Control of gene expression in eukaryotes
Co-workers: Harry Fischl, Radhika Patel, Alastair Louey, Zhiqiao Wang,
In order for a cell to survive and fulfil its role in a particular tissue, it needs to activate and express a particular combination of all the genes that are present in the DNA. The activation of genes is a highly important, tightly controlled process and aberrant expression of genes is a hallmark of cancer and other disease phenotypes. The control of gene expression occurs at multiple stages including epigenetics, transcription, pre-mRNA processing, mRNA translation and post-translational events. When genes are expressed the information that resides in the DNA is copied or transcribed into a pre-mRNA molecule. In order for this primary transcript to serve as a blueprint for protein production in the cytoplasm this initial pre-mRNA needs to be modified or matured by pre-mRNA processing reactions.
In my lab we are interested in the contribution that these pre-mRNA processing reactions make towards the control of gene expression. In particular we are focussing on a process called cleavage and polyadenylation which is responsible to create the mature 3’ends of all protein encoding transcripts. It has recently become clear that from most human genes multiple mRNA isoforms can be produced that only differ in where the 3’end of the mRNA is formed.
This is achieved by a process that we call alternative cleavage and polyadenylation (APA). This process, by selecting different end points in the pre-mRNA, creates mRNA isoforms that code for an identical protein but may differ in how much protein from each isoform can be made. By modulating the ratios between such mRNA isoforms, APA can significantly impact on how much protein is essentially produced from a particular gene. Importantly, many recent studies have shown that this process is linked to the regulation of gene expression during cellular differentiation and growth. In addition, aberrant cleavage and polyadenylation has been linked to several disease phenotypes and cancers.
We use next generation sequencing approaches combined with classic molecular biology methods to establish how cleavage and polyadenylation and APA contributes to the establishment of tissue and cell specific mRNA isoform profiles. We are particularly interested to identify genes that are subjected to APA and are associated with neurodegenerative and other disease phenotypes.
- Harry Fischl, Françoise S. Howe, Andre Furger and Jane Mellor. Paf1 has distinct roles in transcription elongation and differential transcript fate. Molecular Cell. 2017 Jan 31. doi: 10.1016/j.molcel.2017.01.006.
- Jonathan Neve, Kaspar Burger, Wencheng Li, Mainul Hoque, Radhika Patel, Bin Tian, Monika Gullerova and Andre Furger. Subcellular RNA profiling links splicing and nuclear DICER1 to alternative cleavage and polyadenylation. Genome Research, 2016 Jan;26(1):24-35.
- Silva N, Ferrandiz N, Barroso C, Tognetti S, Lightfoot J, Telecan O, Encheva V, Faull P, Hanni S, Furger A, Snijders AP, Speck C, Martinez-Perez E. The Fidelity of Synaptonemal Complex Assembly Is Regulated by a Signaling Mechanism that Controls Early Meiotic Progression. Dev Cell. 2014 Nov 24;31(4):503-11.
- Neve J, Furger A.Alternative polyadenylation: less than meets the eye? Biochem Soc Trans. 2014 Aug;42(4):1190-5
- Ralf Eberhard; Lilli Stergiou; Randal E Hofmann; Jennifer Hofmann; Simon Haenni; André Furger; Michael O Hengartner. Ribosome synthesis and MAPK activity determine irradiation-induced germ cell apoptosis in C. elegans. PLOS Genetics, 2013 Nov;9(11)
- Simon Haenni, Zhe Ji, Nigel Rust, Helen Sharpe, Ralf Eberhard, Cathy Browne, Michael O. Hengartner, Jane Mellor, Bin Tian and André Furger. Analysis of Caenorhabditis elegans intestinal nuclear gene expression using fluorescence-activated nuclei sorting (FANS). Nucleic Acids Res. 2012 Jul;40(13):6304-18
- Dalziel M, Kolesnichenko M, das Neves RP, Iborra F, Goding C and Furger A. a-MSH regulates intergenic splicing of MC1R and TUBB3 in human melanocytes. Nucleic Acids Res. 2011 Mar;39(6):2378-92.
- Nuno Miguel Nunes, Wencheng Li, Bin Tian and André Furger. A functional human Poly(A) site requires only a potent DSE and an A-rich upstream sequence. EMBO J., 2010 May 5;29(9):1523-36.
Figure 1: Expression of chimera MC1R-TUbb3 receptors, the melanocortin 1 receptor (MC1R) is involved in UV induced skin tanning and tubulin beta three a member of the tubulin protein family. The fusion proteins pE_Iso1 and 2 are created by a process called intergenic splicing which is an extreme form of alternative splicing and allows to combine the genetic information of two different adjacent genes. This process is controlled by the usage of the unusual poly(A) signal present at the end of the MC1R gene.
Figure 2: Genome Browser screen shot of an RNAseq experiment to identify alternatively cleaved and polyadenylated mRNA isoforms that differ in their nuclear cytoplasmic distribution. For the TNPO1 transcripts, the isoform with the long 3'UTR is restricted to the nucleus. These type of experiments allow us to determine the physiological consequences of alternative cleavage and polyadenylation on a transcriptome wide level.
Graduate Student and Postdoctoral Positions: Enquiries with CV welcome
Graduate funding: The Oxford-Percival Stanion Graduate Scholarship