Molecular characterization of noncoding regulatory element function in neural development

This is a summer student project supervised by Joaquina Delás Vives in James Briscoe's lab.

Introduction

Introduction to the science

Tightly controlled gene expression is essential in development, when the map to our adult tissues is established. From the same DNA, each cell must establish its unique gene expression pattern. To do this, regulatory sequences within the noncoding genome must be interpreted. Faulty regulatory information that leads to gene miss-expression can therefore have dramatic consequences. Transcription factors bind these cis-regulatory elements (enhancers) but how this binding mediates gene expression is still not well understood.

We study this process in the context of spinal cord development, where different neuronal progenitor cell types form in response to signalling gradients. These neuronal progenitors will go on to differentiate into specific types of neurons, which will integrate into the circuits that control motor and sensory functions. Most importantly for our purposes, the lab has developed cellular models of neuronal spinal cord development that recapitulate this differentiation process.

About the project

Using these in vitro protocols of spinal cord development, we aim at deciphering the molecular mechanisms of how enhancers activate genes. To do this we combine cutting edge proteomics, imaging and genomics techniques. One of these approaches involves identifying the proteins associated to an enhancer as the gene that it controls turns on. We are looking for a summer student that would work on different aspects of this technique, genome editing of cell lines and stem cell differentiations to neuronal progenitors.

This project will be supported by the Rosa Beddington fund, which has been established to support developmental biology and related activities in memory of Dr Beddington. Rosa was an eminent developmental biologist whose career was cut short by her untimely death (https://en.wikipedia.org/wiki/Rosa_Beddington). The successful candidate will be asked to write a short essay (less than a page) about the summer project, and its relevance to developmental biology, at the end of the placement. The essay will be posted on the Crick intranet and submitted for publication in the British Society for Developmental Biology newsletter.

About you

The candidate would gain expertise in tissue culture, molecular cloning, flow cytometry and biochemistry, and would also be exposed to all other aspects of the project. This project would be suitable for anyone with an interest in gene regulation and developmental biology, studying biological/biomedical sciences, or related subjects.

References

  1. Liu, X., Zhang, Y., Chen, Y., Li, M., Zhou, F., Li, K., ... Xu, J. (2017) In situ capture of chromatin interactions by biotinylated dCas9. Cell 170: 1028-1043 e1019.
  2. Sagner, A., Gaber, Z. B., Delile, J., Kong, J. H., Rousso, D. L., Pearson, C. A., ... Novitch, B. G. (2018) Olig2 and Hes regulatory dynamics during motor neuron differentiation revealed by single cell transcriptomics. PLOS Biology 16: e2003127. PubMed abstract