Revision as of 21:46, 29 October 2017

• ABOUT US
  Team Attributions
• BACKGROUND
  Alternative Splicing CRISPR RNA Binding Proteins REST
• PROJECT
  Guides and ASOs mKate-FF4 2 Exon mKate HBG 3 Exon mKate HBG 3 Exon Dual Fluorescence
• LAB WORK
  Parts/Improved Parts Protocols Notebook Future Work
• MODELLING
• HUMAN PRACTICES
  Integrated HP Public Engagement Collaborations InterLab
• AWARDS
  HP Silver HP Gold Education & Public Engagement Model Parts Collection

REST

We have selected misregulation of the transcription factor REST in certain forms of aggressive cancer as a disease state that could potentially be treated with our system for alternative splicing regulation. REST protein, encoded by the REST gene, is a tumor suppressor protein that binds to more than 2000 known target oncogenes. (1) It represses transcription by binding a DNA sequence element called the neuron-restrictive silencer element, known as RE1, recruiting co-repressors as well as chromatin modifying enzymes that change the topology of the oncogenes, all in all down-regulating the expression of these oncogenes.

In a normal splicing event, exon 4 in the pre-mature mRNA is skipped and the mature mRNA is accordingly translated. A certain balance of isoforms from the REST gene is required for functional suppression function.

Loss of REST protein has been linked to forms of SCLC, colon cancer, and recently researchers at Wisconsin University have discovered a subset of breast cancers which display a highly aggressive disease course in which the tumor suppressor gene REST is lost. (2) In this subset, REST gene is mis-spliced, leading to the inclusion of the normally skipped exon. This exon includes a premature stop codon, which, upon its identification by the translation machinery, results in the production of a truncated REST protein called REST4.

The new protein also lacks a C terminus for recruiting the corepressors and chromatin modifying enzymes, leading to the protein’s loss of function as a tumor suppressor.