Award details

Finding the Balance: Repression of Plant Gene Expression

Reference	BB/T001194/1
Principal Investigator / Supervisor	Professor Brendan Davies
Co-Investigators / Co-Supervisors	Dr Barry Causier
Institution	University of Leeds
Department	Ctr for Plant Sciences
Funding type	Research
Value (£)	643,657
Status	Current
Type	Research Grant
Start date	01/03/2020
End date	31/08/2023
Duration	42 months

Abstract

TPL/TPR is a small family of transcriptional corepressors that is involved, through its recruitment by short repression domains found in numerous transcription factors (TFs), in a range of plant processes including biotic and abiotic responses, hormone signalling, pattern formation, leaf development, inflorescence structure and flowering. TPL/TPR acts in a complex including various TFs and histone deacetylase (HDAC), although no direct association between TPL/TPR and HDAC has been demonstrated. TPL/TPRs are essential for normal plant development and responses, but their mode of action remains to be discovered. In animals, HDACs form the catalytic subunit of well-characterized transcriptional corepressor complexes, including NuRD, CoREST and Sin3. Genome data indicates that identical complexes cannot exist in plants, but we have evidence that TPL/TPR proteins are part of an undiscovered analogous plant complex, which shares some core components. One project aim is therefore to characterise the first plant HDAC-complex(es) and compare it to its animal counterpart(s). Current findings show that animal HDAC-containing are actually involved in both activation and repression, by facilitating the turnover of histone acetylation. This model could explain currently inexplicable results in plant science, such as the findings from us and others that the WUS TF requires a repression domain (the domain that recruits TPL/TPR) for both activation and repression of its direct targets. We will discover whether a TPL/TPR-HDAC complex is required for both activation and repression of genome-wide targets. These aims will reveal how plant repression has evolved since animals and plants diverged over 2 billion years ago and provide new ways to modify plant development through engineered gene regulation.

Summary

All life critically depends on the ability of organisms to set the expression levels of each of their genes. Textbook models claim that gene regulation is controlled by transcription factors (TFs); proteins that bind specific regions of the genome to 'turn on' or 'turn off' expression of target genes. The TFs provide specificity, identifying the correct genes to regulate, but they recruit other proteins to actually set the levels of gene expression. Many TFs turn off gene expression by recruiting proteins known as corepressors. Corepressors cannot bind DNA, but, once brought to a target by a specific TF, they can shut down expression of that target gene. More recent studies reject this simplistic model, in favour of a more nuanced model involving a regulated balance between activation and repression, to deliver the appropriate expression levels. Paradoxically then, in animals, repressive factors have been found to be part of complexes required to both repress and activate. An important class of animal and plant corepressors is the GRO/TUP1 family. The major group of these corepressors in plants is called TPL/TPR. TPL/TPRs are involved in multiple diverse plant processes and are absolutely fundamental to normal growth and development. Despite the fact that these regulators are so critical, their mode of action is poorly understood, with many open questions. There is accumulating evidence that plant TPL/TPR proteins inactivate gene expression as part of a larger complex containing histone deacetylase (HDAC) proteins. HDACs modify the chromatin structure of the target gene, rendering it inactive. In animals, HDACs are also associated with repression complexes, the most abundant of which is the nucleosome remodelling and deacetylase complex (NuRD). Currently, no such complex is known in plants. Some, but not all, of the core components of animal NuRDs are present in plant genomes and we recently identified homologues of animal NuRD components as TPL/TPR interaction partners. This raises the intriguing possibility that TPL/TPRs, which are so essential for normal plant function, repress transcription as part of a currently unknown plant NuRD-like complex. Such a complex would necessarily differ from those found in animals, because plants lack homologues of some of the core animal regulatory complex components. One aim of this proposal is therefore to isolate and characterise the first plant TPL/TPR-HDAC complex, both to understand how it controls gene expression and to compare it with the distinct, but analogous animal complexes. Using either newly identified components of the plant TPL/TPR-HDAC complex, or previously identified candidate components, we will then go on to use molecular genetics to investigate their role in gene expression. The balance model of transcriptional regulation is supported by the association of the animal NuRD-complex with both repressed and active genes. This model also provides a potential explanation for some perplexing results in plants. Our final aim is therefore to investigate whether these complexes are involved in both activation and repression in plants. By taking a global view of DNA-binding and gene expression, we will be able to identify the genomic regions that are associated with TPL/TPR corepressors and/or HDAC and to compare this to a genome-wide map of transcriptional activity. This powerful approach will allow us to quantify the genome association with TPL/TPR alone, HDAC alone and both together. We can then assign DNA association to a transcriptional status (activated or repressed) and, in some cases, compare this to the histone acetylation status of the gene. This project will provide a mechanistic framework for establishing a balance between repression and activation in plants that could be manipulated to alter plant development and responses. It will also reveal whether the novel plant regulatory complexes are involved in both repression and activation of gene expression.

Impact Summary

Overview: We want to build a mechanistic understanding of transcriptional corepressor complexes in plants, and to reveal whether they have roles in both repression and activation of gene expression, thereby introducing a new paradigm for gene regulation in plants. In the long term, the project may identify new plant-specific targets suitable for engineering precise regulation of gene expression. The TPL/TPR group of plant corepressors are essential for normal plant growth and development. In addition, TPL/TPRs, which are found in all land plants including crops, also play significant roles in biotic and abiotic stress responses, directly impacting productivity. Given the vital role TPL/TPRs play in regulation of gene expression in response to the environment, the project aligns with the BBSRC's 'grand challenge' of delivering food security through a "fundamental understanding of biological processes and mechanisms". Fundamental research: This is a curiosity-led project proposal that seeks to understand the mechanisms used by corepressor complexes to regulate gene expression. We aim to identify novel HDAC and TPL/TPR complexes involved in transcriptional repression in plants, and to explore the extent to which the rules that govern gene expression differ across kingdoms. This will be of interest and benefit to the scientific community, in particular those interested in gene regulation. We anticipate that technologies developed as part of this project (eg. BioID2 and TurboID), together with the large and comparable datasets that we will generate, will be useful resources for plant biosciences. Applied research: In terms of food security, it is imperative that crop productivity is maintained or increased despite significant environmental challenges. Finding methods to improve a crop's ability to respond to biotic and abiotic stress is an important challenge within plant sciences, and is the focus of research in both the academic and commercial sectors. Transcription regulators are prime targets to manipulate in order to allow rational design of novel plant biomass. A potential long-term outcome of this fundamental research is the possibility to exploit systems controlling gene expression for crop improvement. As key regulators of plant immunity, stress responses, plant architecture and reproductive success, TPL/TPRs represent potential targets for engineering novel crop traits. In particular, these factors and the multiprotein complexes with which they associate, are likely to be unique to plants and will provide new ways to engineer plant development through regulation of specific genes. We therefore anticipate that impact will be delivered in this project through fundamental research underpinning future discoveries, applied research based on current findings, training, public engagement and international interactions. Training: Impact in this area will be delivered by training a PDRA, TA and PhD students in preparation for future employment in academic or commercial environments. This would include specific and interdisciplinary scientific and transferable skills, alongside collaborative experience and contacts. We will also offer research informed teaching by providing laboratory experience to undergraduate students at various stages of their studies, including provision of work experience to graduates. Public engagement: Impact in this area will be delivered through a range of individual activities in schools, higher education and popular science initiatives and also via specific activities of the university publicity office. Together these activities will allow us to us communicate a greater understanding to the public of key events in plant gene/environment interactions and the consequences for food production. Internationality: Interaction, translation and dissemination to those concerned with crop security in the developing world will be facilitated by our formal, established links in China, India and Africa.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	Plant Science
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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