Ruth Williams, PhD - Writer & Journalist: Science, Medicine, Health, Travel

ruth williams, science writer & journalist

Transcription and the territory: the ins and outs of gene positioning.
June 2003. abstract. pdf. web site.

When cells exit mitosis, the neat rod-like chromosomes decondense into their interphase state. However, the chromatin threads are not randomly dispersed throughout the nucleoplasm. Rather, individual chromosomes appear to be organized into discrete, non-overlapping 'territories'. Current studies attempt to unravel how gene loci are organized within these territories, whether their subterritorial positions are dependent on transcription, and the extent to which the loci can move.

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Chromosomes: positions please!
May 2003. abstract. pdf. web site.

Chromosome organization in the interphase nucleus is largely regarded to be non-random. However, the exact nature of this non-randomness and the mechanism for conveying positional information to daughter nuclei is a subject of intense debate, as two recent studies reveal.

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Neural induction promotes large-scale chromatin reorganisation of the Mash1 locus.
21 December 2005. abstract. pdf. web site.

Determining how genes are epigenetically regulated to ensure their correct spatial and temporal expression during development is key to our understanding of cell lineage commitment. Here we examined epigenetic changes at an important proneural regulator gene Mash1 (Ascl1), as embryonic stem (ES) cells commit to the neural lineage. In ES cells where the Mash1 gene is transcriptionally repressed, the locus replicated late in S phase and was preferentially positioned at the nuclear periphery with other late-replicating genes (Neurod, Sprr2a). This peripheral location was coupled with low levels of histone H3K9 acetylation at the Mash1 promoter and enhanced H3K27 methylation but surprisingly location was not affected by removal of the Ezh2/Eed HMTase complex or several other chromatin-silencing candidates (G9a, SuV39h-1, Dnmt-1, Dnmt-3a and Dnmt-3b). Upon neural induction however, Mash1 transcription was upregulated (>100-fold), switched its time of replication from late to early in S phase and relocated towards the interior of the nucleus. This spatial repositioning was selective for neural commitment because Mash1 was peripheral in ES-derived mesoderm and other non-neural cell types. A bidirectional analysis of replication timing across a 2 Mb region flanking the Mash1 locus showed that chromatin changes were focused at Mash1. These results suggest that Mash1 is regulated by changes in chromatin structure and location and implicate the nuclear periphery as an important environment for maintaining the undifferentiated state of ES cells.

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Full list of research publications:

Roessler, S., Gyory, I., Imhof, S., Spivakov, M., Williams, R. R. E., Busslinger, M., Fisher, A. G., Grosschedl, R. Distinct promoters mediate the regulation of Ebf1 gene expression by interleukin-7 and Pax5. Mol. Cell. Biol. 27 (2), p579-594 (2007).

Williams, R. R. E., Azuara, V., Perry, P., Sauer, S., Dvorkina, M., Jorgensen, H., Roix, J., McQueen, P., Misteli, T., Merkenschlager, M., Fisher, A. G. Neural induction promotes large-scale chromatin reorganisation of the Mash1 locus. Jour. Cell Sci. 119 (1), p132-140 (2006).

Mirza, G., Williams, R. R. E., Mohammed, S., Clark, R., Newbury-Ecob, R., Baldinger, S., Flinter, F., Ragoussis, J. Refined Genotype-Phenotype Correlations in Cases of Chromosome 6p Deletion Syndromes. Eur. J. Hum. Genet. 12, p718-728 (2004).

Baxter, J., Sauer, S., Peters, A. H. F. M., John, R., Williams, R. R. E., Caparros, M-L., Arney, K., Otte, A., Jenuvein, T., Merkenschlager, M., Fisher, A. G. Histone hypomethylation is an indicator of epigenetic plasticity in quiescent lymphocytes. EMBO, 23, p4462-4472 (2004).

Williams, R. R. E. Transcription and the Territory: The Ins and Outs of Gene Positioning. Trends Genet. 19, p298-302 (2003).

Williams, R. R. E., Fisher, A. G. Chromosomes, Positions Please! Nat. Cell Biol. 5, p388-390. (2003).

Azuara, V., Brown, K.E., Williams, R. R. E., Webb, N., Dillon, N., Festenstein, R., Buckle, V., Merkenschlager, M., Fisher, A. G. Heritable Gene Silencing in Lymphocytes Delays Sister Chromatid Resolution Without Affecting the Timing of DNA Replication. Nat. Cell Biol. 5, p668-674 (2003).

Williams, R. R. E., Broad, S., Sheer, D., Ragoussis, J. Sub-chromosomal Positioning of the Epidermal Differentiation Complex (EDC) in Keratinocyte and Lymphoblast Interphase Nuclei. Exp. Cell Res. 272, p163-175 (2002).

Williams, R. R. E. Molecular and Cytogenetic analysis of Transcription Control. PhD Thesis, University of London (2002).

Talukder, A. H., Bagheri-Yarmand, R., Williams, R. R. E., Ragoussis, J., Kumar, R., Raz, A. Anti-HER2 Antihuman Epidermal Growth Factor Receptor 2 Antibody Herceptin Inhibits Autocrine Motility Factor Expression and Potentiates Anti-tumor Effects of AMF Inhibitors. Clin. Cancer Res. 8, p3285-3289 (2002).

Williams, R. R. E., Hassan-Walker, A, Lavender, F. L., Morgan, M., Faik, P., Ragoussis, J. The Minisatellite of the GPI/AMF/NLK/MF gene: interspecies conservation and transcriptional activity. Gene, 269, p81-92 (2001).