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Missing link connects cell growth
A new mechanism coordinating embryo communication has been discovered. Researchers at the Wellcome Sanger Institute and the Wellcome, MRC Cambridge Stem Cell Institute in the United Kingdom, found signals inside and between cells also respond to signals from outside the cell via the same protein mediator. Reported in Nature, their study reveals SMAD2 and SMAD3 proteins (known as SMAD2/3) link and coordinate numerous lines of communication previously thought separate.
For the first time researchers identify that SMAD2/3, in addition to switching on specific genes in a developing embryo, precisely regulates the timing of when genes turn, so subsequently their function. In effect, fine-tuning all the processes of embryo development.
The body contains approximately 37 trillion cells, yet the human genome only contains around 20,000 genes. So, to produce every tissue and cell type in the body, different combinations of genes must operate at different moments in the development of an embryo. Being able to turn off genes at specific moments in cell development allows researchers to investigate these changing roles.
This newly identified SMAD2/3 mechanism may be essential in other cellular processes needing a rapid response - such as organ repair, immune response, and even cancer growth. As such, this discovery might inspire novel ways for studying these processes. The SMAD2/3 protein is known to be vital to all cell signalling processes, from controlling growth in some cell types to controlling the response to stress in others. It is also known to interact with DNA-binding proteins called transcription factors. But until now, it was a mystery how SMAD2/3 performs so many different functions.
Studying developing human pluripotent cells, ones that give rise to several unique cell types and not totipotent cells that give rise to all tissues and organs, researchers made observations regarding interactions between SMAD2/3 and other proteins. While SMAD2/3 does bind to some transcription factors, it also coordinates protein cell signalling in a whole range of internal cell molecular processes. One of those recently discovered molecular interactions is RNA editing. Proteins are produced by transcribing DNA into messenger RNA which immediately produces proteins. But RNA transcription also reduces the stability of DNA. The production of proteins can occur faster than stopping transcription altogether.
For the first time researchers saw that SMAD2/3 activates RNA editing, making DNA unstable and quick to degrade. Therefore, SMAD2/3 modifies protein production by switching it on and off quickly, controlling the speed of gene editing.
Dr Alessandro Bertero, a first author on the paper and former PhD student at the Wellcome - MRC Cambridge Stem Cell Institute: "To our knowledge this is the first time that anyone has seen that SMAD2/3 interacts with so many multiple processes, unexpectedly coordinating different cell pathways. Our study shows that SMAD2/3 is like a multi-function Swiss army knife instead of the specialised tool it was previously thought to be, creating a link between various key pathways."
Dr Ludovic Vallier, lead author on the paper from the Wellcome Sanger Institute and Wellcome - MRC Cambridge Stem Cell Institute, adds: "Our study reveals that cell signalling with SMAD2/3 coordinates cellular mechanisms and allows the cells to change state quickly. Understanding this could be important for studying diseases such as cancer where cellular processes are often investigated in isolation. These findings could also change the way mechanisms such as mRNA processing, DNA repair and transcriptional regulations are studied and open entire new fields of investigation."
The TGF? pathway has essential roles in embryonic development, organ homeostasis, tissue repair and disease1,2. These diverse effects are mediated through the intracellular effectors SMAD2 and SMAD3 (hereafter SMAD2/3), whose canonical function is to control the activity of target genes by interacting with transcriptional regulators3. Therefore, a complete description of the factors that interact with SMAD2/3 in a given cell type would have broad implications for many areas of cell biology. Here we describe the interactome of SMAD2/3 in human pluripotent stem cells. This analysis reveals that SMAD2/3 is involved in multiple molecular processes in addition to its role in transcription. In particular, we identify a functional interaction with the METTL3–METTL14–WTAP complex, which mediates the conversion of adenosine to N6-methyladenosine (m6A) on RNA4. We show that SMAD2/3 promotes binding of the m6A methyltransferase complex to a subset of transcripts involved in early cell fate decisions. This mechanism destabilizes specific SMAD2/3 transcriptional targets, including the pluripotency factor gene NANOG, priming them for rapid downregulation upon differentiation to enable timely exit from pluripotency. Collectively, these findings reveal the mechanism by which extracellular signalling can induce rapid cellular responses through regulation of the epitranscriptome. These aspects of TGF? signalling could have far-reaching implications in many other cell types and in diseases such as cancer5.
Authors: Alessandro Bertero, Stephanie Brown, Pedro Madrigal, Anna Osnato, Daniel Ortmann, Loukia Yiangou, Juned Kadiwala, Nina C. Hubner, Igor Ruiz de los Mozos, Christoph Sadée, An-Sofie Lenaerts, Shota Nakanoh, Rodrigo Grandy, Edward Farnell, Jernej Ule, Hendrik G. Stunnenberg, Sasha Mendjan & Ludovic Vallier
The Wellcome Trust - MRC Cambridge Stem Cell Institute is a world-leading centre for stem cell research with a mission to transform human health through a deep understanding of normal and pathological stem cell behaviour. Bringing together biological, clinical and physical scientists operating across a range of tissue types and at multiple scales, we explore the commonalities and differences in stem cell biology in a cohesive and inter-disciplinary manner. In 2018, we will relocate to a new purpose-built home on the Cambridge Biomedical Campus. Housing over 350 researchers, including a critical mass of clinician scientists, the Institute will integrate with neighbouring disease-focused research institutes and also act as a hub for the wider stem cell community in Cambridge. http://www.stemcells.cam.ac.uk
The Wellcome Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease. http://www.sanger.ac.uk
Wellcome exists to improve health for everyone by helping great ideas to thrive. We're a global charitable foundation, both politically and financially independent. We support scientists and researchers, take on big problems, fuel imaginations and spark debate. http://www.wellcome.ac.uk
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