Chromatin remodeling and gene regulation in simple eukaryotes
Co-workers: Dr Françoise Howe, Ms Anitha Nair, Mr Harry Fischl, Ms Ronja Woloszczuk,
Ms Nicola Hall, Dr Struan Murray, Ms Karolina Chocian, Mr Jack Feltham, Mr Thomas Brown and Mr Alberto Merchante Gonzalez
Controlled access to the information stored in our DNA genomes is mediated in part by our epigenome; the layer of information that influences events on the DNA without altering the DNA sequence. Epigenetic control of gene expression occurs in three main ways; by non-coding RNAs, by methylation of CG dinucleotides in DNA and through various reversible covalent modifications to histone proteins. Defects in epigenetic control processes make a significant contribution to age-related diseases and a global effort is underway to decipher the epigenetic code and to understand how it influences gene expression.
My group uses the budding yeast Saccharomyces cerevisiae and the nematode worm, Caenhorrhabitis elegans as model organisms in which to study how non-coding RNAs,
higher order structures in chromatin, and histone modifications influence the response to changes in nutrient availability and ageing. Caloric restriction is known to increase lifespan in a wide range of organisms including yeast and may ameliorate the effects of age-related diseases but the mechanism involved are poorly understood. Yeast and worms offer a powerful tool for dissecting the pathways that allow cells to switch from active growth into a long-lived quiescent state. We use 3C analysis, RNA-FISH, ChIP-seq, RNA-seq, nascent transcript mapping and most standard wet techniques.
Nguyen T, Fischl H, Howe FS, Woloszczuk R, Serra Barros A, Xu Z, Brown D, Murray SC, Haenni S, Halstead JM, O'Connor L, Shipkovenska G, Steinmetz LM, Mellor J.
Transcription mediated insulation and interference direct gene cluster expression switches.
Elife. 2014 Nov 19;3:e03635. doi: 10.7554/eLife.03635. PMID:25407679
Howe FS, Boubriak I, Sale MJ, Nair A, Clynes D, Grijzenhout A, Murray SC, Woloszczuk R, Mellor J.
Lysine acetylation controls local protein conformation by influencing proline isomerization.
Mol Cell. 2014 Sep 4;55(5):733-44. doi: 10.1016/j.molcel.2014.07.004. Epub 2014 Aug 7. PMID:25127513
Murray SC, Serra Barros A, Brown DA, Dudek P, Ayling J, Mellor J.
A pre-initiation complex at the 3'-end of genes drives antisense transcription independent of divergent sense transcription.
Nucleic Acids Res. 2012 Mar;40(6):2432-44. doi: 10.1093/nar/gkr1121. Epub 2011 Nov 28. PMID:22123739
Gkikopoulos T, Schofield P, Singh V, Pinskaya M, Mellor J, Smolle M, Workman JL, Barton GJ, Owen-Hughes T.
A role for Snf2-related nucleosome-spacing enzymes in genome-wide nucleosome organization.
Science. 2011 Sep 23;333(6050):1758-60. doi: 10.1126/science.1206097. PMID:21940898
Figure 3: Pervasive Transcription of Eukaryotic Genomes: Screenshots from the integrated genome viewer (IGV) of examples of nucleotide resolution and strand-specific nascent transcription. Native Elongating Transcript sequencing (NET-seq) (taken from Nguyen et al. Transcription mediated insulation and interference direct gene cluster expression switches. Elife 3: 2014), and mammalian NET-seq (Nojima et al. Mammalian NET-Seq Reveals Genome-wide Nascent Transcription Coupled to RNA Processing. Cell 2015 161(3): 526–540) involve immunoprecipitating elongating RNA polymerase II and sequencing the 3'OH of the nascent transcript. Precision run-on sequencing (PRO-seq) requires the incorporation of a biotin labelled UTP into elongating transcripts (Kwak et al. Precise maps of RNA polymerase reveal how promoters direct initiation and pausing. Science 2013 339:950-3). The figure shows NET-seq in a region around SUT300 in S.cerevisiae (top), PRO-seq for a region around CG3224 in D.melanogaster S2 cells (middle), and mNET-seq around the SIK1 gene from HeLa cells (bottom). C is the Crick strand and W is the Watson strand of DNA. Note the extensive antisense transcription, transcription over promoters and between genes in all three examples.
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