Previously Thought to Serve No Purpose “Phantom Genes” Keep Diabetes at Bay

Artist Concept Phantom Genes

Artist concept phantom genes. New research now shows that one of these phantom genes is important for safeguarding our metabolism.

Unlike what we commonly refer to as ‘genes’, phantom genes or ‘Long noncoding RNA’ (LncRNAs) do not lead to the production of proteins that our cells, and thus our entire bodies are made of.

Previously, it was believed that LncRNAs served no major purpose in cells, but new research now shows that one of these LncRNAs termed ‘LincIRS2’ is important for safeguarding our metabolism as LincIRS2 loss favors the development of metabolic complications in mice.

“In my estimate, only the function of less than 100 of the nearly 60,000 LncRNAs encoded in our genomes has been truly understood,” says Jan-Wilhelm Kornfeld, Danish Diabetes Academy (DDA) professor for Molecular Biology of Metabolic Diseases at University of Southern Denmark.

In clear comparison, researchers have largely understood the function of the 20,344 genes that encode proteins.

“That’s why it’s so exciting that we were able to identify the key role of this particular LncRNA using mice as a model organism,” he says.

In addition, we were able to delineate a new, exciting mechanism for how LncRNAs themselves are controlled.

Editing mice with CRISPR

Using the ‘molecular scissor’ CRISPR/Cas9, Jan-Wilhelm Kornfelds research team succeeded in cutting out LincIRS2 from the mouse’s genome. Next, the researchers observed that mice lacking LincIRS2 developed metabolic complications like elevated blood sugar levels when the LncRNA had been deactivated. Conversely, when performing treatments that activate LincIRS2, mice maintained healthy blood sugar levels even when becoming obese.

It is difficult to predict exactly how this new knowledge can be used, but it is intriguing to speculate that restoring or inhibiting specific LncRNAs could be used to treat diabetic patients or other metabolic disorders one day, says Jan-Wilhelm Kornfeld.

His research team just published these new findings in the prestigious journal Nature Communications. The lead author of the article is Dr. Marta Pradas-Juni, who is a postdoc in Jan-Wilhelm Kornfelds’ research team.

Fact: What is a Long noncoding RNA?

DNA serves as blueprint for producing proteins that constitute the essential building blocks all cells are made of. The molecular intermediary that converts DNA information into proteins is called RNA. Thus, RNA’s primary purpose is to translate the ‘genes’ DNA into protein.

In our bodies, 20,344 different genes are specifically designed to create the many different proteins that our bodies require. The majority of these so-called protein-coding RNAs have been mapped by scientists. That is why we today largely understand exactly which proteins these RNAs give rise to.

However, nearly 60,000 RNAs called ‘Long noncoding RNAs’ are written into our genomes that never contribute to the formation of a protein. How they function, and how they are involved in disease development is largely unknown.

Jan-Wilhelm Kornfeld is DDA professor for Molecular Biology of Metabolic Diseases at the Department for Biochemistry and Molecular Biology at University of Southern Denmark. The research group of Jan-Wilhelm Kornfelds’ lab uses modern genomic techniques like next-generation sequencing and CRISPR/Cas9 mouse models to better understand the biology of LncRNAs in metabolic disease. Their goal is to define novel RNA-based approaches for the treatment of obesity and type 2 diabetes. Their research is supported by the European Research Council (ERC) and the Novo Nordisk Foundation.

Reference: “A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism” by Marta Pradas-Juni, Nils R. Hansmeier, Jenny C. Link, Elena Schmidt, Bjørk Ditlev Larsen, Paul Klemm, Nicola Meola, Hande Topel, Rute Loureiro, Ines Dhaouadi, Christoph A. Kiefer, Robin Schwarzer, Sajjad Khani, Matteo Oliverio, Motoharu Awazawa, Peter Frommolt, Joerg Heeren, Ludger Scheja, Markus Heine, Christoph Dieterich, Hildegard Büning, Ling Yang, Haiming Cao, Dario F. De Jesus, Rohit N. Kulkarni, Branko Zevnik, Simon E. Tröder, Uwe Knippschild, Peter A. Edwards, Richard G. Lee, Masayuki Yamamoto, Igor Ulitsky, Eduardo Fernandez-Rebollo, Thomas Q. de Aguiar Vallim and Jan-Wilhelm Kornfeld, 31 January 2020, Nature Communications.
DOI: 10.1038/s41467-020-14323-y

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