Methylation, an epigenetic modification to DNA, can be thought of as a highlighting pen applied to DNAâ€™s text, adding information but not changing the actual letters of the text.
Are you still with me on the metaphors? If so, consider this wrinkle. (If not, more explanation here.)
Emory geneticist Peng Jin and his colleagues have been a key part of the discovery in the last few years that methylation comes in several colors. His lab has been mapping where 5-hydroxymethylcytosine or 5hmC appears in the genome and inferring how it functions. 5-hmC is particularly abundant in the brain.
Methylation, in the form of 5-methylcytosine or 5mC, is both a control button for turning genes off and a sign of their off state. 5hmC looks like 5mC, except it has an extra oxygen. That could be a tag for a removal, or a signal that aÂ gene is poised to be turned on.
Two recent papers on this topic:
Please recall that an enriched environment (exercise and mental stimulation) is good for learning and memory, for young and old. In the journalÂ Genomics, Jin and his team show that exposing mice to an enriched environmentÂ — a running wheel and a variety of toys — leads to a 60 percent reduction in 5hmC in the hippocampus, a region of the brain critical for learning and memory. Â The changes in 5hmC were concentratedÂ in genes having to do with axon guidance. Hat tip to the all-things-epigenetic site Epigenie.
In Genes and Development, structural biologist Xiaodong Cheng and colleagues demonstrateÂ that two regulatory proteins that bind DNA (Egr1 and WT1) respond primarily to oxidation of their target sequences rather than methylation. These proteins like plain old C and 5mC equally, but they donâ€™t like 5hmC or other oxidized forms of 5mC. â€œGene activity could plausibly be controlled on a much finer scale by these modifications than simply â€˜on or â€˜offâ€™,â€ the authors write.
Doctors are using a â€œdivide and conquerâ€ strategy against lung cancer, and in some corners of the battlefield, itâ€™s working. A few mutations â€“ genetic alterations in the tumor that donâ€™t come from the patientâ€™s normal cells — have been found for which drugs are effective in pushing back against the cancer.
However, most lung tumors do not have one of these mutations, and response rates to conventional chemotherapy in patients with advanced lung cancer are poor. Generally, only around 20 percent of patients show a clinical response, in that the cancer retreats noticeably for some time.
Johann Brandes and colleagues at Winship Cancer Institute have been looking for biomarkers that can predict whether an advanced lung tumor is going to respond to one of the most common chemotherapy drug combinations, carboplatin and taxol.
â€œThe availability of a predictive test is desirable since it would allow patients who are unlikely to benefit from this treatment combination to be spared from side effects and to be selected for other, possibly more effective treatments,â€ Brandes says.
Brandesâ€™ teamâ€™s data comes from looking at patients with advanced lung cancer at the Atlanta VAMC from 1999 to 2010. In a 2013 paper in Clinical Cancer Research, the team looked at a protein called CHFR. It controls whether cells can reign in their cycles of cell division while being bombarded with chemotherapy.
In this group being treated with carboplatin and taxol, patients who had tumors that measured low in this protein lived almost four months longer, on average, than those who had tumors that were high (9.9 vs 6.2 months).
His team takes a similar approach in a new paper published in PLOS One. Postdoc Seth Brodie is the first author of the PLOS One paper; he is also co-first author of the CHFR paper along with Rathi Pillai. Read more
Nature News recently described a trend noticeable at Emory and elsewhere. That trend is epigenomics: studying the patterns of chemical groups that adorn DNA sequences and influence their activity. Often this means taking a comprehensive genome-wide look at the patterns of DNA methylation.
DNA methylation is a chemical modification analogous to punctuation or a highlighter or censorâ€™s pen. It doesnâ€™t change the letters of the DNA but it does change how that information is received.
One recent example of epigenomics from Emory is a collaboration between psychiatrist Andrew Miller and oncologist Mylin Torres, examining the long-lasting marks left by chemotherapy in the blood cells of breast cancer patients.
Their co-author Alicia Smith, who specializes in the intersection of psychiatry and genetics, reports “EWAS or epigenome-wise association studies are being used in complex disease research to suggest genes that may be involved in etiology or symptoms.Â They’re used in medication or diet studies to demonstrate efficacy or suggest side effects.Â Â Theyâ€™re also used in longitudinal studies to see if particular exposures or characteristics (i.e. low birthweight) have long-term consequences.” Read more
Peng Jin and collaborators led by Da-Hua Chen from the Institute of Zoology, Chinese Academy of Sciences have a new paper in Stem Cell Reports. They describe a souped-up method for producing iPS cells (induced pluripotent stem cells).
Production of iPS cells in the laboratory is becoming more widespread. Many investigators, including those at Emory, are using the technology to establish â€œdisease in a dishâ€ models and derive iPS cells from patient donations, turning them into tools for personalized medicine research.
The 2012 Nobel Prize in Medicine was awarded to Shinya Yamanaka and John Gurdon for the discovery that differentiated cells in the body can be reprogrammed. This finding led to the development of â€œinduced pluripotent stem cells.â€
These cells were once skin or blood cells. Through a process of artificial reprogramming in the lab, scientists wipe these cellsâ€™ slates clean and return them to a state very similar to that of embryonic stem cells.Â But not exactly the same.
It has become clear that iPS cells can retain some memories of their previous state. This can make it easier to change an iPS cell that used to be a blood cell (for example) back into a blood cell, compared to turning it into another type of cell. The finding raised questions about iPS cellsâ€™ stability and whether http://www.troakley.com/ iPS cell generation â€“ still a relatively new technique â€“ would need some revamping for eventual clinical use.
It turns out that iPS cells and embryonic stem cells have differing patterns of methylation, a modification of DNA that can alter how genes behave even if the underlying DNA sequence remains the same. Some of these differences are the same in all iPS cells and some are unique for each batch of reprogrammed cells.
Move over, A, G, C and T. The alphabet of epigenetic DNA modifications keeps getting longer.
A year ago, we described research on previously unseen information in the genetic code using this metaphor:
Imagine reading an entire book, but then realizing that your glasses did not allow you to distinguish â€œgâ€ from â€œq.â€ What details did you miss?
Geneticists faced a similar problem with the recent discovery of a â€œsixth nucleotideâ€ in the DNA alphabet. Two modifications of cytosine, one of the four bases http://www.raybani.com/ that make up DNA, look almost the same but mean different things. But scientists lacked a way of reading DNA, letter by letter, and detecting precisely where these modifications are found in particular tissues or cell types.
Now, a teamâ€¦ has developed and tested a technique to accomplish this task.