Genome Folding and Regulation of Gene Expression

My research investigates how the genome is folded and organised in the nucleus and how this organisation influences regulation of gene expression.  We often think about transcription as occurring on a particular gene in a linear manner whereas the nucleus is a three dimension organelle into which the genome is folded and organised.  Recent work has shown that all transcription occurs at discreet compartments within the nucleus, termed transcription factories, with genes moving in and out of these compartments as they are expressed and silenced.  Furthermore, distal enhancers have been shown to physically contact the genes they regulate forming tissue-specific chromatin loops.  My lab uses a combination of Molecular Biology and Cellular Imaging Techniques combined with genome-wide approaches and bioinformatics analysis to investigate the mechanisms that underlie tissue-specific regulation of gene expression and genome folding.

Selected Publications:

JA Mitchell, I Clay, D Umlauf, CY Chen, CA Moir, CH Eskiw, S Schoenfelder, L Chakalova, T Nanano, and P Fraser. Nuclear RNA sequencing of the mouse erythroid cell transcriptome (PLOS ONE in press).

S Davidson, NN Macpherson, and JA Mitchell. Nuclear organisation of RNA polymerase II transcription (The Biochemistry and Cell Biology Journal in press). 

T Sexton, S Kurukuti, JA Mitchell, D Umlauf, T Nagano and P Fraser. Sensitive detection of chromatin co-associations using enhanced chromosome conformation capture on chip. Nat Protoc 2012 Jun 21; 7(7): 1335-50.

CY Chen, Q Morris and JA Mitchell, Enhancer identification in mouse embryonic stem cells using integrative modelling of chromatin and genomic features.  BMC Genomics 2012, 13:152.

S Schoenfelder, T Sexton, L Chakalova, NF Cope, A Horton, S Andrews, S Kurukuti, JA Mitchell, D Umlauf, DS Dimitrova, CH Eskiw, Y Luo, CL Wei, Y Ruan, JJ Bieker and P Fraser, Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells. Nature Genetics. 2010, 42(1):53-61

T Nagano, JA Mitchell, LA Sanz, FM Pauler, AC Ferguson-Smith, R Feil and P Fraser. The Air non-coding RNA epigenetically silences transcription by targeting G9a to chromatin. Science. 2008, 322(5908): 1717-20.

JA Mitchell and P Fraser. Transcription factories are nuclear sub-compartments that remain in the absence of transcription. Genes Dev. 2008, 22(1): 20-5.

J Miles, JA Mitchell, L Chakalova, B Goyenechea, CS Osborne, L O'Neill, K Tanimoto, JD Engel, P Fraser. Intergenic Transcription, Cell-Cycle and the Developmentally Regulated Epigenetic Profile of the Human Beta-Globin Locus. PLoS ONE, 2007, 2(7): e630.

CS Osborne, L Chakalova, JA Mitchell, A Horton, AL Wood, DJ Bolland, AE Corcoran and P Fraser.  Myc Dynamically and Preferentially Relocates to a Transcription Factory Occupied by Igh. PLoS Biol. 2007 5(8):e192.

L Chakalova, E Debrand, JA Mitchell, CS Osborne, and P Fraser, Replication and Transcription: Shaping the Landscape of the Genome. Nat Rev Genet, 2005, 6(9): 669-77.

JA Mitchell and SJ Lye, Differential Activation of the Connexin 43 Promoter by Dimers of Activator Protein-1 Transcription Factors in Myometrial Cells. Endocrinology, 2005, 146(4): 2048-54.

CS Osborne, L Chakalova, KE Brown, D Carter, A Horton, E Debrand, B Goyenechea, JA Mitchell, S Lopes, W Reik and P Fraser, Active genes dynamically co-localise to shared sites of ongoing transcription. Nat Genet, 2004, 36 (10): 1065-1071.

JA Mitchell, O Shynlova B Lowell Langille and SJ Lye, Mechanical Stretch and Progesterone Differentially Regulate Activator Protein-1 Transcription Factors in Primary Rat Myometrial Smooth Muscle Cells.  Am J of Physiol: Endocrinol Metab, 2004, 287: E439-E445.

JA Mitchell, and SJ Lye, Differential Expression of Activator Protein-1 Transcription Factors in Pregnant Rat Myometrium.  Biol Reprod, 2002, 67 (1): 240-246.