PhD candidate, University of Tasmania
The significance of a molecular machinery called mediator complex in ensuring global food security
In 10 seconds? Plants act as primary food producers and play a key role for survival of all other living organisms in the ecosystem. As global population is rising consistently, therefore scientists are constantly innovating molecular genetics based strategies to increase crop yields.
How flowering is important for yield? Flowering time of the plant is directly related to yield as food grains are produced from flowers. Plants decide to flower when the environmental conditions are favourable to do so. Scientists are still lacking detailed knowledge about this mechanism for major crops.
What has been discovered? In the agronomically important crop, pea, two genes namely Cyclin dependent kinase 8 (CDK8) and Cyclin C (CYCC1) which are part of a large molecular machinery called mediator complex (present in major living organisms) found to play important role in regulating flowering time and yield outcome. Besides, they are crucial for survival under environmental stresses such as alteration in temperature and duration of sunlight availability, mechanical injury, UVB exposure and salt stress. Such type of genes are called universal regulators since they regulate function of many other genes and therefore are of high interest for molecular genetics based solution of many agricultural issues.
What is the role of mediator complex? The main role of mediator complex is to control a step of protein manufacturing process called transcription. As genetic information is transferred from genetic element DNA to mRNA, then to protein via molecular processes such as transcription and translation respectively, the ultimate visible outcome is phenotypes like flowering.
Why these findings are so remarkable? The aforementioned findings unveiled significant understanding about the underlying molecular mechanisms that regulate development, reproduction, yield and durability in plants. Such knowledge would assist scientists to deal with serious global issues such as ensuring food security under an altered climatic condition.
Abstract: The Mediator complex is needed for regulated transcription of RNA polymerase II (Pol II)-dependent genes. Initially, Mediator was only seen as a protein bridge that conveyed regulatory information from enhancers to the promoter. Later studies have added many other functions to the Mediator repertoire. Indeed, recent findings show that Mediator influences nearly all stages of transcription and coordinates these events with concomitant changes in chromatin organization. We review the multitude of activities associated with Mediator and discuss how this complex coordinates transcription with other cellular events. We also discuss the inherent difficulties associated with in vivo characterization of a coactivator complex that can indirectly affect diverse cellular processes via changes in gene transcription.
Pub.: 01 Oct '13, Pinned: 26 Jun '18
Abstract: The RNA polymerase II (Pol II) enzyme transcribes all protein-coding and most non-coding RNA genes and is globally regulated by Mediator - a large, conformationally flexible protein complex with a variable subunit composition (for example, a four-subunit cyclin-dependent kinase 8 module can reversibly associate with it). These biochemical characteristics are fundamentally important for Mediator's ability to control various processes that are important for transcription, including the organization of chromatin architecture and the regulation of Pol II pre-initiation, initiation, re-initiation, pausing and elongation. Although Mediator exists in all eukaryotes, a variety of Mediator functions seem to be specific to metazoans, which is indicative of more diverse regulatory requirements.
Pub.: 19 Feb '15, Pinned: 26 Jun '18
Abstract: The Mediator complex is a multi-subunit assembly that appears to be required for regulating expression of most RNA polymerase II (pol II) transcripts, which include protein-coding and most non-coding RNA genes. Mediator and pol II function within the pre-initiation complex (PIC), which consists of Mediator, pol II, TFIIA, TFIIB, TFIID, TFIIE, TFIIF and TFIIH and is approximately 4.0 MDa in size. Mediator serves as a central scaffold within the PIC and helps regulate pol II activity in ways that remain poorly understood. Mediator is also generally targeted by sequence-specific, DNA-binding transcription factors (TFs) that work to control gene expression programs in response to developmental or environmental cues. At a basic level, Mediator functions by relaying signals from TFs directly to the pol II enzyme, thereby facilitating TF-dependent regulation of gene expression. Thus, Mediator is essential for converting biological inputs (communicated by TFs) to physiological responses (via changes in gene expression). In this review, we summarize an expansive body of research on the Mediator complex, with an emphasis on yeast and mammalian complexes. We focus on the basics that underlie Mediator function, such as its structure and subunit composition, and describe its broad regulatory influence on gene expression, ranging from chromatin architecture to transcription initiation and elongation, to mRNA processing. We also describe factors that influence Mediator structure and activity, including TFs, non-coding RNAs and the CDK8 module.
Pub.: 04 Oct '13, Pinned: 26 Jun '18
Abstract: Over the past few years, advances in biochemical and genetic studies of the structure and function of the Mediator complex have shed new light on its subunit architecture and its mechanism of action in transcription by RNA polymerase II (pol II). The development of improved methods for reconstitution of recombinant Mediator subassemblies is enabling more in-depth analyses of basic features of the mechanisms by which Mediator interacts with and controls the activity of pol II and the general initiation factors. The discovery and characterization of multiple, functionally distinct forms of Mediator characterized by the presence or absence of the Cdk8 kinase module have led to new insights into how Mediator functions in both Pol II transcription activation and repression. Finally, progress in studies of the mechanisms by which the transcriptional activation domains (ADs) of DNA binding transcription factors target Mediator have brought to light unexpected complexities in the way Mediator participates in signal transduction.
Pub.: 19 Feb '11, Pinned: 26 Jun '18
Abstract: The Mediator complex serves a crucial function in gene regulation, forming a link between gene-specific transcription factors and RNA polymerase II. Most protein-coding genes therefore require Mediator complex activity for transcriptional regulation. Given the essential functions performed by Mediator complex proteins in gene regulation, it is not surprising that mutations in Mediator complex genes disrupt animal and plant development. What is more intriguing is that the phenotypes of individual Mediator complex mutants are distinct from each other, demonstrating that certain developmental processes have a greater requirement for specific Mediator complex genes. Additionally, the range of developmental processes that are altered in Mediator complex mutants is broad, affecting a variety of cell types and physiological systems. Gene expression defects in Mediator complex mutants reveal distinct roles for individual Mediator proteins in transcriptional regulation, suggesting that the deletion of one Mediator complex protein does not interfere with transcription in general, but instead alters the expression of specific target genes. Mediator complex proteins may have diverse roles in different organisms as well, as mutants in the same Mediator gene in different species can display dissimilar phenotypes.
Pub.: 23 Aug '11, Pinned: 26 Jun '18
Abstract: Since its original discovery in yeast, the Mediator complex has been identified in a wide range of organisms across the eukaryotic kingdom. Despite being experimentally purified from a number of fungal and metazoan organisms, it was not until 2007, thirteen years after its initial discovery, that the Mediator complex was successfully isolated from plants. With a number of papers now beginning to emerge on the plant Mediator complex, this review aims to provide an overview of the diverse functions that have been identified for individual plant Mediator subunits. In addition to demonstrating roles in plant development, flowering, hormone signaling and biotic and abiotic stress tolerance; recent findings have revealed novel functions for plant Mediator subunits, including mRNA, miRNA and rRNA processing, as well as controlling DNA and protein stability. These diverse activities have expanded the known functions of the Mediator complex and demonstrate a variety of new insights that have been gained from investigations into the plant Mediator complex. Future directions for research into this multi-functional protein complex will be discussed.
Pub.: 02 Aug '11, Pinned: 26 Jun '18
Abstract: Upon pathogen infection, plants undergo dramatic transcriptome reprogramming to shift from normal growth and development to immune response. During this rapid process, the multiprotein Mediator complex has been recognized as an important player to fine-tune gene-specific and pathway-specific transcriptional reprogramming by acting as an adaptor/coregulator between sequence-specific transcription factor and RNA polymerase II (RNAPII). Here, we review current understanding of the role of five functionally characterized Mediator subunits (MED8, MED15, MED16, MED21 and MED25) in plant immunity. All these Mediator subunits positively regulate resistance against leaf-infecting biotrophic bacteria or necrotrophic fungi. While MED21 appears to regulate defense against fungal pathogens via relaying signals from upstream regulators and chromatin modification to RNAPII, the other four Mediator subunits locate at different positions of the defense network to convey phytohormone signal(s). Fully understanding the role of Mediator in plant immunity needs to characterize more Mediator subunits in both Arabidopsis and other plant species. Identification of interacting proteins of Mediator subunits will further help to reveal their specific regulatory mechanisms in plant immunity.
Pub.: 10 Jan '13, Pinned: 26 Jun '18
Abstract: The Mediator complex is an important component of the eukaryotic transcriptional machinery. As an essential link between transcription factors and RNA polymerase II, the Mediator complex transduces diverse signals to genes involved in different pathways. The plant Mediator complex was recently purified and comprises conserved and specific subunits. It functions in concert with transcription factors to modulate various responses. In this review, we summarize the recent advances in understanding the plant Mediator complex and its diverse roles in plant growth, development, defense, non-coding RNA production, response to abiotic stresses, flowering, genomic stability and metabolic homeostasis. In addition, the transcription factors interacting with the Mediator complex are also highlighted.
Pub.: 15 Jul '15, Pinned: 26 Jun '18
Abstract: Mediator complex (MED) is an evolutionarily conserved multiprotein, fundamental for growth and survival of all cells. In eukaryotes, the mRNA transcription is dependent on RNA polymerase II that is associated to various molecules like general transcription factors, MED subunits and chromatin regulators. To date, transcriptional machinery dysfunction has been shown to elicit broad effects on cell proliferation, development, differentiation, and pathologic disease induction, including cancer. Indeed, in malignant cells, the improper activation of specific genes is usually ascribed to aberrant transcription machinery. Here, we focus our attention on the correlation of MED subunits with carcinogenesis. To date, many subunits are mutated or display altered expression in human cancers. Particularly, the role of MED1, MED28, MED12, CDK8 and Cyclin C in cancer is well documented, although several studies have recently reported a possible association of other subunits with malignancy. Definitely, a major comprehension of the involvement of the whole complex in cancer may lead to the identification of MED subunits as novel diagnostic/prognostic tumour markers to be used in combination with imaging technique in clinical oncology, and to develop novel anti-cancer targets for molecular-targeted therapy.
Pub.: 18 Dec '13, Pinned: 26 Jun '18
Abstract: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality. The risk factors for CVD include environmental and genetic components. Human mutations in genes involved in most aspects of cardiovascular function have been identified, many of which are involved in transcriptional regulation. The Mediator complex serves as a pivotal transcriptional regulator that functions to integrate diverse cellular signals by multiple mechanisms including recruiting RNA polymerase II, chromatin modifying proteins and non-coding RNAs to promoters in a context dependent manner. This review discusses components of the Mediator complex and the contribution of the Mediator complex to normal and pathological cardiac development and function. Enhanced understanding of the role of this core transcriptional regulatory complex in the heart will help us gain further insights into CVD.
Pub.: 04 Jun '13, Pinned: 26 Jun '18