Super enhancers in the inflamed endothelium

Super-lative insights may yield new therapies for heart disease

2014-09-25

(Press-News.org) Boston, MA – Normally, the lining of blood vessels, or endothelium, when at rest, acts like Teflon, ignoring the many cells and other factors rushing by in the bloodstream. In response to inflammatory signals, as well as other stimuli, endothelial cells change suddenly and dramatically—sending out beacons to attract inflammatory cells, changing their surface so those cells can stick and enter tissues, and initiating a complex cascade of responses essential to fighting infection and dealing with injury. Unfortunately, these same endothelial responses also promote atherosclerosis, the build-up of plaque in arteries that cause heart attacks, strokes and other inflammatory diseases.

Now, a study led by researchers at Brigham and Women's Hospital (BWH) and Dana-Farber Cancer Institute is the first to demonstrate that BET bromodomain-containing proteins help execute this global inflammatory program in the endothelium while BET bromodomain inhibition can significantly decrease atherosclerosis in vivo.

The study is published online September 25, 2014 in Molecular Cell.

"By using tools that interrogate the entire genome, it has been exciting to uncover how inflammatory signals known to promote atherosclerosis employ BET bromodomain-containing proteins as an epigenetic means of directing entire programs of endothelial gene expression," said Jorge Plutzky, MD, director, BWH Preventive Cardiology, co-corresponding senior author. "BET bromodomain-containing proteins have been studied in cancer for some time, where they are in therapeutic trials, but now we have mechanistic evidence for how BETs and their inhibition can impact endothelial inflammation and atherosclerosis."

Looking at the epigenome of endothelial cells, researchers sought to get a better understanding of the inflammatory response responsible for the initiation of atherosclerosis by characterizing the dynamics, structure and function of the elements responsible for regulating inflammatory response. This work involved harnessing the expertise of different research teams. James E. Bradner, MD, Dana-Farber Cancer Institute, developed one of the first BET inhibitors and has been a leader in this field.

"This research demonstrates how environmental influences lead to dynamic changes in genome structure leading to disease states, here the inflammation associated with heart disease," said Bradner. "Further, we have identified a set of compounds we developed initially for cancer that halt the progression of coronary disease. These unexpected findings exemplify the very best outcome of open, interdisciplinary science."

To stimulate transcription of genes that carry out the inflammatory program, researchers demonstrated how activation of NF-kB, a canonical mediator of inflammation, leads to a complex between BET bromomdomain-containing proteins and p65, a key NF-kB protein, at specific DNA regulatory regions. These spots are known as super enhancers or stretch enhancers. Super enhancers have been implicated in oncologic processes by Bradner and others but not in endothelial biology or atherosclerosis, at least up until now.

In pre-clinical models, the researchers found that activating NF-kB rapidly re-distributed the BET protein known as BRD4 to chromosomal sites where super enhancers driving expression of nearby inflammatory genes are located. Bromodomains are amino acid regions that bind to specifically modified sites on histones, the proteins around which DNA is coiled. By binding to these amino acid regions, BET bromodomain inhibitors block the assembly of protein complexes that drive expression of certain genes. In these studies, inhibiting BET bromodomains turned off an inflammatory program in human endothelial cells, decreased white blood cells adhering to endothelial cells, and decreased atherosclerosis in mice.

"By offering new perspectives on transcriptional programs in inflammation and atherosclerosis and how to identify previously unrecognized players in those responses, these studies can offer new therapeutic approaches for atherosclerosis and other inflammatory conditions," said Plutzky. "It also shows what collaborative teams thinking about completely different disease states can uncover by working together."

INFORMATION: This research was supported by the National Institutes of Health (NIH-K08 HL105678, PO1 HL36028, NIH-K08 CA128972, P01 HL048743), Watkins Discovery Research Award, Harris Family Award, Neissa Family Foundation, United States Department of Defense, Sarnoff Cardiovascular Research Foundation, Burroughs-Wellcome Fund, Damon-Runyon Cancer Research Foundation, Richard and Susan Smith Family Foundation, and Next Generation Award. Brigham and Women's Hospital (BWH) is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare. BWH has more than 3.5 million annual patient visits, is the largest birthing center in Massachusetts and employs nearly 15,000 people. The Brigham's medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in patient care, quality improvement and patient safety initiatives, and its dedication to research, innovation, community engagement and educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Brigham Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, more than 1,000 physician-investigators and renowned biomedical scientists and faculty supported by nearly $650 million in funding. For the last 25 years, BWH ranked second in research funding from the National Institutes of Health (NIH) among independent hospitals. BWH continually pushes the boundaries of medicine, including building on its legacy in transplantation by performing a partial face transplant in 2009 and the nation's first full face transplant in 2011. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative. For more information, resources and to follow us on social media, please visit BWH's online newsroom. END

ELSE PRESS RELEASES FROM THIS DATE:

Novel compound prevents metastasis of multiple myeloma in mouse studies

2014-09-25

BOSTON –– In an advance against the problem of cancer metastasis, Dana-Farber Cancer Institute scientists have shown that a specially developed compound can impede multiple myeloma from spreading to the bones in mice. The findings, published in the Sept. 25 issue of Cell Reports, suggest the technique can protect human patients, as well, from one of the most deadly aspects of cancer. The research involves a new approach to the challenge of cancer metastasis, the process by which tumors spread to and colonize distant parts of the body. Whereas research has traditionally ...

Dinosaur family tree gives fresh insight into rapid rise of birds

2014-09-25

The most comprehensive family tree of meat-eating dinosaurs ever created is enabling scientists to discover key details of how birds evolved from them. The study has shown that the familiar anatomical features of birds – such as feathers, wings and wishbones – all first evolved piecemeal in their dinosaur ancestors over tens of millions of years. However, once a fully functioning bird body shape was complete, an evolutionary explosion began, causing a rapid increase in the rate at which birds evolved. This led eventually to the thousands of avian species that we know ...

Strategic or random? How the brain chooses

2014-09-25

Many of the choices we make are informed by experiences we've had in the past. But occasionally we're better off abandoning those lessons and exploring a new situation unfettered by past experiences. Scientists at the Howard Hughes Medical Institute's Janelia Research Campus have shown that the brain can temporarily disconnect information about past experience from decision-making circuits, thereby triggering random behavior. In the study, rats playing a game for a food reward usually acted strategically, but switched to random behavior when they confronted a particularly ...

New protein players found in key disease-related metabolic pathway

2014-09-25

CAMBRIDGE, Mass. (September 25, 2014) – To coordinate their size and growth with current environmental conditions, cells rely on the mechanistic target of rapamycin complex 1 (mTORC1) pathway, which senses cellular stresses, growth factors, and the availability of nutrients, such as amino acids and glucose. For years, Whitehead Institute Member David Sabatini and his lab have been teasing apart the numerous proteins involved in this vital metabolic pathway, in part because mTORC1 function is known to be deregulated in a variety of diseases, including diabetes, epilepsy, ...

Large study pinpoints synapse genes with major roles in severe childhood epilepsies

2014-09-25

An international research team has identified gene mutations causing severe, difficult-to-treat forms of childhood epilepsy. Many of the mutations disrupt functioning in the synapse, the highly dynamic junction at which nerve cells communicate with one another. "This research represents a paradigm shift in epilepsy research, giving us a new target on which to focus treatment strategies," said pediatric neurologist Dennis Dlugos, M.D., director of the Pediatric Regional Epilepsy Program at The Children's Hospital of Philadelphia, and a study co-author. "There is tremendous ...

Protein controlling gut's protective force field identified

2014-09-25

Scientists have identified a protein in the human intestine that helps to protect against attack from opportunistic bacteria that strike when our defences are down. The protein receptor is activated during illness, producing a force field on the gut's surface made of a sugary substance that encourages the growth of protective bacteria. Scientists deleted the IL-22RA1 gene that produces the receptor protein from the mouse genome. In the absence of this gene, which is associated with inflammatory bowel disease (IBD) in humans, the mice were found to be more susceptible ...

NYU Langone scientists identify key factor that maintains stem cell identity

2014-09-25

NEW YORK, September 25, 2014— A protein implicated in several cancers appears to play a pivotal role in keeping stem cells in an immature "pluripotent" state, according to a new study by NYU Langone Medical Center scientists. The study is published online today in Cell Reports. Stem cells are the perpetual adolescents of the cellular world, uncommitted to any cell fate. In principle, they can be programmed to differentiate into any mature cell type, holding the promise of regenerating tissues and organs. A fuller understanding of their biology, however, is needed. ...

Surprising diversity of antibody family provides clues for HIV vaccine design

2014-09-25

LA JOLLA, CA—September 25, 2014—Scientists at The Scripps Research Institute (TSRI) have described how a single family of antibodies that broadly neutralizes different strains of HIV has evolved remarkably diverse structures to attack a vulnerable site on the virus. The findings provide clues for the design of a future HIV vaccine. "In a sense, this antibody family takes more than one shot on goal in order to hit divergent forms of HIV," said Ian A. Wilson, the Hansen Professor of Structural Biology and member of the Skaggs Institute for Chemical Biology at TSRI. "The ...

New genes identified with key role in the development of severe childhood epilepsies

2014-09-25

In the largest collaborative study so far, an international team of researchers, including scientists from VIB and Antwerp University identified novel causes for severe childhood epilepsies. The researchers analyzed the genetic information of 356 patients and their parents. In their analysis, the research teams looked for genes that had acquired new mutations in the children with severe epilepsies when compared to the DNA of the parents. In total, they identified 429 new mutations and in 12% of children, these mutations were considered unequivocally causative for the patient's ...

How the ends of chromosomes are maintained for cancer cell immortality

2014-09-25

VIDEO: The perpetual proliferation of cancer cells requires a means to maintain telomere length. Alternative lengthening of telomeres (ALT) is a poorly understood mechanism of telomere maintenance that is utilized by... Click here for more information. PHILADELPHIA – Maintaining the ends of chromosomes, called telomeres, is a requisite feature of cells that are able to continuously divide and also a hallmark of human cancer. "Telomeres are much like the plastic cap on the ends ...

Super enhancers in the inflamed endothelium

ELSE PRESS RELEASES FROM THIS DATE:

LAST 30 PRESS RELEASES: