Since the completion of the human genome sequence, a question has baffled researchers studying gene control: How is it that humans, being far more complex than the lowly yeast, do not proportionally contain in our genome significantly more gene-control proteins?
Now, a collaborative effort at the Johns Hopkins School of Medicine to examine protein-DNA interactions across the whole genome has uncovered more than 300 proteins that appear to control genes, a newly discovered function for all of these proteins previously known to play other roles in cells. The results, which appear in the October 30 issue of Cell, provide a partial explanation for human complexity over yeast but also throw a curve ball in what we previously understood about protein functions.
"Everyone knows that transcription factors bind to DNA and everyone knows that they bind in a sequence-specific manner," says Heng Zhu, Ph.D., an assistant professor in pharmacology and molecular sciences and a member of the High Throughput Biology Center. "But you only find what you look for, so we looked beyond and discovered proteins that essentially moonlight as transcription factors."
The team suspects that many more proteins encoded by the human genome might also be moonlighting to control genes, which brings researchers to the paradox that less complex organisms, such as plants, appear to have more transcription factors than humans. "Maybe most of our genes are doing double, triple or quadruple the work," says Zhu. "This may be a widespread phenomenon in humans and the key to how we can be so complex without significantly more genes than organisms like plants."
The team set out to figure out which proteins encoded by the genome bind to which DNA sequences. It had been predicted by examining the human genome sequence that about 1,400 to 1,700 of encoded proteins are so-called transcription factors — proteins that bind to specific sequences in DNA to turn a gene on or off. The researchers also included in their study, in addition to these proteins, other types that are known to maintain chromosome structure and bind to structurally different RNA. Also included were proteins that normally relay information within a cell and are not thought to directly come in contact with DNA. In total, they collected nearly 4,200 human proteins together on a protein microarray, or protein "chip."
To identify proteins on that chip that bound DNA directly, the group first reviewed previously published scientific literature and catalogued 460 different, short sequences of DNA that are known or predicted to bind proteins.
One at a time, the team tested each of the 460 DNA sequences against the 4,200 protein-containing chip. In addition to finding many protein-DNA interactions for transcription factors, some confirming previously known interactions, the team found 367 new unconventional DNA binding proteins—proteins known to do other cellular jobs.
"This nearly doubled the number of known protein-DNA interactions," says Jiang Qian, Ph.D., an assistant professor of ophthalmology at Hopkins. "But we only looked at about a fifth of all the proteins in the human genome — there could be hundreds, even thousands more of these unconventional transcription factors that we don't yet know about."
One of the unconventional transcription factors discovered was the protein MAP Kinase 1, also known as ERK2, a protein long studied for its ability to control cell growth and development via its ability to add phosphate groups to other molecules.
"It's one of the best studied proteins out there, but no one ever thought ERK2 could directly regulate gene expression by actually binding to DNA," says Seth Blackshaw, Ph.D., an assistant professor of neuroscience and a member of the High Throughput Biology Center and the Neuroregeneration Program at the Institute for Cell Engineering.
To be certain that ERK2 really does bind DNA and control genes in living cells, the team tested the protein in human cells. They found that ERK2 mutated to no longer bind DNA causes specific genes to be turned on, while both normal ERK2 and ERK2 that's no longer able to chemically modify proteins turn off those same genes. "It clearly acts to repress specific genes," says Blackshaw. "Maybe this will help clear up some of the puzzles that have arisen in ERK2 experiments over the years."
A central question in understanding how genes are controlled is hich of the 20,000 proteins encoded by our genome act on which segments of DNA. "It's not possible to predict this a priori," Blackshaw says. "Someone has to do the experiment — because we just don't know enough about how proteins bind to DNA — patterns have surfaced in this field's 45 year history, but not enough yet to establish any rules."
This study was funded by the National Institutes of Health, a National Eye Institute Vision Core grant, a W. M. Keck Foundation Distinguished Young Investigator in Medical Research Award, a grant from the Ruth and Milton Steinbach Fund and a generous gift from Mr. and Mrs. Robert and Clarice Smith
Authors on the paper are Shaohui Hu, Zhi Xie, Akishi Onishi, Xueping Yu, Lizhi Jiang, Jimmy Lin, Hee-Sool Rho, Crystal Woodard, Hong Wang, Jun-Seop Jeong, Shunyou Long, Xiaofei He, Herschel Wade, Blackshaw, Qian, and Zhu, all of Johns Hopkins.
On the Web:http://www.hopkinsmedicine.org/institute_basic_biomedical_sciences/research
Audrey Huang | EurekAlert!
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