A 'wild card' in your genes

Rahul Kohli and colleagues focus on cytosine, one of the four chemical "bases" that comprise the alphabet that the genetic material DNA uses to spell out everything from hair and eye color to risk of certain diseases. But far from just storing information, cytosine has acquired a number of other functions that give it a claim to being the genome's wild card. "In poker, the rules of the game can occasionally change," they note in the article. "Adding a 'wild card' to the mix introduces a new degree of variety and presents opportunities for a skilled player to steal the pot. Given that evolution is governed by the same principles of risk and reward that are common to a poker game, it is perhaps not surprising that a genomic 'wild card' has an integral role in biology."

They discuss the many faces of cytosine that make it such a game-changer and the biological processes that help to change its identity. Removing something called an amine group from cytosine, for instance, allows the immune system to recognize and destroy foreign invaders such as viruses. Adding so-called "methyl groups" on cytosines acts as on/off switches for genes. The authors say that these many faces of cytosine allow it to play various roles and give it true "wild card" status.

More information: The Curious Chemical Biology of Cytosine: Deamination, Methylation,and Oxidation as Modulators of Genomic Potential, ACS Chem. Biol., Article ASAP. DOI: 10.1021/cb2002895

Abstract
A multitude of functions have evolved around cytosine within DNA, endowing the base with physiological significance beyond simple information storage. This versatility arises from enzymes that chemically modify cytosine to expand the potential of the genome. Some modifications alter coding sequences, such as deamination of cytosine by AID/APOBEC enzymes to generate immunologic or virologic diversity. Other modifications are critical to epigenetic control, altering gene expression or cellular identity. Of these, cytosine methylation is well understood, in contrast to recently discovered modifications, such as oxidation by TET enzymes to 5-hydroxymethylcytosine. Further complexity results from cytosine demethylation, an enigmatic process that impacts cellular pluripotency. Recent insights help us to propose an integrated DNA demethylation model, accounting for contributions from cytosine oxidation, deamination, and base excision repair. Taken together, this rich medley of alterations renders cytosine a genomic “wild card”, whose context-dependent functions make the base far more than a static letter in the code of life.

Provided by American Chemical Society (news : web)

Researchers discover key aspect of process that activates breast cancer genes

Michael R. Stallcup, Ph.D., professor and chair of the Keck School's Department of Biochemistry and Molecular Biology, was the senior author, and Kwang Won Jeong, Ph.D., a postdoctoral student in Stallcup's lab, was the first author of the paper, "Recognition of enhancer element-specific histone methylation by TIP60 in transcriptional activation." It was published online in the research journal Nature Structural & Molecular Biology on Nov. 13.

Researchers at the Keck School of Medicine of the University of Southern California have discovered key processes by which estrogen, the female sex hormone, activates genes in breast-cancer cells. Greater understanding of how this occurs is expected to eventually lead to new treatments for the disease.

The researchers found that a protein, TIP60, recognizes when a common chemical process called methylation occurs in chromatin, the material that enfolds all genes. Methylation controls how genes are folded in the complex structure of chromatin, which determines whether the genes are active or inactive. The researchers discovered that after recognizing the methylation signal, TIP60 then binds to the signal, connecting TIP60 to the chromatin and then changing the chromatin's structure, which helps to activate the gene. The methylation that TIP60 recognizes is generated by another protein, MLL1.

"It's like when you're in your car and come to a red light," said Stallcup. "The light doesn't make you stop, but it is a signal that you have to interpret and then decide to stop. In this case, the methylation modification that TIP60 recognizes is one of those signals, and then TIP60 acts on that signal."

The findings build upon previous work of Stallcup's lab. Earlier published research revealed that the methylation of chromatin and other proteins plays many important roles in controlling the activities of genes.

While the recent findings are significant, Stallcup stressed that there is much more to be discovered.

"We want to understand more about other steps in the process of gene activation," Stallcup said. "In particular, we're interested in the function of the MLL1 protein because we think it plays a key role in controlling chromatin structure and folding, which we think is critical for activation of genes by estrogen."

Stallcup also noted that estrogen regulates just a few hundred of the tens of thousands of genes in every human cell, but that the research has broader implications.

"While the process we're studying is the regulation of gene activity by estrogen, the findings have potentially global significance,,because the methylation modification of chromatin that TIP60 recognizes is found in all active and potentially active genes in human cells," Stallcup said.

Provided by University of Southern California (news : web)

Scientists copy the ways viruses deliver genes

Scientists at the National Physical Laboratory (NPL) have mimicked the ways viruses infect human cells and deliver their genetic material. The research hopes to apply the approach to gene therapy – a therapeutic strategy to correct defective genes such as those that cause cancer.

Gene therapy is still in its infancy, with obvious challenges around targeting damaged cells and creating corrective genes. An equally important challenge, addressed by this research, is finding ways to transport the corrective genes into the cell. This is a problem, because of the poor permeability of cell membranes.

This research describes a model peptide sequence, dubbed GeT (gene transporter), which wraps around genes, transports them through cell membranes and helps their escape from intracellular degradation traps. The process mimics the mechanisms viruses use to infect human cells.

GeT was designed to undergo differential membrane-induced folding - a process whereby the peptide changes its structure in response to only one type of membranes. This enables the peptide, and viruses, to carry genes into the cell. Interestingly, the property also makes it antibacterial and so capable of gene transfer even in bacteria-challenged environments.

To prove the concept, the researchers used GeT to transfer a synthetic gene encoding for a green fluorescent protein – a protein whose fluorescence in cells can be seen and monitored using fluorescence microscopy.

The design can serve as a potential template for non-viral delivery systems and specialist treatments of genetic disorders.

This research, performed at NPL, is a part of the NPL-led international research project 'Multiscale measurements in biophysical systems', which is jointly funded by NPL and the Scottish Universities Physics Alliance.

More information: The team's article GeT peptides: a single domain approach to gene delivery, detailing this research has just been published in Chem. Commun: http://pubs.rsc.or … C/c1cc13043a

Provided by National Physical Laboratory