Selected Publications

• Hughes Jim R, Kowalczyk Monika S, Garrick David, Lynch Magnus D, Sharpe Jacqueline A, Sloane-Stanley Jacqueline A, McGowan Simon J, De Gobbi Marco, Hosseini Mona, Vernimmen Douglas, Brown Jill M, Gray Nicola E, Collavin Licio, Gibbons Richard J, Flint Jonathan, Taylor Stephen, Buckle Veronica J, Milne Thomas A, Wood William G, and Higgs Douglas R (2012) Intragenic enhancers act as alternative promoters. Mol Cell, 45(4):447-58.

• Lynch Magnus D, Smith Andrew JH, De Gobbi Marco, Flenley Maria, Hughes Jim R, Vernimmen Douglas, Ayyub Helena, Sharpe Jacqueline A, Sloane-Stanley Jacqueline A, Sutherland Linda, Meek Stephen, Burdon Tom, Gibbons Richard J, Garrick David, and Higgs Douglas R (2012) An interspecies analysis reveals a key role for unmethylated CpG dinucleotides in vertebrate Polycomb complex recruitment. EMBO J, 31(2):317-29.

• Law Martin J, Lower Karen M, Voon Hsiao PJ, Hughes Jim R, Garrick David, Viprakasit Vip, Mitson Matthew, De Gobbi Marco, Marra Marco, Morris Andrew, Abbott Aaron, Wilder Steven P, Taylor Stephen, Santos Guilherme M, Cross Joe, Ayyub Helena, Jones Steven, Ragoussis Jiannis, Rhodes Daniela, Dunham Ian, Higgs Douglas R, and Gibbons Richard J (2010) ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner. Cell, 143(3):367-78.

• Kassouf M T, Hughes J R, Taylor S, McGowan S J, Soneji S, Green A L, Vyas P, and Porcher C (2010) Genome-wide identification of TAL1's functional targets: Insights into its mechanisms of action in primary erythroid cells. Genome Res, 20(8):1064-83.

• De Gobbi Marco, Viprakasit Vip, Hughes Jim R, Fisher Chris, Buckle Veronica J, Ayyub Helena, Gibbons Richard J, Vernimmen Douglas, Yoshinaga Yuko, de Jong Pieter, Cheng Jan-Fang, Rubin Edward M, Wood William G, Bowden Don, and Higgs Douglas R (2006) A regulatory SNP causes a human genetic disease by creating a new transcriptional promoter. Science, 312(5777):1215-7.

Molecular biology and the biological sciences in general have undergone a technical revolution over the last decade, founded upon the ability to sequence and reconstruct an organism's genomic blueprint in its entirety. Subsequent technical advances such as expression or tiled genomic microarrays and now high-throughput sequencing technologies (HTS) allow us to investigate, on the scale of the whole genome, how and in what situations particular parts of that blueprint are actually used. Although the biological questions remain the same as those asked at an individual gene or genomic loci, the methods to generate, analyse and combine these whole-genome data-types are different and require specialist approaches and skills.

One of the most fundamental questions in molecular biology is how are specific parts of the genomic blueprint used in specific situations when the same underlying genomic sequence is used whether a cell becomes a neuronal cell or a blood cell. The most basic expression of a genome's activity is the RNA it produces or "expresses" as in the form of mRNA this will go on to determine which proteins are produced in the cell. It has also become clear that RNA which does not produce protein (non-coding or ncRNA) also has a vital and complex regulatory function within the genome.

One of the main research interests of the Genome Biology group is to study the processes that determine whether RNA is or is not produced from a genomic locus as cells develop into red blood cells (erythropoiesis) and which factors determine the rate at which it is produced. We employ most of the current genome-wide methods to determine which parts of the genome are being transcribed into RNA (RNA-seq), investigating both the stable fractions (mRNA) and raw output of the genome (nascent). We correlate this activity (transcription) with changes in the distribution and chemical modifications of the nucleosomal proteins associated with genomic DNA (DNase-seq and ChIP-seq) and which regulatory proteins (transcription factor ChIP-seq) are bound to the DNA, in an effort to determine how these changes regulate RNA expression.

Although we use many existing methodologies the group also develops novel assays where needed to fill many of the current deficiencies in our ability to assess genome behavior. We are at present trying to determine which parts of the surrounding genome are functionally required to regulate the transcription of a particular gene or transcript (cis-regulatory elements). This represents a fundamental lack in our current understanding of gene regulation and is a necessary step to a complete understanding of this process.

Due to the size and complexity of the datasets produced the group is heavily reliant on bioinformatics to analyse and correlate these data and has a lot of experience in using and developing these types of tools in its own right and as a strong collaboration with the Oxford Computational Biology Research Group (CBRG). The group is very collaborative in structure and works closely with other groups within the MHU department in particular and the WIMM as a whole. This efficient structure allows observations derived from genome-wide observations to be functionally tested in well-understood paradigms of gene regulation such as the α globin locus and facilitates the genome-wide analysis of concepts gained from the careful interrogation of the model loci.

The epigenetic and transcriptional landscape of the Nprl3 locus in mouse erythroid cells, which contains the regulatory elements of the α globin genes (MCS-R1-R1 and DHS-12)

Basic classification of all of the active elements (Dnase1 Hypersensitive Sites or DHS) in mouse erythroid cells (Ter119+) into enhancer (blue rectangle) and promoter elements (red rectangle) based on the relative enrichment of two chromatin-associated modifications (H3K4me1 and H3K4me3). All panels show different data types associated with these elements in the same sort order and shows the high levels of erythroid transcription factor binding (Gata1, Scl, Klf1 and Ldb1) associated with enhancer elements compared to promoter elements in these cells. This emphasizes the functional relevance of enhancer elements in gene regulation in Ter119+ cells.