CeMM identifies fundamental gene silencing mechanism

Scientists in the research group of Denise Barlow at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences have identified a fundamental gene silencing mechanism that depends only on the transcription of unusual long non-coding RNAs ('lncRNAs' for short). LncRNAs, which do not code for proteins are some of the most abundant transcripts in a human cell and are thought to control the activity of protein-coding genes. Florian Pauler (together with past group members Martha Koerner and Paulina Latos) in the team of Denise Barlow, took a risky approach of testing if the lncRNA abundant transcript was needed at all to silence an overlapped protein-coding gene. Their results (published on December 14, 2012 in Science), which show that only transcription is needed for silencing, while the abundant lncRNA transcript is an unused byproduct, are a wake-up call for the non-coding RNA community.

The investigation focused on the way that the IGF2 receptor (IGF2R) is silenced by expression of a lncRNA. IGF2R is a scavenging receptor for the IGF2 growth hormone and by reducing its circulating levels, works as both an embryonic growth repressor in mice and a tumor suppressor gene in some human cancers. Denise Barlow’s early work identified that IGF2R is only expressed from a maternally inherited chromosome in mice, making it the first identified imprinted gene (Barlow et al. 1991, Nature). How IGF2R is silenced on a paternally inherited chromosome became the focus of Denise Barlow’s work since this time and proven to be a discovery model for epigenetic gene regulatory mechanisms that act independent of the DNA sequence. One early major surprise was that at the heart of the process that represses IGF2R is an unusual transcript: a long non-protein-coding RNA (lncRNA) that overlaps the IGF2R gene promoter in antisense orientation and is therefore called Airn (Antisense Igf2r Noncoding RNA) (Sleutels et al. 2002, Nature).

In a recent article published in the journal “Science”, the Barlow lab reports that only Airn transcription is needed for silencing the IGF2R gene on the paternally inherited chromosome, while the abundant lncRNA transcript is a dispensable unused byproduct. LncRNAs are now accepted as the largest class of transcripts in humans and mice, with a suggested function of regulating the activity of protein-coding genes in different tissues. It had, however, been expected that the lncRNA transcript or product would be important for its function. Airn is the first lncRNA where the act of transcription was convincingly shown to be the regulatory mechanism. But why did it take so long - more than ten years from the discovery of Airn in the Barlow lab – to reveal its mechanism of action? Denise Barlow explains this by using a train analogy: “We behaved like aliens that looked down to earth and saw a large amount of smoke coming from a steam train. The train is here the polymerase that produces the Airn lncRNA - 'the smoke'. Because of the large amount of smoke we thought this must be the important thing and it took a long time with many small steps and publications to realize we went in the wrong direction.” It needed a change in thinking, spearheaded again by the Barlow lab and involving Florian Pauler, one of the main authors on this current publication, to propose a model where the Airn train works by kicking off the Igf2r train, independent of the smoke (first explained in Pauler et al. 2007, TIG). This model (see cartoon) was the basic foundation that allowed the design of the experiments that lead to this current landmark discovery.

Very large numbers of lncRNAs have been discovered recently in the mouse and human genome and many lncRNAs are found to be deregulated in cancer where they have been suggested to act as drivers of disease progression or to provide useful biomarkers for staging disease. In close collaboration with the groups of Christoph Bock and Robert Kralovics (both CeMM Principal Investigators), a team of Florian Pauler, Philipp Guenzl and Alexandra Kornienko in the Barlow group, is using high-throughput RNA sequencing (so called RNA-seq) to identify lncRNAs in normal human blood cells and chart their expression changes during cancer progression. In this context the discovery that the act of transcription plays a central role in silencing protein-coding genes will be very important to plan strategies that could abolish their silencing effects on protein-coding genes.

This study was supported by CeMM and the OeAW and in part by the Austrian Science Fund FWF F4302-B09 and W1207-B09 and Genome Research in Austria GEN-AU 820980.

Publication: Airn Transcriptional Overlap, but Not Its lncRNA Products, Induces Imprinted Igf2r Silencing by Paulina A. Latos,1*† Florian M. Pauler,1*‡ Martha V. Koerner,1*§ H. Başak Şenergin,1 Quanah J. Hudson,1 Roman R. Stocsits,2 Wolfgang Allhoff,1 Stefan H. Stricker,1|| Ruth M. Klement,1 Katarzyna E. Warczok,1 Karin Aumayr,2 Pawel Pasierbek,3 Denise P. Barlow1‡
(30 July 2012; accepted 25 October 2012, 10.1126/science.1228110)

1CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090 Vienna, Austria.
2Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, 1030 Vienna, Austria.
3Institute of Molecular Biotechnology, Dr. Bohr-Gasse 3, 1030 Vienna, Austria.
*These authors contributed equally to this work.
†Present address: Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
‡To whom correspondence should be addressed. E-mail: dbarlow(at)cemm.oeaw.ac.at (D.P.B.); fpauler(at)cemm.oeaw.ac.at (F.M.P.)
§Present address: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, UK.
||Present address: UCL Cancer Institute, University College London, London WC1E 6DD, UK.

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