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How do you make a Cajal body or superenhancer and what do they have in common?

Reference	BB/W000172/1
Principal Investigator / Supervisor	Professor Stuart Wilson
Co-Investigators / Co-Supervisors	Dr Ian Sudbery
Institution	University of Sheffield
Department	School of Biosciences
Funding type	Research
Value (£)	493,735
Status	Current
Type	Research Grant
Start date	11/07/2022
End date	10/07/2025
Duration	36 months

Abstract

Chromatin adopts a complex 3 dimensional shape in the mammalian nucleus which involves inter and intra-chromosomal contacts. The cohesin complex together with CTCF regulate chromatin architecture, driving loop formation and chromatin contacts. However, RNA represents a major component of chromatin with a poorly defined role in the maintenance of its conformation. CTCF binds RNA but whether other RNA binding proteins associate with CTCF and form an RNA:protein complex governing chromatin architecture remains unresolved. Our hypothesis is that an RNA binding protein we have identified works together with other RNA binding proteins and CTCF to form an RNA:protein network. This network serves at least three roles i) formation of intra-chromosomal contacts leading to Cajal body formation ii) establishment of superenhancer:promoter loops iii) coupling between transcription and the RNA:protein network enforcing a specific chromatin architecture whilst RNA production continues. This latter function ensures efficient coordinated synthesis of RNA and provides the potential for feedback control. We propose to test these ideas.

Summary

Chromatin adopts a complex 3 dimensional shape in the mammalian nucleus which involves inter and intra-chromosomal contacts. How these contacts are made and enforced is not clear. When chromatin is isolated from cells, a large proportion of the material is RNA and proteins which associate with it. The role of this RNA remains largely uncharacterised, yet increasingly proteins which influence chromatin topology such as CTCF are being shown to associate with RNA. Therefore RNA is likely to play a key role in chromatin architecture and influence its activity. The Cajal body is an example of a region in the nucleus where intra chromosomal contacts occur, bringing together a specific collection of genes and the proteins which allow efficient transcription and processing of the RNA produced form those genes. A second example of chromatin contacts involves superenhancers which form loops with multiple target gene promoters, regulating their transcription. We have identified a protein which connects both Cajal body and superenhancer activities and binds RNA, chromatin and CTCF. We aim to test whether this protein forms part of an RNA:protein network which drives chromatin interactions in cells and ensures optimal transcription of target genes by recruitment of RNA polymerase II.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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