CeMM Principal Investigator
Honorary Professor of Genetics
University of Vienna
Denise P. Barlow
(*31.1.1950 - ✝21.10.2017)
Epigenetic Mechanisms in Development & Disease
Genomic imprinting occurs when the expression of a gene is restricted to one of the two parental chromosomes in a diploid cell. Since the discovery of Denise Barlow and her team in 1991 of the first imprinted gene in mammals to show parental-specific gene expression and our later finding that long non-protein-coding (lnc) RNAs mediate imprinted gene silencing, the group has been interested in understanding the epigenetic mechanisms controlling imprinting during development, and how they contribute to diseases such as cancer.
They were particularly interested in how lncRNAs act throughout the mouse and human genome as regulators of gene expression and used cell-based models of genomic imprinting, and mouse models, as well as high-throughput sequencing technology to extend the results to human diseases.
Molecular mechanisms underlying gene regulation by long non-coding RNAs
Genomic imprinting is a premier example of epigenetics (i.e., heritable changes in gene activity that are not encoded in the DNA). The study of imprinted genes has uncovered many unpredictable findings about what controls the on/off state of a gene. The group investigated the molecular mechanism by which lncRNAs silence imprinted genes. To do this, they used genetic approaches in a mouse embryonic stem (ES) cell model that they developed, which allowed them to manipulate lncRNA expression, and knockout mice.
Recent work led to the discovery that a special class of lncRNAs is able to silence imprinted genes by the act of their transcription. It is known that other lncRNAs work via alternative mechanisms, and they were also studying those using similar techniques.
Long non-coding RNAs and disease
The team of Denise Barlow has developed an optimized RNA-Seq pipeline incorporating high-throughput sequencing (one of CeMM ' s core technologies) and bioinformatics to efficiently identify macro lncRNAs. They applied this approach to identify lncRNAs expressed in inbred mouse tissues for our mechanistic studies. In order to study the role of lncRNAs in disease, we were using a pipeline in human white bloods cells to analyse how lncRNAs influence gene expression changes that arise in hematological malignancies such as leukemia, which may lead to the identification of new disease biomarkers and ultimately form a basis for treatment approaches.
Denise Barlow trained as a State Registered Nurse in the UK before completing her PhD at Warwick University, and postdoctoral studies in ICRF, London, and EMBL, Heidelberg. She then held group leader positions at the IMP (Vienna), the NKI (Amsterdam) and the IMB institute (Salzburg). She joined CeMM in 2003 and retired in 2015. Denise died aged 67, on October 21st, 2017. (Obituary)
Latos PA, Pauler FM, Koerner MV, Şenergin HB, Hudson QJ, Stocsits RR, Allhoff W, Stricker SH, Klement RM, Warczok KE, Aumayr K, Pasierbek P, Barlow DP. Airn transcriptional overlap, but not its lncRNA products, induces imprinted Igf2r silencing. Science. 2012 Dec 14;338(6113):1469-72.. (abstract)
Koerner MV, Pauler FM, Hudson QJ, Santoro F, Sawicka A, Guenzl PM, Stricker SH, Schichl YM, Latos PA, Klement RM, Warczok KE, Wojciechowski J, Seiser C, Kralovics R, Barlow DP. A downstream CpG island controls transcript initiation and elongation and the methylation state of the imprinted Airn macro ncRNA promoter. PLoS Genet. 2012;8(3):e1002540. (abstract)
Pauler FM, Barlow DP, Hudson QJ. Mechanisms of long range silencing by imprinted macro non-coding RNAs. Curr Opin Genet Dev. 2012 Jun;22(3):283-9. (abstract)