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Archive - Jan 7, 2018


Penn Study on Super-Silenced DNA Hints at New Ways to Reprogram Cells

Newly described stretches of super-silenced DNA reveal a fresh approach to reprogram cell identity to use in regenerative medicine studies and one day in the clinic, according to a study published in the December 21, 2017 issue of Molecular Cell by investigators from the Perelman School of Medicine at the University of Pennsylvania. The study is titled “Genomic and Proteomic Resolution of Heterochromatin and Its Restriction of Alternate Fate Genes.” "In the past, most labs, including my own, used gene activators to turn on a new program to change the identity in a given cell," said senior author Ken Zaret, PhD, Director of the Penn Institute for Regenerative Medicine and a Professor of Cell and Developmental Biology. "Our study shows that in some cases we will need to disassemble a cell's gene repression machinery to activate important genes to reprogram a cell's identity." The team attempted to reprogram skin cells to make new liver cells. Conversions of one cell type to another usually have low efficiencies, and this study identifies one reason why. The long-term goal of this preclinical research is to be able to replenish diseased liver tissue with healthy tissue derived from a different tissue, such as skin cells, from the same individual in a process called direct-cell reprogramming. The Zaret lab untangled an extreme form of gene silencing, opening up regions of tightly wound DNA that is difficult for activators to reach to turn on certain genes. The researchers found the regions by characterizing an increase in chemical cross-linking due to DNA being more compacted in the scaffolding of repressed regions of chromosomes. "Think of a piece of fishing line that has been used for a while, with several knots along its length," Dr. Zaret said.

Worm Species Lost 7,000 Genes After Evolving to Fertilize Itself; Genes for Sperm Competition Proteins Among Those Lost

Reproduction in most animal species requires breeding between two individuals. But some worms have evolved the ability to go it alone. In these species, a single individual can breed with itself to produce offspring. A new University of Maryland (UMD)-led study found that gaining this ability, known as "selfing," may have caused a worm species to lose a quarter of its genome, including genes that give male sperm a competitive edge during mating. "Our results suggest that genes that are essential for tens of millions of years can suddenly become useless or liabilities, even, when the sex system changes," said Eric Haag, PhD, a Professor of Biology at UMD and lead investigator of the study, which was published in the January 5, 2018 issue of Science. The article is titled “Rapid Genome Shrinkage in a Self-Fertile Nematode Reveals Sperm Competition Proteins.” A million years ago, a species of tiny worms called Caenorhabditis briggsae evolved the ability to breed via selfing. As a result, most C. briggsae are hermaphrodites with both male and female sex organs. Dr. Haag's group, which focuses on the evolution of sex, has long studied C. briggsae because of their unusual reproductive behavior. To study how selfing shaped the evolution of C. briggsae, Erich Schwarz, PhD, an Assistant Research Professor of Molecular Biology and Genetics at Cornell University and co-corresponding author of the study, sequenced the genome of Caenorhabditis nigoni, the closest relative of C. briggsae. C. nigoni always reproduce by mating with other individuals, or outcrossing. By comparing the genomes of the two species, the researchers found that the selfing C. briggsae worms had 7,000 fewer genes than C. nigoni. Over time, C. briggsae lost approximately a quarter of its genome.

Gene Therapy Restores Normal Blood Glucose Levels in Mice with Type 1 Diabetes

Type 1 diabetes is a chronic disease in which the immune system attacks and destroys insulin-producing beta cells in the pancreas, resulting in high blood levels of glucose. A study published in the January 4, 2018 of Cell Stem Cell demonstrates that a gene therapy approach can lead to the long-term survival of functional beta cells, as well as normal blood glucose levels for an extended period of time in mice with diabetes. The researchers used an adeno-associated viral (AAV) vector to deliver to the mouse pancreas two proteins, Pdx1 and MafA, which reprogrammed plentiful alpha cells into functional, insulin-producing beta cells. The article is titled "Endogenous Reprogramming of Alpha Cells into Beta Cells, Induced by Viral Gene Therapy, Reverses Autoimmune Diabetes." "This study is essentially the first description of a clinically translatable, simple single intervention in autoimmune diabetes that leads to normal blood sugars, and importantly with no immunosuppression," says senior study author George Gittes, MD, of the University of Pittsburgh School of Medicine. "A clinical trial in both type 1 and type 2 diabetics in the immediate foreseeable future is quite realistic, given the impressive nature of the reversal of the diabetes, along with the feasibility in patients to do AAV gene therapy." Approximately 9% of the world's adult population has diabetes, which can cause serious health problems such as heart disease, nerve damage, eye problems, and kidney disease. One fundamental goal of diabetes treatment is to preserve and restore functional beta cells, thereby replenishing levels of a hormone called insulin, which moves blood glucose into cells to fuel their energy needs.