Defining RNA polymerase II transcription units across the mammalian genome (360G-Wellcome-219443_Z_19_Z)

£2,400,000

We will define the extent of RNA polymerase II (Pol II) transcription units (TUs) across mammalian genomes, both protein coding (pc) and long noncoding (lnc). For each TU class, termination sites and mechanisms will be scrutinised, especially by definition of XRN2 "torpedo" entry sites at positions of co-transcriptional endonuclease cleavage. Multiple endonucleases will be investigated including CPSF-73, Drosha and Integrator-S11. For lncRNA their mechanism of transcriptional initiation will also be investigated, especially R-loop dependant promoters. Pilot experiments show that R-loops promote antisense lncRNA particularly at pc-gene promoters and enhancers, so defining a new class of Pol II promoter that we intend to fully characterise at a molecular level. Histone genes represent an unusual, ubiquitous Pol II pc-gene class. We will also characterise the termination mechanism for these genes and in particular the role of the novel endonuclease MBLAC1. Finally, we will study the particular case of the H2AX gene that employs both a histone like, poly(A)- termination mechanism as well as a poly(A)+ mechanism. Overall, we will characterise mechanisms that define gene TUs across mammalian genomes to better inform gene function in the rapidly expanding repertoire of genomic sequences being generated for normal and pathogenic human cells.

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Grant Details

Amount Awarded 2400000
Applicant Surname Proudfoot
Approval Committee Science Interview Panel
Award Date 2019-12-03T00:00:00+00:00
Financial Year 2019/20
Grant Programme: Title Investigator Award in Science
Internal ID 219443/Z/19/Z
Lead Applicant Prof Nicholas Proudfoot
Partnership Value 2400000
Planned Dates: End Date 2026-07-31T00:00:00+00:00
Planned Dates: Start Date 2021-08-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region South East