Mechansims for the propagation of epigenetic states: Role of ATP-dependent chromatin remodelling by SMARCAD1

Lead Research Organisation: Babraham Institute
Department Name: Nuclear Dynamics

Abstract

The genetic material in each cell is packaged and organized by an extremely complex, heterogeneous structure, called chromatin. The basic building block of this structure is called the nucleosome, a molecular protein spool around which DNA winds in almost two turns. Nucleosomes are modified and interact with other proteins to create chromatin structures that shut down genes or allow access to the machinery that read out the information from genes. We will study how nucleosome remodelling and modification enzymes interact to assemble a specific chromatin structure to shut down genes and to stabilise the genome. This research has implications for our understanding of normal development, but also for cancer and fertility.

Technical Summary

Chromatin is an incredibly complex, heterogeneous assembly. Specific chromatin structures mediate gene regulation and are required for genome stability and chromosome segregation. Such structures have to be faithfully duplicated for the maintenance of gene expression patterns through development and genome stability. Defects in heterochromatin have been linked to genome instability, infertility, accelerated aging and an enhanced risk of cancer. Despite this fundamental importance, our knowledge how specific chromatin structures, such as heterochromatin, are assembled and maintained through replication is limited.
Our recent research implicates an ATP-dependent remodelling factor, SMARCAD1, in the assembly of heterochromatin during replication. The analysis of chromatin remodelling by SMARCAD1 provides a unique entry point to gain mechanistic insights into how heterochromatin is assembled and what happens if this process is impeded. We use available mice that are deficient in this factor and a combination of cell biology and biochemistry to gain insights into how SMARCAD1 and its binding partners are involved in setting up silenced chromatin during replication. We will test if SMARCAD1 has a role in meiosis through its function in heterochromatin assembly. This research will uncover novel mechanisms into how histone deacetylation, histone ubiquitination, histone variant exchange and nucleosome remodelling are coordinated to propagate condensed chromatin structures.

Publications

10 25 50
 
Description BBSRC-Brazil Partnering Award
Amount £76,021 (GBP)
Funding ID BB/L026988/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 11/2014 
End 10/2018
 
Description FAPESP Pump-Priming Awards
Amount £13,500 (GBP)
Funding ID BB/N013565/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 11/2015 
End 05/2017
 
Description MRC collaborative grant: Next generation sequencing high throughput epigenomics
Amount £943,678 (GBP)
Funding ID G0801156 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2009 
End 09/2013
 
Description MRC project grant
Amount £406,182 (GBP)
Funding ID MR/N009398/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 03/2016 
End 02/2019
 
Title Conditional Smarcad1 knockout mouse 
Description We create a conditional knockout model for chromatin remodeling factor Smarcad1 
Type Of Material Biological samples 
Year Produced 2012 
Provided To Others? Yes  
Impact Collaborations with Professor Kazuyuki Ohbo's group , Yokohama City University, Japan, and Anne Corcoran's, Marc Veldhoen's groups, Babraham Institute. 
 
Description Brazil Partnering Award 
Organisation University of Sao Paulo
Country Brazil 
Sector Academic/University 
PI Contribution Principle Investigator
Collaborator Contribution Co-investigators
Impact Brazilian Partnering Award from BBSRC: BB/L026988/1
Start Year 2014
 
Description Collaboration with Dr Kazuyuki Ohbo 
Organisation Yokohama City University
Country Japan 
Sector Academic/University 
PI Contribution Role of Smarcad1 in testis development
Collaborator Contribution expertise in testis development
Impact ongoing
Start Year 2013
 
Description Collaboration with Marc Veldhoen, Babraham Institute 
Organisation Babraham Institute
Country United Kingdom 
Sector Private 
PI Contribution We investigate the role of chromatin remodeling by Smarcad1 in maintenance of intestinal immunity, especially of intraepithelial lymphocytes.
Collaborator Contribution Expertise in intestinal immunity.
Impact This work led to a grant application to the BBSRC (not successful) and a joint application to the EU under the HORIZON 2020 programme.
Start Year 2012
 
Description Collaboration with TB 
Organisation European Institute of Oncology (IEO)
Country Italy 
Sector Charity/Non Profit 
PI Contribution provided research question and materials
Collaborator Contribution provided expert mass spec analysis
Impact Funded MRC project grant
Start Year 2013
 
Description In vivo interaction between chromatin remodeling factors and PCNA 
Organisation University of Cambridge
Department Department of Zoology
Country United Kingdom 
Sector Academic/University 
PI Contribution We provided the overall research question and idea, reagents and man power in from of my PHD student
Collaborator Contribution Performed live cell fluorescence energy transfer (FRET) study, assisted with microscopy setup and data analysis.
Impact Paper: Maintenance of silent chromatin through replication requires SWI/SNF-like chromatin remodeler SMARCAD1. Rowbotham SP, Barki L, Neves-Costa A, Santos F, Dean W, Hawkes N, Choudhary P, Will WR, Webster J, Oxley D, Green CM, Varga-Weisz P, Mermoud JE. Mol Cell. 2011 May 6;42(3):285-96.
Start Year 2009
 
Description Schools day 2014 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact 8 pupils attended for a school visit to the research organisation, which sparked questions and discussion afterwards, and the school reported increased interest in related subject areas
Year(s) Of Engagement Activity 2012,2013,2014,2015
 
Description Schools' Day on 23rd March 2011 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact My School's day project was called 'Visualization of chromatin in a cell nucleus' and I had 4 GCSE or A level students in the morning and afternoon (8 total).

For Schools' Day 2011 I ran a project which received excellent scores on the questionnaires students completed at the end of the day. One student wrote About your project 'interesting insights with added bonus of getting to learn more about chromatin.'
Year(s) Of Engagement Activity 2011