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Dr Melanie Ott and Dr Ya-Lin Chiu Appointed
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Melanie Ott, PhD
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Dr. Ott received an MD degree from the University of Frankfurt/Main, Germany and a PhD in molecular medicine from the Picower Graduate School in New York. She directed an independent research group at the German Cancer Center (DKFZ) in Heidelberg from 1997 to 2002, when she joined the Gladstone Institute of Virology and Immunology. Dr. Ott is an adjunct member of the UCSF Liver Center and an adjunct professor of medicine at the University of Heidelberg.
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Ya-Lin Chiu, PhD
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Dr. Chiu earned a PhD in biochemistry and molecular pharmacology from the University of Massachusetts. She received a BS in biology and an MS in virology from the National Taiwan University. Honors include an amfAR Fellowship Award, The Dean’s Award for Outstanding Academic Achievement at UMass, and the 2007 Dean's Postdoctoral Prize at UCSF. She has authored 20 peer-reviewed papers (11 as 1st author) and two pending patents.
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After an intensive search, the Gladstone Institute of Virology and Immunology has added two new investigators to its faculty. Melanie Ott, MD, PhD, is a new associate investigator, and Ya-Lin Chiu, PhD, is a new assistant investigator.
“I could not be more pleased with the result of these two international searches,” said Warner Greene, GIVI director. “Melanie and Ya-Lin represent two of the most outstanding young investigators in the field of HIV biology. Both were highly sought by other institutions.”
Until her appointment, Dr. Ott was a staff research investigator in GIVI. Her research concerns the molecular mechanisms of pathogenesis of two viruses, HIV-1 and hepatitis C virus. Specifically, she examines the control of viral gene transcription (see article on page 14).
“Gladstone is an extraordinary organization,” said Dr. Ott. “I am very happy to be able to continue to be a part of it.”
Dr. Chiu was most recently a research scientist in the laboratory of Dr. Greene. Her research focuses on the anti-HIV factor APOBEC3G (A3G). In addition to its activity against external retroviral threats, such as HIV, A3G also limits the retrotransposition of internal retroelements, thereby helping to protect the integrity of the human genome (see article on page 16).
“I am thrilled with this opportunity,” said Dr. Chiu. “Gladstone and UCSF are remarkable places to do research, and I feel very fortunate to be able to continue my studies here.”
Dr. Greene echoes those sentiments. “Now in its 16th year of existence, GIVI has made significant contributions to our understanding of HIV and other viruses. With the addition of Melanie and Ya-Lin to our excellent faculty, I look to the future of the Institute with great confidence.”
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Scientists often speak of genes as “on” or “off.” Those simple terms belie the complex mechanisms that control gene activity. Regulatory elements in the DNA sequence are the targets of a myriad of proteins that enhance or repress gene transcription. The activities of those proteins are, in turn, mediated by reversible chemical and other modifications.
New Gladstone investigator Melanie Ott studies how genes are controlled during HIV-1 infection. Her work focuses primarily on the interactions of the HIV-1 Tat protein with enzymes previously thought only to chemically modify histones, the proteins that package chromosomes. She also studies the mechanisms that control replication of hepatitis C virus.
When HIV infects a cell, its genetic material or genome is incorporated into the complex of DNA and proteins that form the cell's chromosomes. During this step, the HIV genome is tightly packaged by histones, which can pose a significant barrier to efficient gene expression. The HIV genome can be freed from the complex in several ways. For example, enzymes modify the N-terminal tails of histones to loosen or tighten the complex. Once the chromatin structure is loosened, the HIV-1 genes can be expressed.
“Transcription is very carefully controlled and involves many factors,” said Dr. Ott. “The situation is further complicated because many of the factors, including Tat, can be posttranslationally modified, and those modifications influence their activity as transcription factors.”
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While “off” and “on” may be a simple
flip of the switch to us, genes are turned
on and off by the complex interaction of
many factors and modifications.
Dr. Ott focuses her studies on a
few key proteins.
Click here to view the figure
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The most common posttranslational modifications are phosphorylation, methylation, acetylation, ADP-ribosylation, glycosylation, ubiquitination, SUMOylation, and lipid additions. Each modification involves a specific enzyme and occurs at a distinct amino acid. Often, the catalytic activity of one modifying enzyme is counterbalanced by another that reverses the reaction. That balance allows a critical fine regulation of transcription.
“These modifications effectively increase the genetic repertoire of the 20 basic amino acids to effectively more than 140 amino acids,” said Dr. Ott.
Dr. Ott showed that Tat binds to modifying enzymes called histone acetyltransferases and is itself then acetylated. She also found that Tat activates HIV gene expression by interacting with a histone kinase, the p90 ribosomal S6 kinase 2 (RSK2). Kinases are enzymes that add a phosphate group to a protein. Histones are phosphorylated in response to several cellular events.
Phosphorylation of serine 10 in histone H3 is an early marker of mitogen-induced gene activation and can synergize with histone acetylation events. Dr. Ott's group found that Tat increases the phosphorylation of histone H3 associated with the HIV promoter. A dominant-negative form of RSK2, but not of other histone kinases, inhibited Tat activity, indicating that RSK2 is necessary for Tat's function.
The activation of the kinase activity of RSK2 by Tat was a surprise and suggests that HIV enhances its own replication by interfering with RSK2. In HIV-infected T cells, HIV gene expression was suppressed by treatment with a small-molecule inhibitor of RSK2. This finding supports the concept that the Tat/RSK2 complex is a potential new target for the treatment of AIDS.
“We are very excited about the implications of these results for HIV and other diseases,” said Dr. Ott. “For example, mutations in the RSK2 gene cause Coffin-Lowry syndrome, which results in severe mental retardation and progressive skeletal deformations. Perhaps more importantly, our results can be generalized to the transcription of all proteins, and so they may have applications to many situations.”
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Recently, the cytidine deaminase APOBEC3G (A3G) has been the subject of great interest in the HIV research community. This potent inhibitor of HIV found normally in cells forms an exciting new target for anti-HIV drug development because HIV devotes its Vif gene product for destroying this factor.
However, A3G existed in cells for millions of years before the retroviral precursor of HIV crossed over from chimps to humans. What has it been doing in cells for all this time? New Gladstone assistant investigator Ya-Lin Chiu answered this intriguing question in the process of studying A3G's unexpected participation in large RNA-protein complexes in activated T cells.
“Of course, then we wanted to know what additional proteins and RNAs were present in large complexes,” said Dr. Chiu. “We were very surprised to detect retroelement RNAs as well as 95 proteins in the complex.”
The retroelement RNAs are produced by mobile genetic elements that can jump from one place to another in human chromosomes. This process called retrotransposition involves a reverse transcription step, similar to that used by HIV. Retroelements are believed to have played an important role in genome evolution and speciation. However, mobilization of these elements can also be deleterious to the host cell and result in various genetic disorders and cancers.
To limit the negative effects of retrotransposition, host genomes have adopted several strategies to restrict the mobility of transposable elements. Dr. Chiu showed that recruitment of retrotransposon RNAs such as Alu into the large A3G complexes blocked the ability of these RNAs to undergo reverse transcription and thus limited their
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APOBEC3G interrupts the retrotransposition
of Alu retroelements by sequestering Alu
RNAs in cytoplasmic HMM APOBEC3G
complexes.
Click here to view the figure
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retrotransposition. Thus, A3G is involved not only in defending the host from external retroviral threats like HIV but also has been active over millions of years limiting the retrotransposition of internal retroelements thereby helping to protect the integrity of the human genome.
Interestingly, there are four to five times more retroelements in the human genome than in the mouse genome (42% vs. 8–10%), but mice have 100 times more retrotransposition activity than humans. The abrupt decline in retrotransposition activity in primates happened at about the same time that the APOBEC3 gene cluster expanded from one gene in mice to seven in primates.
“These evolutionary events happened long before the emergence of the primate lentiviruses that took place about 1 million years ago,” said Dr. Chiu. “It seems likely that the original function of these genes was to constrain the genomic instability caused by endogenous retroelements.”
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TOP
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