Enhancer RNAs Alter Gene Expression

New class of molecules may be key emerging “enhancer therapy”

In a pair of distinct but complementary papers, researchers at the University of California, San Diego School of Medicine and colleagues illuminate the functional importance of a relatively new class of RNA molecules. The work, published online this week in the journal Nature, suggests modulation of “enhancer-directed RNAs” or “eRNAs” could provide a new way to alter gene expression in living cells, perhaps affecting the development or pathology of many diseases. … Read the full story from the UCSD Newsroom


Christopher K. Glass

Christopher K. Glass, MD, PhD

Drs. Christopher Glass (left) and M. Geoffrey Rosenfeld (at right below) are the principal investigators of the two studies reported in Nature.

M. Geoffrey Rosenfeld, MD

M. Geoffrey Rosenfeld, MD

Christopher Glass, MD, PhD, is professor of medicine and cellular and molecular medicine. M. Geoffrey Rosenfeld is professor of medicine and biology and is a Howard Hughes Medical Institute professor.

Both are members of the Division of Endocrinology & Metabolism in the Department of Medicine.

Citations for the study reports:

Glass report:

Michael T. Y. Lam, Han Cho, Hanna P. Lesch, David Gosselin, Sven Heinz, Yumiko Tanaka-Oishi, Christopher Benner, Minna U. Kaikkonen, Aneeza S. Kim, Mika Kosaka, Cindy Y. Lee, Andy Watt, Tamar R. Grossman, Michael G. Rosenfeld, Ronald M. Evans & Christopher K. Glass.  Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription.  Nature (2013) doi:10.1038/nature12209. Published online 02 June 2013.  |   Full Text  (UCSD only)

Rosenfeld report:

Wenbo Li, Dimple Notani, Qi Ma, Bogdan Tanasa, Esperanza Nunez, Aaron Yun Chen, Daria Merkurjev, Jie Zhang, Kenneth Ohgi, Xiaoyuan Song, Soohwan Oh, Hong-Sook Kim, Christopher K. Glass & Michael G. Rosenfeld. Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature (2013) doi:10.1038/nature12210. Published online 02 June 2013.  |  Full text  (UCSD only)

More Information:

Dr. Rohit Loomba on Fatty Liver Disease: HHMI Bulletin

Dr. Rohit LoombaDr. Rohit Loomba, a UCSD hepatologist who specializes in fatty liver disease, is interviewed in an article about the disease in the Fall 2012 health bulletin from the Howard Hughes Medical Institute.

In “The Fat You Can’t See,” Loomba describes the rising incidence of fatty liver disease and points to society’s general increase in dietary sugar intake as a major cause. He emphasizes the importance of identifying individuals who are at highest risk for developing the disease and he predicts there will be a dramatic increase in our understanding of the disease in the next five years.

Rohit Loomba, MD, MHSc, is assistant professor of clinical medicine in the Division of Gastroenterology. He also holds an appointment in the Division of Epidemiology in the Department of Family and Preventive Medicine.

Loomba conducts his clinical practice in UC San Diego Health System’s liver disease clinics. In his research laboratory, he conducts a variety of studies of nonalcoholic fatty liver disease (NAFLD), including a number of clinical trials.

With a four-year mentored patient-oriented research career development grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Loomba is investigating the genetic epidemiology of NAFLD in a twin-pair study. In that work, his mentors are UCSD researchers Daniel T. O’Connor, MD, professor of medicine and pharmacology; Elizabeth Barrett-Connor, MD, distinguished professor and chief of the Division of Epidemiology in the Department of Family and Preventive Medicine; and David Brenner, MD, Vice Chancellor for Health Sciences and Dean of the School of Medicine.

Loomba serves as the UCSD site principal investigator for the Nonalcoholic Steatohepatitis Clinical Research Network (NASH-CRN) studies in adult patients with NAFLD. NASH-CRN, an NIDDK-sponsored research consortium funded via a UO1 research program-cooperative agreement mechanism, aims to improve understanding of the natural history, pathophysiology and management of NAFLD.

In addition, he is the founding director and principal investigator of the San Diego Integrated NAFLD Research Consortium (SINC), which includes four centers: UCSD, Kaiser Permanente Health System, Sharp Health System, and Balboa Naval Medical Center. SINC is a collaborative network that allows community-based patients to participate in NAFLD studies conducted at UCSD.

Loomba has established a major NAFLD research program at UCSD with recently published investigator-initiated treatment studies in NASH (Le et al., Hepatology September 2012) and several in progress.

In various NAFLD translational research studies currently ongoing at UCSD, Loomba collaborates with Drs. Jerrold Olefsky, David Brenner, Claude Sirlin, Bernd Schnabl, Lars Eckmann, Edward Dennis, Ariel Feldstein and Ekihiro Seki.

He also directs the UCSD fellowship training program in liver epidemiology and patient-oriented outcomes research.

More Information:

A New Approach to Faster Anticancer Drug Discovery

Tracking the genetic pathway of a disease offers a powerful, new approach to drug discovery, according to scientists at the University of California, San Diego School of Medicine who used the approach to uncover a potential treatment for prostate cancer, using a drug currently marketed for congestive heart failure. Their findings are published in the current online issue of the Proceedings of the National Academy of SciencesRead the full story from the UCSD Newsroom

M. Geoff Rosenfeld, MD,
M. Geoff Rosenfeld, MD, is an investigator in the study. Dr. Rosenfeld is professor of medicine in the Division of Endocrinology and Metabolism and a Howard Hughes Medical Institute investigator. |  Read the article in the Proceedings of the National Academy of Sciences.

Roche Funds Drug Discovery Projects at UC San Diego

The new UC San Diego-Roche Extending Innovation Network (EIN) program has been launched with selection of its first three research projects at the University of California, San Diego School of Medicine. The UC San Diego-Roche EIN program, which was formalized in June 2011, aims to accelerate the discovery of new drug therapies through research innovation at the interface of industry and academia. The program is slated to grow in the coming years as additional rounds of proposals are solicited. … Read the full story from the UCSD Newsroom

M. Geoffrey Rosenfeld, MD
M. Geoffrey Rosenfeld, MD (pictured above), is a co-investigator with Xiang-Dong Fu, PhD, on one of the three UC San Diego-Roche EIN-funded projects, in which the investigators will use genomic and RNA-based approaches to identify new drug targets.

Dr. Rosenfeld is Professor of Medicine in the Division of Endocrinology and Metabolism and a professor of the Howard Hughes Medical Institute. Dr. Fu is Professor of Cellular and Molecular Medicine and a member of the Institute for Genomic Medicine.

Non-Coding RNA Relocates Genes When It’s Time To Go To Work

Cells develop and thrive by turning genes on and off as needed in a precise pattern, a process known as regulated gene transcription. In a paper published in the November 9 issue of The Journal of Neuroscience, researchers at the University of California, San Diego School of Medicine say this process is even more complex than previously thought, with regulated genes actually relocated to other, more conducive places in the cell nucleus…. Read the full story from the UCSD Newsroom

Illustration of a double helix

Senior author of the study is M. Geoff Rosenfeld, MD, professor of medicine in the Division of Endocrinology and Metabolism and a Howard Hughes Medical Institute investigator. Co-first authors Liuqing Yang, PhD, and Chunru Lin, PhD, are postdoctoral researchers in Dr. Rosenfeld’s laboratory.

Plasticity of Hormonal Response Permits Rapid Gene Expression Reprogramming

Gene expression reprogramming may allow cancer cell growth as well as normal differentiation

Gene expression is the process of converting the genetic information encoded in DNA into a final gene product such as a protein or any of several types of RNA. Scientists have long thought that the gene programs regulated by different physiological processes throughout the body are robustly pre-determined and relatively fixed for every specialized cell. But a new study by researchers from the University of California, San Diego School of Medicine reveals the unsuspected plasticity of some of these gene expression programs. … Read the full story from the UCSD Newsroom

M. Geoffrey Rosenfeld, MD

Co-principal investigator of the study is Dr. M. Geoffrey Rosenfeld (pictured at left). M. Geoffrey Rosenfeld, MD, is Professor of Medicine in the Division of Endocrinology and Metabolism and Howard Hughes Medical Institute investigator.

Department of Medicine coauthor Christopher K. Glass, MD, PhD, is Professor of Medicine in the Division of Endocrinology and Metabolism and Professor of Cellular and Molecular Medicine.

Read the published study in Nature (free full text).

Looking for Fusion Transcripts in Breast Cancer: Project Funded by Susan G. Komen for the Cure

Dr. Dafne (Maria) Cardamone is one of two breast cancer researchers to receive grant awards from Susan G. Komen for the Cure, as described in the UCSD Newsroom story, “Two UC San Diego Researchers Awarded $780,000 in Grants from Susan G. Komen for The Cure.”

Dr. Cardamone is a postdoctoral researcher in the laboratory of Dr. M. Geoffrey Rosenfeld, Howard Hughes Medical Institute investigator and Professor of Medicine in the Division of Endocrinology and Metabolism.

Med Into Grad Program Wins More Funding

With a new $700,000 grant from the Howard Hughes Medical Institute, UCSD’s innovative Med Into Grad education program will expand over the next four years.  |  Read the full story from UC San Diego News

Launched in 2006, the UCSD Med Into Grad program offers biomedical graduate students the opportunity to receive 10-12 weeks of clinical instruction during their doctoral training.

Under the guidance of physician mentors, the graduate students immerse in patient care settings that relate directly to their thesis work.  |  Read our profile of a Med Into Grad student

With this stint of medical training, the Med into Grad program aims to inspire the new basic researchers with a passion for developing the treatments and diagnostic tools that patients most urgently need.

The program founders and co-directors of Med Into Grad are Kenneth Kaushansky, MD, MACP, Helen M. Ranney Distinguished Professor and Chair of the Department of Medicine, and Mark P. Kamps, PhD, Professor of Pathology.

Visit the UCSD Med Into Grad website for a program description and students’ personal accounts of their Med Into Grad experiences.

Med Into Grad “Makes it All Real,” Says UCSD Doctoral Researcher

From basic science laboratory to Peruvian TB clinic: Scarlet Shell, UCSD doctoral candidate in Biomedical Sciences and graduate of the Med Into Grad program.

Scarlet Shell, UCSD graduate researcher and Med Into Grad participantWhen Scarlet Shell leaves UCSD this year, she’ll have a new doctorate in biomedical sciences and an unforgettable grounding in the real world of infectious disease.

Deeply interested in tuberculosis diagnosis and treatment, she’s headed for postdoctoral research in a TB laboratory at Harvard.

And, thanks to the Med Into Grad program, she knows exactly what it’s like to diagnose and treat TB with scant resources, time-consuming tests, and trial-and-error antibiotic therapy.

Last year, UCSD’s Med Into Grad program took her to clinics and laboratories in Peru, where TB is a major health problem.

She accompanied healthcare workers to remote clinics, assisted Peruvian laboratory researchers, and met patients face to face.

“It makes it all real,” she says, “in a way that never quite happens from reading about it or hearing about it.”

Peru

Med Into Grad is a science education program that gives basic scientists a clinical experience during their doctoral training. The goal is to help medical researchers focus directly on improving patient care in their future work.

Each student is placed for three to six months in a clinical setting that matches his or her research interests.

“My Med Into Grad experience has provided a big picture view of the problem of TB and all its different facets,” Scarlet says.

“I think it’s important for setting research priorities: what questions can we ask to get the information we need to tackle this problem?”

She says the experience confirmed her decision to change her research focus and intensified her desire to find better ways to detect and treat TB.


“I was in the right place
at the right time –
or Med Into Grad was.”


Scarlet did most of her graduate studies in Dr. Richard Kolodner’s cancer research laboratory investigating DNA mismatch repair.

Dr. Kolodner is Professor of Medicine, Adjunct Professor of Cellular and Molecular Medicine and head of the Cancer Genetics program at the Moores UCSD Cancer Center.

As time went on, Scarlet became increasingly interested in infectious disease, particularly tuberculosis and malaria.

She read extensively about TB and decided she wanted to change her research focus, but didn’t know how the transition was going to happen.

Then she heard about Med Into Grad. “I was in the right place in the right time,” she says. “Or the Med Into Grad program was.”

Last April, she left her laboratory bench on the UCSD campus for Peru. The opportunity came through Dr. Joseph Vinetz, Professor of Medicine in the Division of Infectious Diseases at UCSD.

Dr. Vinetz is an expert in tropical infectious diseases including malaria and leptospirosis. In addition to his UCSD laboratory, he collaborates with Peruvian and other U.S. investigators in a lab in Iquitos, a rural city in the Peruvian Amazon rain forest.

Scarlet spent several weeks in Dr. Vinetz’s malaria laboratory in Iquitos.

She visited the local hospital with nurses and other health workers. There, she had her first up-close encounters with infectious disease patients.

“I got to see what kinds of diseases people came in for, how they were diagnosed, and how they were treated,” she said.

She went on to Lima, the capital city, where she worked in laboratories operated by collaborators of Dr. Vinetz under the auspices of the Universidad Peruana Cayetano Heredia.

The laboratories conduct basic and clinical research in improving TB diagnosis and drug sensitivity testing. The aim is to find techniques that do not require costly equipment or extensive resources, so that they can be used in underdeveloped countries.


“Being in that environment
made the barriers to treatment
really obvious.”


Until she went to Peru, her career had involved an entirely different kind of interaction – with yeast, the organism used as a model system in her laboratory studies.

Now she had the chance to see how Peruvian mothers juggled transportation and child care issues as they went through the slow and arduous process of TB testing and treatment.

“Being in that environment made the barriers to treatment really obvious,” she says.

She watched how patients and doctors wrestled with logistics. TB diagnosis takes several clinic visits, and often takes many weeks. Drug therapy has to be given several times a week for at least 6 months.

“Most people don’t have cars,” she said. “The patients face choices day by day – do I go to the clinic for my treatment, or do I go to work?”

She saw how greatly the situation would improve if there were a way to diagnose TB more rapidly, and treat it with a shorter course of medicines.

In Lima, Scarlet took part in clinical research in the laboratory and she helped analyze a large database of experimental results from a clinical study.

She worked with Dr. Carlton A. Evans, an English infectious disease researcher from Imperial College London, who spends most of his time in the field in Peru.

Last November, she presented some of the Peruvian TB research data at the annual meeting of the American Society of Tropical Medicine and Hygiene in Philadelphia.


On to Harvard
with “another level of motivation”


At Harvard, Scarlet will choose her research studies in light of her Med Into Grad experience. She’s considering investigations of how TB evades the immune response to persist inside the host, or why treatment takes so long.

Med Into Grad has given her “another level of motivation,” she says.

It has also given her research connections and projects to help establish her career.

She helps with data analysis for the Lima laboratory on her own time now. It’s part of her own connection with a healthcare effort that has become personally significant to her.

“I got to see how they did what they do,” she says. “It was a really cool experience to actually get to participate.

“It makes it all real. TB is a disease that causes so much death and so many problems. There is a need for better diagnosis and better treatment.”

About Med Into Grad at UCSD

“The Med Into Grad program gives a basic science student the chance to witness firsthand the opportunities where science can improve clinical medicine,” says Dr. Ken Kaushansky.

Dr. Kaushansky and Dr. Mark P. Kamps are founders and co-directors of the Med Into Grad program at UCSD.

Dr. Kaushansky is Helen M. Ranney Distinguished Professor and Chair of the Department of Medicine. Dr. Kamps is Professor and Director of the Graduate Program in the Department of Pathology.

UCSD is one of several leading universities to offer Med Into Grad. The program is funded by a science education grant from the Howard Hughes Medical Institute (HHMI), a nonprofit research institution.

More Information

Helping Young Scientists Design Better Medicine

A new UCSD program is taking researchers-in-training into the clinics to help them design their research with patient care in mind.

Med Into Grad, now in its second year at UCSD, gives young scientists the chance to spend up to six months with patients before they embark on their laboratory careers.

It’s a new approach to developing what Dr. Ken Kaushansky calls “bilingual” medical scientists – those individuals who speak both the language of basic science and the language of clinical medicine.

Dr. Kaushansky and Dr. Mark P. Kamps lead the UCSD Med Into Grad program.

Dr. Kaushansky is Helen M. Ranney Professor and Chair of the Department of Medicine. Dr. Kamps is Professor of Pathology and Director of the Graduate Program in Pathology.

“There are two basic pathways to develop ‘bilingual’ biomedical scientists,” Dr. Kaushansky says. “One is the classic MD/PhD program, and the other is teaching science to ‘straight MDs,’ the so-called ‘late bloomer’ pathway.

“The Med Into Grad program provides a new pathway; taking a basic science student and providing them with clinical experiences, allowing them to witness, first hand, the opportunities where science can improve clinical medicine.”

UCSD is one of several leading universities to offer Med Into Grad. The program is funded by a science education grant from the Howard Hughes Medical Institute (HHMI), a nonprofit research institution.

“The Med Into Grad program gives students a better understanding of the clinical basis of the diseases they are studying scientifically,” Dr. Kaushansky says. “It helps them design their science in ways that we can apply directly to better patient care.”