Dr. Grzechnik’s lab is interested in uncovering the biological mechanisms underlying PWS. The deletion in the PWS locus affects the regulation of gene expression in neurons, but scientists are not exactly sure how this mechanism works. This current project is testing how coding and non-coding regions of the human genome are transcribed in cells lacking specific PWS-related non-coding RNAs, which will help to identify regulators of gene expression in PWS.
Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.
This grant was funded in part by FPWR-UK.
This project aims to uncover the biological mechanisms underlying Prader-Willi syndrome (PWS) which is the most common syndromic cause of life-threatening obesity in humans. My goal is to pinpoint genetic elements missing in PWS that are required for normal functioning of neuronal cells. Development and maintenance of neurons are dictated by a specific gene expression pattern where information encoded in DNA is transcribed to coding mRNAs which are used as templates for protein synthesis. This simple chain is controlled by a sophisticated network of regulatory factors, proteins and non-coding RNAs (ncRNAs). The deletion in locus q11-13 of chromosome 15 (PWS locus) affects the regulation of gene expression in neurons and manifests as PWS, but the exact mechanism is not known. The deleted fragment harbours small nucleolar RNAs (snoRNAs) which have been assumed as major players in neuronal development. However, despite extensive studies, there is no clear indication of how these snoRNAs may regulate gene expression. Recent research uncovered that PWS-associated snoRNAs can be also included into two different long non-coding RNAs (lncRNAs) and form so-called sno-lncRNAs or SPA-lncRNAs. Owing to snoRNAs secondary structures and association with proteins, such snoRNA-lncRNA hybrids are protected from degradation. These lncRNAs have the potential to sequester factors that control mRNA synthesis and therefore, gene expression.
Dr. Grzechnik will investigate roles in RNA transcription for particular ncRNA classes transcribed from the PWS locus. For the first time in PWS research, I will test how coding and non-coding regions of the human genome are transcribed in cells lacking specific PWS-related ncRNAs.
Understanding ncRNA functions in PWS will prove fundamental for future therapeutic approaches. Here, I will identify PWS-associated bona fide regulators of gene expression. This will allow the identification of the defective cellular pathways that are the primary source for the global deregulation of gene expression that triggers PWS.
This project can be developed further. Identification of the regulatory ncRNAs will be the first step to understand their functions. Additional experiments may uncover various roles of these ncRNAs during different stage of neurodevelopment. Also, experimental work is needed to assess how to rescue defective transcriptional pathways in affected cells.
The outcomes of this project will not result in the immediate therapeutic approach. However, they will be absolutely essential to lay a foundation for future gene therapies and will have a clinical effect within the next 10-15 years. The impact of this research can be described by paraphrasing Edward Teller’s quote – “The science of today is the medicine of tomorrow”.
Pawel Grzechnik, PhD
University of Birmingham