Epigenetic control of transcription termination
Lead Research Organisation:
University of Liverpool
Department Name: Biomedical Sciences
Abstract
Chromatin structure shapes the epigenetic landscape of the eukaryotic genome and plays an essential role in gene transcriptional regulation. How chromatin controls termination of transcription by RNA Polymerase II (RNAPII) is poorly understood. The objective of this project is to characterize the role and function of chromatin in regulation of transcriptional termination.
Terminating transcription is an intricate process, involving disassembly of the transcribing RNAPII and simultaneous 3' processing of the nascent RNA. Transcription downstream the transcription termination site (TTS) has to be efficiently terminated to avoid invasion and aberrant expression of downstream genes. Transcriptional termination also feeds back to transcriptional initiation, through gene looping. How coordination between these discrete pathways is accomplished is poorly understood.
The eukaryotic genome is packaged and organized into the chromatin nucleoprotein structure. The concerted actions of chromatin regulators alters the nucleosomal organization of the genome, commanding epigenetic information that dictates transcriptional output. Chromatin aberrations lead to defective transcription termination. However, the role of chromatin in termination remains poorly understood.
The ATP-dependent chromatin remodelling enzymatic complex INO80 is highly conserved across eukaryotes. In plants, INO80 loss causes severe developmental defects such as dwarfisms and late flowering, and its activity is required for the proper expression of a large number of genes, including FLC (FLOWERING LOCUS C) a master regulator of flowering time control. This indicates an important, yet unclear role for INO80 in plant development.
MPC recently demonstrated in S.cerevisiae that INO80 facilitates removal of RNAPII from chromatin (Lafon et al., Mol.Cell 2015) and promotes transcription termination and mRNA stabilization (Luzzi et al., submitted). However, the INO80-mediated mechanism in termination is not known.
Our work revealed a network of nucleosome regulators as novel players of the transcriptional termination process. This project will test the hypothesis that dynamic regulation of the underlying chromatin structure at the TTS defines an uncharacterized pathway that coordinates RNA processing with release of RNAPII, ensuring efficient termination and expression of functional mRNAs.
We will ask:
- How does INO80 regulate transcription termination and couples it with mRNA stability?
- How does chromatin regulation of transcription termination integrate with the spatio-temporal regulation of plant plasticity?
Our strategy employs a powerful combination of genomics, high-throughput genetics and chromatin biochemical assays in the model organisms S.cerevisiae and Arabidopsis thaliana. This approach will uncover the physical and functional crosstalk between chromatin and the termination machinery and elucidate the molecular underpinnings of this novel transcriptional regulatory pathway.
Terminating transcription is an intricate process, involving disassembly of the transcribing RNAPII and simultaneous 3' processing of the nascent RNA. Transcription downstream the transcription termination site (TTS) has to be efficiently terminated to avoid invasion and aberrant expression of downstream genes. Transcriptional termination also feeds back to transcriptional initiation, through gene looping. How coordination between these discrete pathways is accomplished is poorly understood.
The eukaryotic genome is packaged and organized into the chromatin nucleoprotein structure. The concerted actions of chromatin regulators alters the nucleosomal organization of the genome, commanding epigenetic information that dictates transcriptional output. Chromatin aberrations lead to defective transcription termination. However, the role of chromatin in termination remains poorly understood.
The ATP-dependent chromatin remodelling enzymatic complex INO80 is highly conserved across eukaryotes. In plants, INO80 loss causes severe developmental defects such as dwarfisms and late flowering, and its activity is required for the proper expression of a large number of genes, including FLC (FLOWERING LOCUS C) a master regulator of flowering time control. This indicates an important, yet unclear role for INO80 in plant development.
MPC recently demonstrated in S.cerevisiae that INO80 facilitates removal of RNAPII from chromatin (Lafon et al., Mol.Cell 2015) and promotes transcription termination and mRNA stabilization (Luzzi et al., submitted). However, the INO80-mediated mechanism in termination is not known.
Our work revealed a network of nucleosome regulators as novel players of the transcriptional termination process. This project will test the hypothesis that dynamic regulation of the underlying chromatin structure at the TTS defines an uncharacterized pathway that coordinates RNA processing with release of RNAPII, ensuring efficient termination and expression of functional mRNAs.
We will ask:
- How does INO80 regulate transcription termination and couples it with mRNA stability?
- How does chromatin regulation of transcription termination integrate with the spatio-temporal regulation of plant plasticity?
Our strategy employs a powerful combination of genomics, high-throughput genetics and chromatin biochemical assays in the model organisms S.cerevisiae and Arabidopsis thaliana. This approach will uncover the physical and functional crosstalk between chromatin and the termination machinery and elucidate the molecular underpinnings of this novel transcriptional regulatory pathway.
