Analysis of microRNA function in B lymphocytes.

Lead Research Organisation: Babraham Institute
Department Name: Lymphocyte Signalling and Development

Abstract

B lymphocytes are a type of white blood cells. They provide long term immunity following disease or vaccination, being therefore essential for normal health. Deregulation of B lymphocytes may lead to autoimmune diseases or cancer. Consequently, understanding the molecular mechanisms of B cell differentiation is an important priority.

MicroRNAs are a recently discovered type of molecule increasingly recognised as being essential for many biological processes. Until recently, nothing has been known on the role of specific microRNAs in B lymphocyte differentiation, but it is anticipated that microRNAs will be shown to be important regulators of B cell function. In this regard, I have observed that one microRNA, miR-155, regulates important functions of B cells necessary for antibody secretion. This project is designed to gain a better understanding of how this and other microRNAs work. MicroRNA expression is altered in cancer and it is likely that in the future pharmaceutical companies will target them. The knowledge obtained from my proposed work will provide insights into a new mechanism regulating lymphocyte differentiation which in the long term may impact on the design of therapies for treatment of human diseases

Technical Summary

MicroRNAs (miRNAs) are increasingly being recognised as major regulators of gene expression. They provide an additional level of regulation beyond transcriptional control, permitting more rapid establishment of stable gene expression patterns. MiR-155 is encoded within an exon of the bic non-coding RNA transcript and is highly expressed in antigen receptor-activated B lymphocytes.

During the course of adaptive immune responses B lymphocytes must respond rapidly to antigenic stimulation by initiating complex changes in gene expression that allow differentiation into effector and memory cells. These events lead to the production of high affinity antibodies and development of lasting immunological protection which underpins effective vaccination.

My previous work has implicated bic/miR-155 in optimal adaptive immune responses of B cells in a cell-autonomous manner. Those results led me to propose that bic/miR-155 regulates the selection of high affinity germinal centre B cells to become plasma cells. In this project, an integrative approach combining cellular biology, biochemical and bioinformatics methodologies aims to test this hypothesis and to provide further mechanistic insights by identifying miR-155 target genes. Furthermore, I have previously identified a group of miRNAs differentially regulated during B cell development. I will use synthetic molecules which can specifically antagonise miRNAs (antagomirs) to determine how this group of miRNAs control B cell function.

MiRNAs appear to be deregulated in certain forms of cancer: miR-155 is an example of a miRNA with oncogenic potential. Although the prospect of targeting miRNAs for therapeutic use is exciting, more research is needed to assess their validity in the clinic. In particular, a deep understanding of specific miRNA function in health is essential to provide insights into the underlying mechanisms of oncogenesis. Only by understanding the normal biological processes regulated by miRNAs and their network of target genes will it be possible to safely unlock their full potential for pharmaceutical intervention in the treatment of human diseases.

Publications

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Kohlhaas S (2009) Cutting edge: the Foxp3 target miR-155 contributes to the development of regulatory T cells. in Journal of immunology (Baltimore, Md. : 1950)

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Nakagawa R (2016) MicroRNA-155 controls affinity-based selection by protecting c-MYC+ B cells from apoptosis. in The Journal of clinical investigation

 
Description Project grant
Amount £780,869 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2011 
End 09/2014
 
Description Targeting miRNAs with oligonucleotides 
Organisation Medical Research Council (MRC)
Department MRC Laboratory of Molecular Biology (LMB)
Country United Kingdom 
Sector Public 
PI Contribution Study the effectiveness of oligonucleotides to target miRNAs in mice
Collaborator Contribution Production of oligonucleotides and expertise in synthesis and delivery
Impact Two papers (listed in publication list). Another one submitted.
Start Year 2008
 
Description Students visit at BI 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact groups of 10-12 students attended hands-on lab work which inspired pupils to work in science

Schools asked to repeat the experience
Year(s) Of Engagement Activity 2009,2010,2011,2012
 
Description school teachers visiting babraham institute 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact 20 teachers attended scientific talks

the scheme will be repeated this year
Year(s) Of Engagement Activity 2009