A role for microRNA in viral suppression

Apparently microRNAs are not solely responsible for regulation of endogenous genes. Here is an example of a microRNa used to suppress viral infectivity. Suppressing the suppressor also enhanced infectivity.

Bystander gene activation by a locus control region

Locus control regions (LCRs) are regulatory elements that can activate high levels of gene transcription from remote locations relative to target genes. Transcription of the human growth hormone (hGH) gene cluster depends on epigenetic regulation by an hGH LCR located 16-32kb upstream of the cluster. The hGH LCR may establish an extensive activated chromatin domain that encompasses target hGH gene promoters. The immunoglobulin associated beta gene (hIgβ), which plays a specific role in B-cell differentiation, is situated between the hGH LCR and the hGH gene cluster on chromosome 17. Gene expression experiments predictably found hIgβ transcription in the spleen, but unexpectedly found strong hIgβ transcription in human pituitary tissues. A lack of function ascribed to hIgβ in the pituitary combined with the expectation that insulator/boundary regulatory elements would shield hIgβ from epigenetic alterations associated with the hGH LCR hyper-acetylated chromatin domain in which it is located, suggested an unlikeliness of robust pituitary transcription.

The fortuitous positioning of hIgβ as a ‘bystander’ within the activated domain is a likely pituitary-specific explanation for hIgβ transcription in the pituitary. This unexpected finding impacts on current concepts of tissue specificity and suggests that simple linear insulator/boundary models of gene insulation may be insufficient.

Shaun Mason

[Journal article reference: Cajiao, I., Zhang, A., Jae Yoo, E., Cooke, N.E., & Liebhaber, S.A. (2004). Bystander gene activation by a locus control region, EMBO, 23(19), 3854-3863.]

The effect of radiation on DNA methylation and its links to cancer

One of the most widely studied areas of epigenetics is DNA methylation. Methylation has been linked to a number of different phenomena, including gene silencing, chromosomal stability and carcinogenesis.

DNA methylation occurs when a methyl group is added to a Cytosine-Guanine base pair. As mentioned previously, one of the outcomes of DNA methylation is gene silencing. Methylation is thought to silence a gene by switching off its promoter, through the methylation of GpG islands located in the promoter sequence.

CpG islands are simply a Cytosine nucleotide followed by a Guanine nucleotide, with the “p” representing the phosphate located between the two nucleotides.

Igor Pogribny et al. (2004) of carried out a study to examine the effect of radiation on the DNA methylation state of three different types of tissue; liver, spleen and lung. After the tissue was exposed to varying doses of radiation, the proportion of methylation in the treated tissue was compared with control samples.

Results from the study indicated that exposure to radiation can cause demethylation of DNA. Based on the results it was suggested that demethylation is DNA-repair related. It was also suggested the demethylation, and the subsequent undesirable activation of certain genes, may be part of the pathway by which certain types of radiation cause cancer.

Reference:

Pogribny I, Raiche J, Slovack M, Kovalchuk O (2004) Dose-dependence, sex- and tissue-specificity, and persistence of radiation-induced genomic DNA methylation changes. Biochem Biophys Res Commun. 2004 Aug 6;320(4):1253-61

“A small modulatory dsRNA specifies the fate of adult neural stem cells”, by Kuwabara et al. (Cell 2004; 116: 779 – 793) & reviewed by Mark Mayhew.

Epigenetics involves modifications to the genome that generally result in silencing of gene expression. In this study, a novel small RNA has been discovered that is involved in the activation of gene expression. These so-called small modulatory RNAs (smRNAs) interact with a transcriptional repressor of neuron-specific genes, NRSF/REST, & an associated DNA sequence element, NRSE/RE-1, found in the promoter region of these genes. Interestingly, upon binding of smRNAs, NRSF/REST remains attached to NRSE/RE-1 & subsequently activates gene expression. This gene expression induces differentiation of neurons from progenitor or “stem” cells. Experimentation has shown that smRNAs are sufficient & necessary for this process. smRNAs are an exciting discovery & have a potential application in “stem” cell therapies which seek to replace CNS neurons that have been damaged through injury or disease.

The Genographic Project

"New DNA studies suggest that all humans descended from a single African ancestor who lived some 60,000 years ago. To uncover the paths that lead from him to every living human, the National Geographic Society today launched the Genographic Project at its Washington, D.C., headquarters."

National geographic, IBM and the Waitt Family Foundation will collaborate in a five-year large scale worldwide DNA study, in which cheek swab samples are taken from diverse (and isolated) indigenous peoples as well as from the more general population in order to piece together a picture of how the earth was colonized by homosapiens.

(With the purchase of a kit containing all of the necessary materials for US $99.95, the general public are able to add their own genetic information to the growing database!)

By studying the Y chromosome and mitochondrial genome (passed down the maternal line), genetic markers can be identified that may be traced back to the point of origin, or when a new lineage began. Both the Y chromosome and mitrochondrial DNA do no undergo recombination, thus these regions of DNA remain basically unchanged through generations apart from random mutations. These identified mutations serve as the genetic markers for study. Prehistoric migration patterns may be tracked if lineages can be traced to a particular geographic region.

According to one project leader, "We need to take a genetic snapshot of who we are as a species before the geographical and cultural context are lost in the melting pot" (believing that the world is becoming less genetically and culturally diverse as a result of factors such as increased globalization, leading to a reduced isolation of groups of people).

It is estimated that more than 100,000 samples will be taken for lab and computational analysis, forming the world's largest DNA database.

Link to News article: http://news.nationalgeographic.com/news/2005/04/0413_050413_genographic.html

Link to the Genographic Project website: http://www5.nationalgeographic.com/genographic/

Shaun

Useful review on small RNAs

Found a good review: Kim VN (2005) Molecules & Cells 19(1): 1 - 15.

non-polyA transcripts in cytoplasm

In a brief review of a current paper, the comment is made that twice as much non-polyadenylated RNA is in the cytoplasm as polyadenylated mRNA. Much of the transcribed RNA is apparently complementary to mRNA, suggesting a great deal of dsRNA in a typical cell.