RLS is NOT Hereditary: Welcome to the AMAZING World of Epigenetics! (PART THREE: Inflammation and Epigenetics)

ImageAs a society we are faced with an epidemic of chronic inflammation.

Epigenetics’ role in lessening this condition is of the highest interest to restless legs sufferers.

Scientists have reached a level where the “cause” of diseases can actually be determined and altered.

Unfortunately, at this time, RLS is not a high priority for researchers when it comes to tapping into the vast healing powers of epigenetics.

Obviously, cancer is at the top of the list. It is followed by other heavy-hitters such as Alzeimer’s, depression, obesity etc.

But that’s still good news for you. Cancer and RLS have something in common – they are both deeply connected to inflammation.
Therefore, whatever switches are discovered that lessen the inflammation involved with cancer, could also be of help to RLS sufferers.

As you’ll read below in the interview with Doctors Belkina and Denis that “changes to one master regulator can affect many different, apparently unrelated, diseases.”

In other words, people with inflammatory diseases other than cancer, such as RLS, could still benefit from any major discoveries made in epigenetic cancer research.

Image“Inflammation and epigenetics: an interview with Dr Belkina and Dr Denis, Boston University School of Medicine.” Interview conducted by April Cashin-Garbutt, BA Hons (Cantab). Published on March 28, 2013.

“What diseases are associated with inflammation?

Inflammation can be thought of as taking two major forms: acute or chronic.

Acute inflammation, which can be painful, usually arises quickly and resolves quickly. It accompanies bacterial infections, traumatic injury and is useful to fight infections and promote healing. But unresolved, severe, acute inflammation can be fatal, such as acute respiratory distress syndrome or influenza, where the lungs develop edema; or sepsis, where ‘cytokine storms’ cause organ damage and shock.

Chronic inflammation is a low-grade form that fails to resolve and can persist over years. Cardiovascular disease, insulin resistance, Type 2 diabetes are good examples; this inflammation is often not acutely painful in a way that might warn the sufferer. Its subtle nature renders it dangerous, and associated with sudden death due to cardiac arrest or stroke. Chronic inflammation can be a serious problem in older, obese humans and has been linked to obesity-associated cancer.

What are macrophages and how do they cause inflammation?

Macrophages differentiate from blood monocytes, they are recruited to different organs in response to signals called chemokines; or they permanently reside in tissues, and so are called ‘resident macrophages’. These cells produce small proteins called cytokines that promote inflammation in the tissue or help with wound healing, tissue remodelling or other kinds of housekeeping.

In acute and chronic inflammatory diseases, the net output of inflammatory cytokines results in organ dysfunction, pain, deteriorating health and even cellular death.

How can genetically identical cells express their genes differently without DNA sequence changes?

The controlling regions of genes, called ‘promoters’ or ‘enhancers’ are packaged into chromatin, which can be permanently marked by epigenetic ‘writer’ enzymes, such as histone acetylases, and read in daughter cells by ‘reader’ proteins, such as bromodomain proteins. These marks can dramatically affect gene expression in otherwise genetically identical cells.

DNA itself can be marked by epigenetic writer enzymes, such as DNA methylases, and read by yet other proteins to change gene expression. Yet in none of these cases has the DNA been mutated or the genetic sequences altered; so that daughter cells can have very different gene expression, yet be genetically identical.

What epigenetic mechanisms did your research into inflammation identify?

We found that the BET family of double bromodomain-containing ‘reader’ proteins is essential for transcriptional regulation of a broad array of genes that produce inflammatory cytokines.

We found that one BET protein in particular, Brd2, is a ‘master regulator’ of many different inflammatory cytokine genes. Thus, if one inhibits this master regulator of inflammation, it’s like throwing a bucket of cold water on the inflammatory fire.

What epigenetic mechanisms did your research into inflammation identify?

We found that the BET family of double bromodomain-containing ‘reader’ proteins is essential for transcriptional regulation of a broad array of genes that produce inflammatory cytokines.

We found that one BET protein in particular, Brd2, is a ‘master regulator’ of many different inflammatory cytokine genes. Thus, if one inhibits this master regulator of inflammation, it’s like throwing a bucket of cold water on the inflammatory fire.

How did your research into the epigenetic mechanisms that connect diseases associated with inflammation originate?

We had been studying Brd2 for many years, and knew that high level expression of Brd2 and other BET family proteins causes cancer. We expected that when we deleted Brd2 in mice that they would not be viable, but got a huge shock when not only did they live, but they became obese.

We experienced an even bigger shock when we found that they did not develop glucose intolerance or insulin resistance, despite their incredible obesity, which was the human equivalent of 600 pounds.

We discovered that their reduced inflammatory profile, brought about by low Brd2 levels, rather than zero Brd2 levels, paradoxically kept them alive, made them fat, and protected their metabolism from inflammatory complications.

There are humans like this, e.g., ‘metabolically healthy obese’ patients who actually perplex their physicians because, although they may be severely obese, they actually preserve many metabolic features of lean and healthy people, including lower risks for cardiovascular disease and Type 2 diabetes, in part because they have a reduced inflammatory profile.

We felt we had no choice but to pursue this amazing, accidental discovery.

Does your research suggest that the different diseases associated with inflammation are linked?

The ‘master regulators’ form a very limited set of proteins that share control of many diverse genes. Thus, changes to one master regulator can affect many different, apparently unrelated, diseases.

By analogy, if you want to cut power quickly to numerous household appliances, you could just trip the master circuit breaker, rather than running around the house and turning off each appliance individually.

Do you think that the current division of medical specialities will need to change in the future to reflect this?

Yes. It will be necessary for cardiologists and endocrinologists to attend immunology meetings, for oncologists to attend endocrinology meetings, and for everyone to ‘think outside of the box’.

Our research shows that many diseases such as atherosclerosis, insulin-resistant obesity, obesity-associated cancer, Type 2 diabetes and other chronic inflammatory diseases are deeply related through common mechanisms of shared networks that control chromatin.

What impact do you think your research will have on controlling the inflammatory response associated with diseases such as type 2 diabetes, cancer and so forth?

New BET protein inhibitors are in the pipeline in a number of research groups and pharmaceutical companies. Some of these agents, if shown to be safe and on target, might become excellent new drugs to treat problems in insulin production, insulin resistance or chronic inflammation, which often accompany obesity and exacerbate risks for obesity-associated cancers.

However, these safety issues are complex and will not be straightforward to overcome.

How important do you think the study of epigenetics will be in the future of medicine?

Epigenetics is a critical new area of research. The Dutch ‘Hunger Winter’ of 1944 – 1945 taught us about the importance and long-lasting impact of maternal starvation, which apparently transmitted cardiometabolic risk epigenetically from the deprived, pregnant mothers to their unborn children.

New research with rodent models is showing us that inflammation in the uterine environment can epigenetically reprogram the young into unhealthy metabolic patterns after birth. Therefore, proper support for maternal health and metabolism will be shown to matter all the more, and we may be able to define specific steps to protect the fetus.

Best of all, we may be able to develop epigenetic drugs that will ultimately be useful to correct these epigenetically transmitted diseases. Until then, there is no cure for the adult children of the Dutch ‘Hunger Winter’ mothers, or patients like them.”

Imagefrom Nature “Unravelling the cancer code.” by Vicki Brower, March 2011  

“A prime candidate at the interface of environment and genetics is chronic inflammation, which is known to precede the development of numerous types of precancerous lesions — and indeed certain cancers themselves, including oesophageal, liver and colon cancers. Inflammation has been linked with increased DNA methylation in otherwise healthy looking tissue. Jean-Pierre Issa, an epigeneticist at the MD Anderson Cancer Center in Houston, and a researcher on the Cancer Genome Project calls chronic inflammation “a truly epigenetic phenomenon.”

“Induction of epigenetic alterations by chronic inflammation and its significance on carcinogenesis.” by Niwa T, Ushijima T. Carcinogenesis Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan. Adv Genet. 2010;71:41-56. doi: 10.1016/B978-0-12-380864-6.00002-X.

“Chronic inflammation is deeply involved in development of human cancers, such as gastric and liver cancers. Induction of cell proliferation, production of reactive oxygen species, and direct stimulation of epithelial cells by inflammation-inducing factors have been considered as mechanisms involved. Inflammation-related cancers are known for their multiple occurrences, and aberrant DNA methylation is known to be present even in noncancerous tissues. Importantly, for some cancers, the degree of accumulation has been demonstrated to be correlated with risk of developing cancers. This indicates that inflammation induces aberrant epigenetic alterations in a tissue early in the process of carcinogenesis, and accumulation of such alterations forms “an epigenetic field for cancerization.” This also suggests that inhibition of induction of epigenetic alterations and removal of the accumulated alterations are novel approaches to cancer prevention. Disturbances in cytokine and chemokine signals and induction of cell proliferations are important mechanisms of how inflammation induces aberrant DNA methylation.“

“Role of epigenetics in inflammation-associated diseases.” by Shanmugam MK, Sethi G. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore. Subcell Biochem. 2012;61:627-57. doi: 10.1007/978-94-007-4525-4_27.

“There is considerable evidence suggesting that epigenetic mechanisms may mediate development of chronic inflammation by modulating the expression of pro-inflammatory cytokine TNF-α, interleukins, tumor suppressor genes, oncogenes and autocrine and paracrine activation of the transcription factor NF-κB. These molecules are constitutively produced by a variety of cells under chronic inflammatory conditions, which in turn leads to the development of major diseases such as autoimmune disorders, chronic obstructive pulmonary diseases, neurodegenerative diseases and cancer. Distinct or global changes in the epigenetic landscape are hallmarks of chronic inflammation driven diseases.“

Imagefrom “Inflammatory signalling as mediator of epigenetic modulation in tissue-specific chronic inflammation.” Liselotte Backdahl, Andrew Bushell & Stephan Beck. Medical Genomics Group. 09/2008; 41(1):176-84. DOI:10.1016/j.biocel.2008.08.023

“Recent successes of therapeutic intervention in chronic inflammatory diseases using epigenetic modifiers such as histone deacetylase inhibitors and inhibitors of DNA methylation suggest that epigenetic reprogramming plays a role in the aetiology of these diseases. The epigenetic signature of a given immune cell is reflected in the history of modifications from different signals the cell has been subjected to during differentiation. Like other cells, differentiating immune cells are dependent on a complex combination of inter- and intracell signalling as well as transcription machineries to modulate their epigenomes in order to mediate differentiation.”

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