Important steps toward reactivating the maternal allele in PWS: new study examines how drugs can regulate PWS/AS gene expression

One common question in the PWS community is “isn’t there a way to just ‘turn on’ the silent PWS genes on chromosome 15?” As a reminder, the PWS genes are present but silenced on the maternal (mom’s) chromosome 15 in all people with PWS, regardless of genetic subtype.

In theory, if you could ‘turn on’ those maternal PWS genes, you might be able to produce a therapeutic effect. There are a number of researchers working in this area and although simple as a basic concept, the mechanisms underlying this research are very complicated in practice. FPWR is fortunate to have funded several projects aimed at picking apart this question. The findings of one of those projects has just been published in the Proceedings of the National Academy of Sciences (Powell, 2013), and it investigates the molecular mechanisms by which drugs might be used to regulate/re-activate genes in the Angelman’s/PWS region. The study examines specific structures (R loops) made by genes in the PWS region and determines how the drug-DNA/RNA interactions influences expression of genes in the region. The findings advance the basic understanding of PWS genes regulation and also have potential therapeutic implications for both PWS and Angelman’s syndrome (AS).

The results show that there is crosstalk and cross-regulation between the imprinted PWS and AS regions of chromosome 15, which are closely linked and coordinately regulated. Specifically, in AS, the drug topotecan modulates expression of genes in the normal functioning PWS region, which in turn reactivates genes that are silenced in the Angelman’s region. Topotecan itself is not a potential therapeutic for PWS as it acts through the SNORD116 region, a portion of DNA that is either absent or not active in PWS. In addition, topotecan is historically used as a cancer therapeutic and slows/stops cell growth, a clear contra-indication for development as a treatment in children. Further, its effects on DNA are not specific to the AS/PWS region. Nonetheless, it has proven a good tool to begin to explore the possibility of drug-induced activation of AS/PWS genes.

Although “just turning on the maternal genes” may be quite a ways in the future, this work provides important advances in our basic understanding of gene regulation at this imprinted PWS/AS locus, and in how the chromosome is differentially regulated depending on whether it comes from the mother (maternal) or father (paternal). These studies lay important groundwork upon which to build as the research community moves forward in developing drugs or other genetic strategies targeted at reactivation of PWS genes.

In addition to the exciting and promising research results, this publication illustrates several goals and priorities of the FPWR grant program. First, this work was additionally supported by funds from large, multi-year NIH grants; grants that the investigators were awarded in part due to the preliminary results generated from the initial funds from FPWR. Importantly, this work is also the result of a new collaborative effort between two independently funded FPWR researchers. Dr. Janine LaSalle was awarded an FPWR grant in 2011 for the project “R-loop formation and chromatin decondensation at the PWS critical locus” and Dr. Frederic Chenin was awarded FPWR grants in 2008 and 2009 for his project “R Loop structures maintain epigenetic imprints at the Prader-Willi Imprinting Center”. Finally, a third FPWR-supported researcher, Dr. David Segal, is acknowledged as a critical reviewer of the paper. Dr. Segal is one of FPWR’s 2012 grant recipients for his work in the area of “Reactivation of maternally-silenced genes in PWS” and is looking at a different, gene-based strategy to accomplish the same goal. We look forward to seeing where these exciting collaborative efforts will take us in the future.

A press release from UC Davis also describes the paper and its implications.

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Topics: Research

Theresa Strong

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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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