Scientist. Colorectal cancer genetics. Equality, Diversity and Inclusion advocate. Horror aficionado. She/Her. Own views.
Edinburgh, City of Edinburgh
Joined February 2019
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Dr Vidya Rajasekaran-Sutherland retweeted
@Ce_recilla, @group_tomlinson, @HoulstonLab_ICR, @myantlab, Farhat Din, @mariytimofeeva, all greatly supervised by Malcolm Dunlop and @ccgg_edinburgh. Of course, thanks also to the donors, their families, and support from @CRUKresearch, @EdinCRC, @EdinUni_IGC!
Dr Vidya Rajasekaran-Sutherland retweeted
Plenty more in the paper, so do check it out! Huge thanks to all who contributed to this work: Claire Smillie, Kevin Donnelly, Marion Bacou, @EsiriBloom, Li-Yin Ooi, @AllanMorven, Marion Walker, Stuart Reid, @AMeynert, @bioggrimes, @BlackmurJames, @PVaughanShaw, Philip Law … 16/
Dr Vidya Rajasekaran-Sutherland retweeted
The function of tuft cells in the colon is not well characterised, and so understanding how these two phenomena are linked will be difficult, but key to providing potentially actionable insights into prevention of this morbid disease. /15
Dr Vidya Rajasekaran-Sutherland retweeted
Together, this study builds upon growing interest in Pou2af2 function in different contexts, and provides a body of evidence to indicate this gene as both causal of CRC risk and transcriptional regulation of colorectal tuft cells. 14/
Dr Vidya Rajasekaran-Sutherland retweeted
To cement the correlation between these phenotypes and tumourigenesis, we then crossed these single knockouts onto a tumourigenic background. What is really cool? We also find only Pou2af2 genotype to be associated with changes to survival and tumour burden. 13/
Dr Vidya Rajasekaran-Sutherland retweeted
Remarkably, we found expression and tuft cell abundance changes to be strikingly specific to Pou2af2 genotype. While consistent with the expression we saw at the single cell level, this now experimentally decouples the function of these genes in the colon. 12/
Dr Vidya Rajasekaran-Sutherland retweeted
For this, we went to mice. Initiated by @RubyTOsborn, we first validated mice as a reliable model of CRC-associated molecular phenotypes at 11q23.1, and then knocked out homologs of the cis-genes independently.
Dr Vidya Rajasekaran-Sutherland retweeted
To regroup: CRC risk-associated genetic variation at 11q23.1 is correlated with the expression of several cis- and trans-genes, as well as tuft cell loss. However, one thing we can’t disentangle yet – which (or which combination) of the cis-genes is governing this effect? 10/
Dr Vidya Rajasekaran-Sutherland retweeted
Dividing samples by 11q23.1 genotype, we found individuals with the risk genotype at 11q23.1 do indeed have a reduced number of tuft cells! Something we believe is a result of the complex transcriptional relationship laid out above. 9/
Dr Vidya Rajasekaran-Sutherland retweeted
So could reduced expression of these genes be indicative of tuft cell loss? Thanks to our clinicians, we got our hands on epithelial strips of normal colonic mucosa and devised a method of rolling these strips (videos in supp) to stain and count many cells in one go. 8/
Dr Vidya Rajasekaran-Sutherland retweeted
We used data for the former to show both POU2AF2 and POU2AF3 are capable of binding the trans-genes, in a way that overlaps with activating transcription marks. This could be a potential mechanism for the expression regulation. 7/
Dr Vidya Rajasekaran-Sutherland retweeted
But how could this locus cause such specific expression of distant genes? Well, recent work (nature.com/articles/s41586-0…) and (science.org/doi/10.1126/scii…) showed POU2AF2 and POU2AF3 encode proteins capable of transcriptional regulation…. 6/
Dr Vidya Rajasekaran-Sutherland retweeted
We replicate our previous findings (nature.com/articles/s41598-0…) showing many trans-genes are specifically expressed by a rare epithelial cell-type called ‘tuft cells’. Interestingly, they seem specifically correlated with POU2AF2. Perhaps this is the important local gene? 5/
Dr Vidya Rajasekaran-Sutherland retweeted
Using bulk RNAseq, we find cis gene expression regulation to strongly overlap with CRC risk. We also consolidate the trans-effects and indicate their expression to be likely relevant to CRC risk by MR. Importantly, CRC risk increases with reduced expression of all these genes. 4/
Dr Vidya Rajasekaran-Sutherland retweeted
Along with increasing CRC risk, variation at 11q23.1 modifies expression of both nearby (cis-: POU2AF2, COLCA1 and POU2AF3) distant (trans-) genes. The immediate questions – which of these are relevant? And how do they predispose to the disease? 3/
Dr Vidya Rajasekaran-Sutherland retweeted
As with other common complex diseases, most loci that confer genetic risk for CRC lie in non-coding regions. This makes their interpretation challenging, and so we wanted to change this for one of the strongest signals identified back in 2008 (!) - 11q23.1. 2/
Dr Vidya Rajasekaran-Sutherland retweeted
Delighted to share the bulk of my PhD has just been published in @Gut_BMJ! (gut.bmj.com/content/early/20…). In this multidisciplinary study I co-led with @vidya87_, we sought to investigate how variation at a single genetic region increased colorectal cancer (CRC) risk. A 🧵: 1/
Dr Vidya Rajasekaran-Sutherland retweeted
We're wearing #Red4Research today as we celebrate the #BowelCancer research community and everyone who takes part in research.
Every development in bowel cancer diagnosis and treatment starts as a research idea. We want to say a huge thank you to the amazing researchers whose hard work develops those ideas into something that can make a difference to people affected by bowel cancer.
Dr Vidya Rajasekaran-Sutherland retweeted
Do you want to hear more about what's going on in bowel cancer research, and the difference this could make to patients? I'll be chatting to two bowel cancer specialists on Thursday - join live or watch the recording.
tickettailor.com/events/nihr…
