Nature: Revealing the role of phase separation in neurodevelopmental diseases!

!--:page title"--July 28, 2020 /PRNewswire/ -- New findings on the destruction of condenses in neurodevelopmental disorderRett syndrome provide insights into how cells divide chromosomes, as well as new and potential therapeutic pathways. foryears, scientists have defined cells as a relatively free-flowing space where -- in addition to the tissues provided by a particular cell structure -- molecules float freely, eventually reaching the right place in some way at the right time.However, in recent years, scientists have found that because of a mechanism called phase separation, cells have more spatial tissue than previously thought.phase separation occurs in cells, when certain molecules form a large droplet-like structure, separating the substance inside the droplet from the rest of the cell.these droplets are called condensate, which helps to isolate and concentrate molecules at specific locations and appears to improve the efficiency of certain cell functions. Richard Young, aWhitehead Institute and a professor of biology at the Massachusetts Institute of Technology, has been exploring the role of previously unknown condensates in the molecules needed to collect gene transcription.to better understand when and how cells are used to isolate phase, Young Lab's graduate student, Charles Li, has set out to identify more proteins that form condensates.Young's colleague at the Whitehead Institute, Rudolf Jaenisch, is also a professor of biology at the Massachusetts Institute of Technology, and has studied MeCP2.MeCP2 is a protein associated with rett syndrome, a severe neurodevelopmental disorder.there is no cure for Rett syndrome, and Jaenisch's lab has been studying the biology of the disease in the hope of finding a medical treatment to save the neurons affected by Rett's syndrome.with the discovery of MeCP2's ability to form condensate, Young and Jaenisch saw opportunities for hope to work together in their laboratories.led by co-first author Li and Young Lab's other graduate student, Eliot Coffey, who studied MeCP2 and whether the interruption in its coagulation ability led to Rett syndrome.in these studies, researchers also revealhow how cells use condensate to help organize the active and inactive parts of the chromosomes.their findings, published recently in the journal Nature, report these insights and suggest new avenues for developing treatments for rett syndrome.picture source: The proteins that form condensates from Charles Li phase separation and Rett syndrome usually contain essentially disordered areas (IDRs), long chains like noodles that are briefly glued together to form dynamic mesh structures.previous studies have focused on the structural regions of proteins, where the binding of these regions to other molecules is very specific, and IDRs have been largely ignored.in this case, MeCP2's Big IDRs is the reason for Li's attraction.to Li's surprise, the protein has been studied for decades, so much function is thought to be the role of the protein as a whole, but it has only one structural region with recognized function, the DNA binding region., the whole protein is disordered, and the function of its parts is largely unknown.researchers found that MeCP2 uses its IDRs to aggregate and form condensing.then they tested many mutations in the MECP2 gene associated with Rett syndrome and found that they undermined MECP2's ability to form condensate.their findings suggest that treatments for coagulation associated with the protein, rather than the protein itself, may be promising in finding treatment for Rett syndrome.many laboratories have studied MeCP2 and Rett syndrome for years, but a single treatment has not yet been developed.when the project started, Coffey was immediately captivated by the idea that they might find a new disease mechanism that could help us finally understand how Rett syndrome is produced and how to treat it. ""Rick (Young) has shown that condensants play a key role in maintaining normal cellular function, and our recent collaboration sows how their destruction can lead to diseases such as Rett syndrome," Jaenisch said. "I hope that the insights we have will prove useful for our continued search for treatments for Rett syndrome and for more broadly research into condensate and disease,"." division of chromosomes researchers' investigations into MeCP2 condensate formation also revealed how chromosomes are organized into active and inactive gene regions.When MeCP2 works, it helps maintain heterogeneism, where about half of the genes in our chromosomes are "closed" and cannot be interpreted as RNA or further processed to make proteins.MeCP2 is combined with DNA sequences labeled with a typical hetero-chromatin regulatory label.this helps to squeeze MeCP2 to the threshold concentration required to form heterogeneous coagulation.these concentrations, in turn, help isolate molecules that maintain its separation from constant chromatin, half of our chromosomes are full of active genes.different proteins gather near the normal chromatin, where the molecular machines needed to transcribe the active gene are concentrated.Because of the coagulation that forms when proteins are combined with large, pasta-like IDRs, one might think that any protein containing IDRs can interact with any other protein containing IDRs to form droplets, as researchers often see. However, what they observed in MeCP2 associated with heterogeneity was the rejection of protein-forming proteins in key condensate-related substances associated with normal chromatin. important to the health of cells, genes in heterogeneous chromatin cannot be inadvertently opened. the researchers concluded that discrete constant chromatin and heterogeneous coagulants may play a key role in ensuring that transcription mechanisms are only positioned in normal chromatin, while inhibition mechanisms such as MeCP2 are positioned in heterogeneous chromatin. researchers excitedly turned their attention to how proteins can selectively bind to condensate and when they do so elsewhere in the cell. "There is a chemical syntax to be deciphered to explain the difference in the ability of certain proteins to transform into one condensat !--e and another," says !--.ewebeditor." finding these mechanisms can help us understand how cells maintain a critical balance between the active and silent parts of our genome, and how to treat diseases like rett syndrome. " () References: MeCP2 links heterochromatin condensates and neurodevelopmental disease, Nature (2020). DOI: 10.1038/s41586-020-2574-4Proteins-and-labs-together to prevent-ret-!--/ewebeditor-page."