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Cancer Research UK Cambridge Institute

 

Evolution of transcriptional regulation

In the last five years, our lab has shown that relationships between transcription factor functionality and conservation of transcription factor binding in vertebrates are complex and difficult to predict (Ballester et al., 2014; Schmidt et al., 2010b; Stefflova et al., 2013). Previously we have shown that DNA sequence variation is the ultimate driver of regulatory evolution by using an existing mouse model of Down’s syndrome carrying human chromosome 21 to place human genetic sequence into mouse diet, lifestyle, epigenetic machineries, developmental processes, and nuclear concentration of transcription factors (Wilson et al., 2008). Our more recent exploration using the Tc1 mouse has afforded insight into the co-evolution of species-specific repeats and the control mechanisms to restrain them (Ward et al., 2013). Our laboratory has recently reported the first large-scale analysis of mammalian enhancer evolution using functional genomics approaches to profile regulatory activity in tissues from twenty species of mammals (Villar et al., 2015).

Non-coding RNAs – tRNAs and lncRNAs

Our work has broadened our understanding of the evolution and control of the noncoding genome. For example, by investigating how RNA polymerase III controls tRNAs in multiple mammals, we have discovered that the polymerases responsible for gene expression appear to be under constraint at the level of their transcripts (Kutter et al., 2011), the mechanisms for which we are continuing to investigate (Schmitt et al., 2014). In addition, our work has shown how the rapid birth and death of lncRNAs strongly influences transcription of nearby genes (Kutter et al., 2012). Alongside this, we have recently shown that the nuclear lncRNA GNG12-AS1 regulates the tumour suppressor DIRAS3 but also independently has an effect on MET signalling and cell migration (Stojic et al., 2015).

CTCF and Cohesin

We have also explored how repetitive element expansions have been actively remodelling the genomes of most mammalian lineages for hundreds of millions of years by carrying CTCF binding into tens of thousands of new locations (Schmidt et al., 2012), and what genomic features dictate the conservation of CTCF binding in primates (Schwalie et al., 2013). In addition, we have explored how TF binding evolution and gene expression appear to be evolutionarily decoupled (Wong et al., 2015) and the roles that cohesin can play in connecting TF binding in enhancers with their target proximal promoters (Faure et al., 2012; Merkenschlager and Odom, 2013; Schmidt et al., 2010a).

Mechanisms connecting transcription and cancer

Our lab is currently undertaking a systematic, large-scale project to dissect how tissue-specific regulatory networks and epigenetics help guide the evolution of liver cancer.