The control of cellular differentiation by chromatic proteins

Lead Research Organisation: University of Dundee
Department Name: Biological Sciences

Abstract

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Technical Summary

Chromatin structure is central to the way that gene expression is controlled. Indeed, mutations in genes that encode chromatin-modifying enzymes give rise to several human diseases and cancer. The aim of this study is to understand how different chromatin modifications coordinate developmental gene expression. This has proven to be hard to do in higher eukaryotes because of functional redundancy or lethal phenotypes. In contrast, analysis in yeasts is hampered by their lack of developmental options. I have therefore chosen to use the slime mold Dictyostelium as a model organism. It has a simple and well-defined developmental programme, and a small and fully sequenced genome that encodes chromatin proteins and modifying enzymes that are conserved with those in higher eukaryotes. Lastly, targeted mutagenesis by homologous recombination is a rapid procedure in this organism.
I will generate complete knockouts which eliminate specific chromatin modifications, and which give rise to obvious developmental phenotypes in Dictyostelium. I will analyse the consequent changes in gene expression using microarrays, to address to what extent a particular modification or combination of modifications can specify distinct programs of developmental gene expression. I will determine whether the perturbed genes are dispersed in the genome, or clustered - which would indicate that chromatin modifying proteins act over specific genomic domains. I will identify the signalling pathways interacting with specific chromatin states using suppression screens for chromatin protein over-expression phenotypes. One role of chromatin in eukaryotic cells is proposed to be the reduction of transcriptional noise and inappropriate gene expression. I shall address this hypothesis using an in vivo RNA detection system to visualize gene activity at individual sites of transcription. This will allow a description of transcriptional dynamics at a single genomic locus and an assessment of the level of transcriptional noise in the absence of specific chromatin proteins and modifications.

Publications

10 25 50
 
Description MRC Research Grant
Amount £406,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2007 
End 01/2010
 
Description Wellcome Trust Senior Res. F'ships In Basic Biomedical Science (Control of noise in gene expression)
Amount £1,059,276 (GBP)
Funding ID 090904 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2010 
End 10/2015
 
Title techniques for imaging transcription 
Description cell lines, DNA constructs and technical expertise for imaging genes in living cells 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact We have changed the way people think about genes 
 
Title transcriptional imaging 
Description A method to visualise gene activity in living cells, using fluorescence microscopy 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact Conceptual enrichment of a wide area of biological research 
 
Description 3 radio interviews 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact interviewed by 3 Scottish stations, and several newspapers, and general scientific magazines about our findings

How does one measure this (please advise)? The effects are small, but cumulative, as with most forms of dissemination
Year(s) Of Engagement Activity 2006
 
Description Written Wkipedia sites (see Transcriptional Bursting, MS2 tagging, transcriptional noise) and contributor to many others (transcription, chromatin etc.) 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Wrote contributed to these pages. Unlike journals, lectures, textbooks- this information allows anyone to look at our research field. We have linked the sites to other, more targeted pages (eg. noise)

Lots of hits. Wikipedia (or derivatives) may well displace textbooks and the review journals, maybe journals themselves. I think it is therefore critical to get the ball rolling.
Year(s) Of Engagement Activity 2009,2011,2012
 
Description lecture 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact invited to Japanese protist meeting

educated broad non-specialist audience
Year(s) Of Engagement Activity 2008
 
Description school visits, Glasgow, West of Scotland 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact multiple lectures to UK and international audiences- both by myself and other members of the group.

Communication was acheived. The meaning of our science was communcated.
Year(s) Of Engagement Activity 2007,2009
 
Description various talks 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact myself and lab members (for their training purposes) have presented our work at various scientific meetings

general awareness of our work- suggestions for future directions, new potential collaborations
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
 
Description watching genes- school lectures 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 4 lectures to sixth form students given before Xmas 2007 (probably 600 students in Glasgow area reached). They saw and comprehended, our primary research.

Hopefully some of them will become scientists
Year(s) Of Engagement Activity 2007