Dr. Jeremy Sanford, Associate Professor at the University of California, Santa Cruz.

Dr. Jeremy Sanford, Associate Professor at the University of California, Santa Cruz.

Dr. Jeremy Sanford is an Associate Professor in the department of Molecular, Cellular and Developmental Biology at the University of California, Santa Cruz. The goal of Dr. Sanford’s lab is to understand post-transcriptional networks coordinated by RNA binding proteins. He is currently trying to address the following questions:

  • How is exon identity established in pre-mRNA?
  • What is the functional impact of alternative splicing?
  • How are the different steps of post-transcriptional gene expression pathway integrated?
  • How do RNA binding proteins contribute to pathogenesis?

To answer these questions, Dr. Sanford employs genomic, biochemical and computational methods to identify cis-acting RNA elements recognized by a complete family of phylogenetically conserved, essential RNA binding proteins in a comprehensive manner.

In his research seminar last week, Dr. Sanford discussed how nuclear pre-mRNA processing influences the polyribosome association of alternative mRNA isoforms. He also described the characterization of the Insulin-like growth factor 2 mRNA binding protein 3 (IMP-3) in pancreatic ductal adenocarcinoma cells. Expression of the oncofetal RNA binding protein is strongly correlated with malignancy in many different tumor types. Using a technology called Crosslinking Immunoprecipitation and high throughput sequencing (CLIP-Seq), he also determined that IMP-3 is a pleiotropic regulator of cellular adhesion and proliferation. Loss of IMP-3 function in cancer cells restores cellular adhesion and reduces invasiveness, which demonstrated that IMP-3 plays a direct role in the pathogenesis of some cancers.


Q: How is your field related to aging?

JS: One thing we study related to aging is somatic mutations: humans accumulate somatic mutations as they age. I think understanding how mutations affect gene expression is very important. Signal-dependent regulation of splicing regulates our genetic code so that you can have a non-sense mutation that can change the way the exon get spliced. It would be interesting to understand how DNA sequence variants promote aberrant splicing.

Q: Could you talk a little more about the project “Regulation of post-transcriptional gene expression by rapamycin”?

JS: For the rapamycin story, as a postdoc, I was investigating how the RNA binding protein, SF2/ASF mediates post-splicing activities such as mRNA export and translation. We found that SF2/ASF promotes translation initiation by suppressing the activity of 4E-BP through mTOR. I got a grant from The Ellison Medical Foundation to support this study. I went to my first Ellison meeting in 2009, where I saw the study of rapamycin in mice. I thought it is amazing that people found rapamycin significantly extends lifespan. I wondered what happened in the post-transcriptional gene expression of rapamycin treated mice. So this is how we started to look into the link between post-transcriptional gene expression and aging.

One thing we have found is that rapamycin enhances nonsense-mediated decay, which is a surveillance mechanism that helps reduce errors in gene expression by eliminating mRNA that has premature stop codons. This quality control mechanism is also a way to deal with mutations that cause premature stop codons. Another thing we did was test the impact of rapamycin on alternative mRNA isoforms. We looked into the polyribosome fraction in the cells treated with and without rapamycin. There is a really clear difference: in the control cells, you can still see the nonsense-mediated decay mRNA isoforms in the polyribosome, but you don’t see them in the rapamycin treated cells. I think it suggests that you may be able to dynamically regulate the fate of mRNA isoforms on the ribosome. So it seems that the way that ribosome deal with translation can be dynamically regulated. People also found that in stem cells the nonsense-mediated decay activity is very high, but in the highly differentiated cells the nonsense-mediated decay activity is decreased. So I think if you give the differentiated cells rapamycin, maybe you can return the nonsense-mediated decay to a robust state and maybe that can promote longevity.

Q: What are the big challenges in your field right now?

JS: One of the challenges is to understand the specificity of the RNA binding proteins and how they compete and interact to affect gene expression. There is also a big challenge of connecting post transcriptional control to the big biological problem. Sorting out which RNA isoform is important in a given condition is also a problem. Moreover, really understanding what RNA based diseases are big things too. We want to understand whether a certain disease is caused by an RNA problem or not.

Q: What would you like to suggest to our postdocs who want to pursue academic careers?

JS: The key is to find where your field is going and what the gap is, and trying to be the first person to develop tools to address them. Constantly think about what your next step is in terms of where you want to go and how you get there. And be lucky!

Q: Which field of basic research do you think influences your research the most?

JS: I was working on biochemistry of splicing as a graduate student. I think the biochemistry work had an impact of pushing me away from biochemistry. I feel like my field was getting narrower and narrower, which is normal if you are working on mechanisms. But I wanted to work on something more broadly, so I decided to bridge the gap between the mechanism of splicing and disease. And this is the reason I worked on the cell biology of splicing after my PhD.

 For more about Dr. Jeremy Sanford and his research, check out the Sanford Lab Website.