Altering gene expression

Here's a very interesting summary of a research article just published in the journal Cell. The important point here (at least for the sake of this conversation) is not the prostate cancer link - but rather the identification of another protein that can change the methylation status of histones - thereby reactivating previously silent DNA.

Histones are the proteins that DNA wraps itself around in order to fit in the cell - think about how your garden hose (sometimes) wraps around its holder - the DNA is the hose and the histone is the garden hose holder. Inactivated DNA gets methylated (including the DNA on the maternal chromosome in the PWS region); that has been well known for many years now. What is becoming more clear is that the associated histones are also modified (by methylation, and another process called acetylation/deacetylation), and these modifications also strengthen or weaken how inactive the accompanying DNA is. This new study identified a protein that can demethylate the histones that are associated genes important in prostate cancer, and reactivate gene expression from those genes.
The important point is that up until recently, it was thought that these histone modifications were permanent and the associated genes, once silenced, couldn't be reactivated. This newly described protein allows those genes to be reactivated. And of course, that's what we like to do in Prader-Willi syndrome - since all people with PWS have all the right genes, but they are sitting there, silent - we would like to be able to reactivate them (and the earlier the better, most likely). The problem is specificity - you want to reactivate the PWS genes, but not other genes that should remain silent. Identifying and understanding these new proteins may eventually provide new approaches to specifically reactivating PWS genes.

Novel enzyme offers new look at male hormone regulation UNC scientists' findings have implications for prostate cancer.

For the second time in less than a year, University of North Carolina at Chapel Hill scientists have purified a novel protein and have shown it can alter gene activity by reversing a molecular modification previously thought permanent. The findings, published in the journal Cell, also show that the new protein plays a role in gene activation mediated by androgen receptor, a protein that responds to androgen hormones. In this regard, the novel protein may figure in the development of prostate cancer. Androgens, particularly testosterone and dihydrotestosterone, determine male secondary sex characteristics and stimulate prostate cell growth. Lowering androgen levels usually can make prostate cancers shrink or grow more slowly.In the study, the researchers said the new protein called JHDM2A, like the protein they reported on in the journal Nature in December 2005, is able to remove a methyl group from histone H3, one of four histone proteins bound to all genes. "Human genes are so tightly compact within the nucleus that if the DNA of a single cell were unwound and stretched, it would be a line of about two meters in length. Histones are necessary to package the DNA so that it fits inside a cell's nucleus," said senior author Dr. Yi Zhang, professor of biochemistry and biophysics at UNC's School of Medicine and the university's first Howard Hughes Medical Institute investigator. Zhang also is a member of the UNC Lineberger Comprehensive Cancer Center. Because histones are so intimately associated with DNA, even slight chemical alterations of these proteins can have profound effects on nearby genes. Depending on their precise location and how many methyl groups are added, the presence of alterations can either turn on or turn off a gene. In the study, Zhang learned that the JHDM2A specifically removesmethyl-groups from lysine 9 of histone H3. "The important thing is that H3K9 demethylation has been linked to transcription silencing, turning genes off. So that led us to pay attention to this protein's role in reversing whatever function K9 methylation might have," Zhang said. In their experiments, the researchers learned that consistent with reversing a marker of gene silencing (H3K9 methylation), the protein functions as a co-activator - in this case, a co-activator for the androgen receptor target genes. Using human tissue cultures, including prostate cells, Zhang and his colleagues found that over-expression of JHDM2A greatly reduced H3K9 methylation level and led to upregulation, or switching on, of androgen receptor target genes. In contrast, when methylation was increased, the gene was silenced - switched off. It remains unclear for how many different human genes JHDM2A is a primary regulator. According to Zhang, the new findings indicate that the protein will provide another tool to enlist in studies of gene expressionregulation. "Given the androgen receptor link, we're now trying to identify the downstream target genes, as well as its role in prostate cancer," he said. "Theoretically, this protein is a very important tool for gene expression studies. Practically, it provides a potential target for prostate cancer because of its enzymatic activity. And it is enzymatic activity that's the favorite target of drug development."

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Theresa Strong


Theresa V. Strong, Ph.D., received a B.S. from Rutgers University and a Ph.D. in Medical Genetics from the University of Alabama at Birmingham (UAB). After postdoctoral studies with Dr. Francis Collins at the University of Michigan, she joined the UAB faculty, leading a research lab focused on gene therapy for cancer and directing UAB’s Vector Production Facility. Theresa is one of the founding members of FPWR and has directed FPWR’s grant program since its inception. In 2016, she transitioned to a full-time position as Director of Research Programs at FPWR. She remains an Adjunct Professor in the Department of Genetics at UAB. She and her husband Jim have four children, including a son with PWS.

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