.D., Director of Proteomics Center. Raymond Trievel, Ph.D., of the University of Michigan also contributed.
The Shilatifard Lab also has collaborated with Robert Roeder and colleagues at The Rockefeller University on a publication in Cell that sheds new light on the process of communication between histones known as histone crosstalk. This process has been a topic of interest to the Shilatifard Lab for many years, and they have made a number of important contributions to its understanding.
Through a series of laborious biochemical and genetic screens in yeast and over five years of work, the Shilatifard Lab identified the molecular machinery required for proper H3K4 methylation by COMPASS. This includes the modification of histone H2B by attaching a single ubiquitin – a regulatory protein that is very similar from species to species – by the Rad6/Bre1 complex in a process called histone crosstalk. In the Cell publication, the team demonstrated that human Rad6/Bre1 also functions in histone crosstalk as it does in yeast.
"This study demonstrates the awesome power of simple genetic and biochemical model systems such as yeast in deciphering molecular machinery involved in chromatin biology and how yeast can play a role as a template in identifying the human counterparts of these proteins," said Dr. Shilatifard. "Indeed, as reported this week in Cell, human Rad6 can functionally replace yeast Rad6, and H2B monoubiquitination in humans functions by the same histone crosstalk mechanism as it does in yeast, demonstrating the conservation in this system from yeast to humans."
Jung-Shin Lee, Ph.D., Postdoctoral Research Associate in the Shilatifard Lab also contributed to this paper. Authors from The Rockefeller University include Jaehoon Kim, Ph.D., Mohamed Guermah, Robert McGinty, Zhanyun Tang, Ph.D., Thomas Milne, Ph.D., and Tom Muir, Ph.D.
Dr. Shilatifard joined the Stowers Institute in 2007 from the Saint Louis University School of Medicine. Learn more about his work at www.stowers.org/labs/ShilatifardLab.asp.
About the Stowers Institute for Medical Research
Housed in a 600,000 square-foot state-of-the-art facility on a 10-acre campus in the heart of Kansas City, Missouri, the Stowers Institute for Medical Research conducts basic research on fundamental processes of cellular life. Through its commitment to collaborative research and the use of cutting-edge technology, the Institute seeks more effective means of preventing, treating, and curing disease. Jim and Virginia Stowers endowed the Institute with gifts totaling $2 billion. The endowment resides in a large cash reserve and in substantial ownership of American Century Investments, a privately held mutual fund company that represents exceptional value for the Institute's future.
Marie Jennings | EurekAlert!
Further reports about: > Chromosome > H2B > H3K4 > H3K4 methylation > MLL > Medical Wellness > Mixed Lineage Leukemia > Rad6 > Rad6/Bre1 > acute leukemias > cell death > childhood leukemia > chromosomal DNA > chromosomal translocation > genetic error > hematological malignancies > histone crosstalk > specimen processing > synthetic biology
Transport of molecular motors into cilia
28.03.2017 | Aarhus University
Asian dust providing key nutrients for California's giant sequoias
28.03.2017 | University of California - Riverside
The Institute of Semiconductor Technology and the Institute of Physical and Theoretical Chemistry, both members of the Laboratory for Emerging Nanometrology (LENA), at Technische Universität Braunschweig are partners in a new European research project entitled ChipScope, which aims to develop a completely new and extremely small optical microscope capable of observing the interior of living cells in real time. A consortium of 7 partners from 5 countries will tackle this issue with very ambitious objectives during a four-year research program.
To demonstrate the usefulness of this new scientific tool, at the end of the project the developed chip-sized microscope will be used to observe in real-time...
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
29.03.2017 | Materials Sciences
29.03.2017 | Physics and Astronomy
29.03.2017 | Earth Sciences