DOCSLIB.ORG

The Molecular Basis of Mecp2 Function in the Brain

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Molecular Basis of Mecp2 Function in the Brain Edinburgh Research Explorer The molecular basis of MeCP2 function in the brain Citation for published version: Tillotson, R & Bird, A 2020, 'The molecular basis of MeCP2 function in the brain', Journal of Molecular Biology, vol. 432, no. 6. https://doi.org/10.1016/j.jmb.2019.10.004 Digital Object Identifier (DOI): 10.1016/j.jmb.2019.10.004 Link: Link to publication record in Edinburgh Research Explorer Document Version: Publisher's PDF, also known as Version of record Published In: Journal of Molecular Biology General rights Copyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorer content complies with UK legislation. If you believe that the public display of this file breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 02. Oct. 2021 Review The Molecular Basis of MeCP2 Function in the Brain Rebekah Tillotson 1,2 and Adrian Bird 3 1 - Genetics and Genome Biology Program, The Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 0A4, Canada 2 - Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK 3 - Wellcome Centre for Cell Biology, University of Edinburgh, The Michael Swann Building, King's Buildings, Max Born Crescent, Edinburgh, EH9 3BF, UK Correspondence to Adrian Bird: [email protected] https://doi.org/10.1016/j.jmb.2019.10.004 Edited by Tuncay Baubec Abstract MeCP2 is a reader of the DNA methylome that occupies a large proportion of the genome due to its high abundance and the frequency of its target sites. It has been the subject of extensive study because of its link with ‘MECP2-related disorders’, of which Rett syndrome is the most prevalent. This review integrates evidence from patient mutation data with results of experimental studies using mouse models, cell lines and in vitro systems to critically evaluate our understanding of MeCP2 protein function. Recent evidence challenges the idea that MeCP2 is a multifunctional hub that integrates diverse processes to underpin neuronal function, suggesting instead that its primary role is to recruit the NCoR1/2 co-repressor complex to methylated sites in the genome, leading to dampening of gene expression. © 2019 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). Introduction Next-generation sequencing technologies have revealed where MeCP2 binds in the genome and Numerous chromatin-associated proteins and how it interprets the DNA methylome to influence noncoding RNAs work together to establish cell gene expression. Finally, structural studies have type-specific epigenetic states that regulate gene defined in molecular detail the interactions between expression. These factors are vital for normal MeCP2 and its key binding partners. Together, the mammalian development, with deletion of individual findings provide a coherent picture of MeCP2 members often resulting in lethality in mutant mice function as an essential reader of the DNA methy- [1]. Additionally, epigenetic factors often have links lome in the brain that optimises neuronal transcrip- to neurological disease, caused by mutations tion programmes. affecting dosage such as haploinsufficiency, locus duplications or hypomorphic alleles [2]. Here, we discuss the role of MeCP2, a reader of the DNA MECP2-Related Disorders and Mouse methylome, encoded by the X-linked MECP2 gene. Models The gene has been implicated in several ‘MECP2- related disorders’ [3] prompting numerous studies of Loss of function mutations in the MECP2 gene in MeCP2 protein function. We discuss a spectrum of hemizygous male patients cause neonatal encepha- evidence that sheds light on the molecular mechan- lopathy, which is usually fatal before the age of 2 isms involved, including clinical genetic investiga- years [4]. The same mutations cause the severe tions of genotype-phenotype correlations and neurological disorder Rett syndrome (RTT) in mouse models of the resulting human conditions. heterozygous females [5]. RTT occurs in 1 in 0022-2836/© 2019 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). Journal of Molecular Biology (2020) 432, 1602e1623 MeCP2 function in Brain 1603 10e15,000 live female births [6], making it one of the fied 10 other proteins that contain this domain: most common causes of monogenic intellectual MBD1-4, MBD5 (alternative names TAM1, disability in females. The condition is characterised KIAA1461), MBD6 (alternative names TAM2, by 6e18 months of normal development before KIAA1887), BAZ2A (alternative name TIP5), cognitive regression. Affected individuals lose BAZ2B, SETDB1 (alternative names ESET, learned speech and purposeful hand movements, KMT1E) and SETDB2 (alternative name CLLD8) develop stereotypies such as ‘hand-wringing’ and [25e32]. Of these, only MeCP2, MBD1, MBD2 and acquire motor deficiencies including gait ataxia [3]. MBD4 have been shown to bind DNA in vitro in a Symptoms can also include microcephaly [7], methylation-specific manner [23,26,32,33]. Specifi- respiratory problems [8] and seizures [9]. Disease city for the same binding sites in DNA raises the progression plateaus and although patients show possibility of competition between these proteins, slow regression in later life, 70% reach the age of 50 though analysis of their temporal-spatial expression [10]. Other MECP2 mutations that may retain more patterns reveals differences between cell types. protein function have been implicated in milder MeCP2 is expressed in all tissues but reaches psychiatric disorders, such as autism and schizo- near-histone abundance in neurons (~16 Â 106 phrenia in both males and females [http://mecp2. molecules per nucleus) [34]. Its levels increase chw.edu.au/]. The importance of correct MeCP2 during embryonic and postnatal development, pla- dosage is evidenced by MECP2 duplication syn- teauing at 10 years in humans [35] and 5 weeks in drome, which doubles MeCP2 levels and mostly mice [34]. MBD1 is expressed during neurogenesis affects males as the locus containing MECP2 is but is then downregulated [36]. MBD2 and MBD4 are almost always copied within the X chromosome. more widely expressed across somatic tissues, and This condition can run in families, with carrier MBD4 is the only family member detected in females developing no or mild symptoms because embryonic stem cells [36,37]. Whereas complete of extreme (>90%) skewing of X chromosome deletion of Mecp2 in mice leads to severe neurolo- inactivation, thereby silencing the duplicated locus gical symptoms and death around 9 weeks of age [11]. Affected boys display some symptoms that [13,14], knocking out the other members results in overlap with RTT including intellectual disability, minimal phenotypes [36,38e43]. Even though loss of impaired language, gait abnormalities and seizures. MBD1 causes decreased neurogenesis, the animals Individuals with this condition suffer from recurrent have a normal lifespan and only mild behavioural infections because of immunological dysfunction, defects [38,39]. These results suggest that MeCP2 is often leading to death at around 25 years of age the MBD family member with the greatest role in [11,12]. Both RTT and MECP2 duplication syndrome interpreting the DNA methylome in the brain. have been extensively modelled in mice, which MeCP2 protein levels in human and mouse tissues display overt neurological defects as well as correlate poorly with transcription of the MECP2/ phenotypes that can be assessed by behavioural Mecp2 gene [35]. This may be explained by the testing (Table 1)[13e17]. Such studies have activity of several posttranscriptional regulatory established that MeCP2 is required for maintenance mechanisms, including alternative splicing, use of of neuronal function since deletion of the gene in different polyadenylation sites and posttranslational adult mice causes RTT-like defects [18,19]. Excit- modification. The gene spans four exons, which are ingly, reactivation of Mecp2 in symptomatic MeCP2- transcribed and spliced to form two isoforms, e1 and deficient mice leads to phenotypic reversal, indicat- e2, where only e2 includes exon 2 (Fig. 1)[44,45]. ing that development in the absence of MeCP2 Isoform e1 is the ancestral form, conserved across causes little or no lasting damage [20,21]. Similarly, vertebrates, whereas isoform e2 is only present in the behavioural phenotypes of mice overexpressing mammals. The two isoforms are very similar, MeCP2 can be rescued by genetic deletion or differing only at the extreme N-terminus, and most antisense oligonucleotideemediated downregula- evidence indicates that they are functionally inter- tion of one copy [22]. These findings provide hope changeable [46]. Importantly, e2 mRNA is translated that both disorders will be curable. at a much lower efficiency because of the presence of an upstream ATG [44], so the great majority of MeCP2 protein in the brain is derived from e1. The MeCP2 is an Essential Reader of DNA gene contains four alternative polyadenylation sites, 0 Methylation in the Brain producing 3 UTRs ranging from 0.1 to 8.6 kb, although only the longest and shortest mRNAs are MeCP2 was initially discovered over quarter of a detected in neurons. The use of different polyade- century ago because of its ability to bind DNA in a nylation sites determines whether they contain methylation-specific manner [23]. The ~90 amino binding sites for proteins and miRNAs that regulate acid region responsible for binding was called the mRNA stability and translation [47e49]. MeCP2 methyl-CpG binding domain (MBD) [24].
Load more

Recommended publications
  • 2011 Gairdner Foundation Annual Report
    2011 GAIRDNER FOUNDATION ANNUAL REPORT May 30, 2012 TABLE OF CONTENTS TABLE OF CONTENTS ...................................................................................................................................... 2 HISTORY OF THE GAIRDNER FOUNDATION .............................................................................................. 3 MISSION,VISION ................................................................................................................................................ 4 GOALS .................................................................................................................................................................. 5 MESSAGE FROM THE CHAIR .......................................................................................................................... 6 MESSAGE FROM THE PRESIDENT/SCIENTIFIC DIRECTOR ..................................................................... 7 2011 YEAR IN REVIEW ..................................................................................................................................... 8 REPORT ON 2011 OBJECTIVES ..................................................................................................................... 12 THE YEAR AHEAD: OBJECTIVES FOR 2012 ............................................................................................... 13 2011 SPONSORS ................................................................................................................................................ 14 GOVERNANCE
    [Show full text]
  • Acknowledgment of Reviewers, 2015
    Acknowledgment of Reviewers, 2015 The PNAS editors would like to thank all the individuals who dedicated their considerable time and expertise to the journal by serving as reviewers in 2015. Their generous contribution is deeply appreciated. A Peter B. Adler Colin J. Akerman Eric E. Allen James Ammerman Duur K. Aanen Ralph Adolphs Joshua M. Akey Heather C. Allen David M. Amodio Adam R. Abate Ruedi Aebersold Anna Akhmanova Jim Allen Valentin Amrhein John T. Abatzoglou Hugo Aerts Hajime Akimoto Karen N. Allen Esther Amstad Jonathan Abbatt Hagit P. Affek Akin Akinc Michael F. Allen Ronald Amundson Allison Abbott Arash Afraz Shizuo Akira Paul M. Allen Weihua An Jeffrey Abbott Theodor Agapie Ozan Akkus Rosalind J. Allen Zhiqiang An Larry F. Abbott David A. Agard Ivona Aksentijevich Morten Erik Allentoft Laura Diaz Anadon Nicholas L. Abbott Sapan Agarwal Serap Aksoy Stefano Allesina Ganesh Srinivasan Anand Chaouki T. Abdallah Joel W. Ager III Yousef Al-Abed David B. Allison Cort Anastasio Omar Abdel-Wahab Ingi Agnarsson Ashraf Al-Amoudi Steven D. Allison Lefteris Jason Ikuro Abe Anurag A. Agrawal Eric E. Alani Julian M. Allwood Anastasopoulos Stephen Tobias Abedon Ashutosh Agrawal Balbino Alarcón Eric J. Alm Hossain Anawar Moshe Abeles Rakesh Agrawal Qais Al-Awqati Benjamin A. Alman Elissar Andari Asa Abeliovich Jon Ågren Joseph Albanesi Ingvild Almas William R. L. Anderegg John Aber Alan Agresti Francis Albarede Steven C. Almo John M. Anderies Clara Abraham Jeremy J. Agresti Umberto Albarella Douglas Almond Mark L. Andermann John Abraham Jay J. Ague Silas D. Alben Uri Alon Bogi Andersen Daniel A. Abrams Fernan Agüero Frank Alber José M.
    [Show full text]
  • DNA Methylation Patterns and Cancer
    restriction/modification system, which brought Werner Arber, Daniel Nathans and Hamilton Smith the 1978 Nobel Prize in Physiology or Medicine, and made restriction enzymes the primary tools of Charles Rodolphe Brupbacher Foundation molecular biology. Four decades have passed since then, but the role of 5-methylcytosine in eukaryotic DNA metabolism is still shrouded in mystery. We know that the sperm methylation pattern is largely The erased after fertilization and that methylation is gradually reintroduced Charles Rodolphe Brupbacher Prize during embryogenesis and differentiation, but the processes that for Cancer Research 2017 regulate the cell type- and tissue-specific methylation patterns remain is awarded to to be elucidated. We have also learned that DNA can be not only methylated, but also demethylated, and that aberrant methylation can lead to disease - including cancer. Again, how these processes are regulated remains to be discovered. However, we have learnt a great Sir Adrian Peter Bird, deal about 5-methylcytosine metabolism during the past three decades and much of our knowledge came from the laboratory of Adrian Bird. PhD Adrian spent his doctoral and postdoctoral time in Max Birnstiel’s for his contributions to our understanding laboratory, first in Edinburgh and then in Zurich, studying the amplification of ribosomal DNA in Xenopus laevis. In this organism, of the role of DNA methylation in genomic rDNA in somatic tissues is highly methylated, while the development and disease extrachromosomal amplicons are unmethylated. When he returned to Edinburgh to establish his own group, Adrian set out to study The President The President of the Foundation of the Scientific Advisory Board the methylation pattern of these loci using the newly-available methylation-sensitive restriction enzymes.
    [Show full text]
  • Trial Please Esteemed Panel of Researchers
    The Biomedical and Life Sciences Collection • Regularly expanded, constantly updated • Already contains over 700 presentations • Growing monthly to over 1,000 talks “This is an outstanding Seminar style presentations collection. Alongside journals and books no self-respecting library in institutions hosting by leading world experts research in biomedicine and the life sciences should be without access to these talks.” When you want them, Professor Roger Kornberg, Nobel Laureate, Stanford University School of Medicine, USA as often as you want them “I commend Henry Stewart Talks for the novel and • For research scientists, graduate • Look and feel of face-to-face extremely useful complement to teaching and research.” students and the most committed seminars that preserve each Professor Sir Aaron Klug OM FRS, Nobel Laureate, The Medical senior undergraduates speaker’s personality and Research Council, University of approach Cambridge, UK • Talks specially commissioned “This collection of talks is a and organized into • A must have resource for all seminar fest; assembled by an extremely eminent group of comprehensive series that cover researchers in the biomedical editors, the world class speakers deliver insightful talks illustrated both the fundamentals and the and life sciences whether in with slides of the highest latest advances academic institutions or standards. Hundreds of hours of thought provoking presentations industry on biomedicine and life sciences. • Simple format – animated slides It is an impressive achievement!” with accompanying narration, Professor Herman Waldmann FRS, • Available online to view University of Oxford, UK synchronized for easy listening alone or with colleagues “Our staff here at GSK/Research Triangle Park wishes to convey its congratulations to your colleagues at Henry Stewart for this first-rate collection of talks from such an To access your free trial please esteemed panel of researchers.
    [Show full text]
  • The Birth of the Hong Kong Laureate Forum
    The Birth of the Hong Kong Laureate Forum On 26 September 2017, I attended the Shaw Prize Award Presentation Ceremony for the first time as Chief Executive of the Hong Kong Special Administrative Region. On that occasion, five distinguished scientists in Astronomy, Life Science and Medicine, and Mathematical Sciences were honoured. They are distinguished individuals who have achieved significant breakthrough in academic and scientific research and whose work has resulted in a positive and profound impact on mankind. As I was then drawing up a multi-pronged strategy to develop innovation and technology in Hong Kong, including the promotion of popular science education, I asked myself how we could bring together this pool of great scientific minds to help nurture the next generation of young scientists. This was the beginning of a year-long endeavour to create the Hong Kong Laureate Forum. I presented prizes at the Shaw Prize Award Presentation Ceremony 2017. From right are Laureate in Astronomy, Professor Simon DM White; Laureate in Life Science and Medicine, Professor Ronald D Vale; Laureates in Mathematical Sciences, Professor János Kollár and Professor Claire Voisin. Another Laureate in Life Science and Medicine, Professor Ian R Gibbons, did not attend the Ceremony. 1 Under the vision and generosity of the late Sir Run Run Shaw and with the unfailing support of his wife the late Lady Shaw, the Shaw Prize was established in 2002 to recognize advances and outstanding contributions in three disciplines, namely, Astronomy, Life Science and Medicine, and Mathematical Sciences. In less than two decades, the Shaw Prize has become a world-renowned award for the highest achievements in mankind.
    [Show full text]
  • Communicating Biochemistry: Meetings and Events
    © The Authors. Volume compilation © 2011 Portland Press Limited Chapter 3 Communicating Biochemistry: Meetings and Events Ian Dransfield and Brian Beechey Scientific conferences organized by the Biochemical Society represent a key facet of activity throughout the Society’s history and remain central to the present mission of promoting the advancement of molecular biosciences. Importantly, scientific conferences are an important means of communicating research findings, establishing collaborations and, critically, a means of cementing the community of biochemical scientists together. However, in the past 25 years, we have seen major changes to the way in which science is communicated and also in the way that scientists interact and establish collabo- rations. For example, the ability to show videos, “fly through” molecular structures or show time-lapse or real-time movies of molecular events within cells has had a very positive impact on conveying difficult concepts in presentations. However, increased pressures on researchers to obtain/maintain funding can mean that there is a general reluctance to present novel, unpublished data. In addition, the development of email and electronic access to scientific journals has dramatically altered the potential for communi- cation and accessibility of information, perhaps reducing the necessity of attending meetings to make new contacts and to hear exciting new science. The Biochemical Society has responded to these challenges by progressive development of the meetings format to better match the
    [Show full text]
  • Role of DNA Methyl-Cpg-Binding Protein Mecp2 in Rett Syndrome Pathobiology and Mechanism of Disease
    biomolecules Review Role of DNA Methyl-CpG-Binding Protein MeCP2 in Rett Syndrome Pathobiology and Mechanism of Disease Shervin Pejhan † and Mojgan Rastegar * Regenerative Medicine Program, and Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada; [email protected] * Correspondence: [email protected]; Tel.: +1-(204)-272-3108; Fax: +1-(204)-789-3900 † Current Address: Neuropathology Program, Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C, Canada. Abstract: Rett Syndrome (RTT) is a severe, rare, and progressive developmental disorder with patients displaying neurological regression and autism spectrum features. The affected individuals are primarily young females, and more than 95% of patients carry de novo mutation(s) in the Methyl- CpG-Binding Protein 2 (MECP2) gene. While the majority of RTT patients have MECP2 mutations (classical RTT), a small fraction of the patients (atypical RTT) may carry genetic mutations in other genes such as the cyclin-dependent kinase-like 5 (CDKL5) and FOXG1. Due to the neurological basis of RTT symptoms, MeCP2 function was originally studied in nerve cells (neurons). However, later research highlighted its importance in other cell types of the brain including glia. In this regard, scientists benefitted from modeling the disease using many different cellular systems and transgenic mice with loss- or gain-of-function mutations. Additionally, limited research in human postmortem brain tissues provided invaluable findings in RTT pathobiology and disease mechanism. MeCP2 expression in the brain is tightly regulated, and its altered expression leads to abnormal brain function, implicating MeCP2 in some cases of autism spectrum disorders.
    [Show full text]
  • AUTUMN 2012 8/10/12 13:17 Page 1
    sip AUTUMN 2012 8/10/12 13:17 Page 1 SCIENCE IN PARLIAMENT A proton collides with a proton The Higgs boson appears at last sip AUTUMN 2012 The Journal of the Parliamentary and Scientific Committee www.scienceinparliament.org.uk sip AUTUMN 2012 8/10/12 13:17 Page 2 Physics for All Science and engineering students are important for the future of the UK IOP wants to see more people studying physics www.iop.org / 35 $' 3$5/, $ LQGG sip AUTUMN 2012 8/10/12 13:17 Page 3 Last years's winter of discontent was indeed made SCIENCE IN PARLIAMENT glorious summer by several sons and daughters of York. So many medals in the Olympics were won by scions of Yorkshire that the county claimed tenth place in the medals table, something hard to accept on my side of the Pennines! As well as being fantastic athletic performances the Olympics and Paralympics were stunning demonstrations of the efficiency of UK engineering, and sip the imagination of British science. The Journal of the Parliamentary and Scientific Surely we have good reason to be all eagerly awaiting Andrew Miller MP Committee. Chairman, Parliamentary The Committee is an Associate Parliamentary the announcements from Stockholm of this year's Nobel and Scientific Group of members of both Houses of Prizes? Surely the Higgs boson will be recognised? John Committee Parliament and British members of the European Parliament, representatives of Ellis recently eloquently described the "legacy" of the scientific and technical institutions, industrial hadron collider and we would be missing an important organisations and universities.
    [Show full text]
  • Rett Syndrome Research Trust Awards $5.8 Million to Advance the Development of Treatments and Cures for Rett Syndrome and MECP2 Disorders
    Press Release: Rett Syndrome Research Trust Awards $5.8 Million to Advance the Development of Treatments and Cures for Rett Syndrome and MECP2 Disorders February 3, 2015 Media Contact: Monica Coenraads Executive Director, RSRT [email protected] 203.445.0041 Rett Syndrome Research Trust Awards $5.8 Million to Advance the Development of Treatments and Cures for Rett Syndrome and MECP2 Disorders Today the Rett Syndrome Research Trust (RSRT) announced research investments of $5.8 million awarded in 2014. RSRT’s sole and urgent goal is to abolish Rett Syndrome and related disorders. To that end, RSRT has awarded $25 million to research since its launch in 2008. Rett Syndrome is caused by mutations in a gene called MECP2 that result in a cascade of devastating symptoms that worsen over time. These symptoms begin to manifest in early childhood and leave Rett sufferers dependent on 24-hour-a-day care for the rest of their lives. The 2014 awards support projects ranging from basic science to drug development and clinical trials. Each project was selected via a rigorous peer review process that assures the highest scientifc integrity. To receive funding, every project was required to demonstrate that it has the potential to advance the development of treatments and cures. Highlights of RSRT’s 2014 awards: Funding of $1.3 million was awarded to Case Western Reserve University and the Cleveland Clinic for a Phase 2 dose escalating, placebo controlled clinical trial of low-dose ketamine for the treatment of Rett Syndrome. The study is being led by David Katz, Ph.D., Professor of Neurosciences and Psychiatry at Case Western Reserve University School of Medicine and Daniel I.
    [Show full text]
  • BGI Founder and President Visits EMBO the Stars of Biomedicine The
    AUTUMN 2012 ISSUE 22 encounters The 4th EMBO Meeting PAGES 3 AND 10 –12 The stars of biomedicine PAGE 8 ©Karlsruhe Institute of Technology (KIT) ©Karlsruhe (KIT) Institute of Technology Eric | Côte d’Azur | Vence Zaragoza PAGE 4 Focus on partnerships BGI founder and President visits EMBO INTERVIEW Gunnar von Heijne, Director of FEATURE The Milan-based Institute of INTERVIEW Sir Paul Nurse discusses the Center for Biomembrane Research at Molecular Oncology Foundation is expanding science, society, and his new venture, The Stockholm University, explains why life would into Asia to recruit top research talent to Italy. Francis Crick Institute, in an interview at be impossible without biological membranes. The 4th EMBO Meeting in Nice, France. PAGE 9 PAGE 6 PAGE 12 www.embo.org COMMENTARY Inside scientific publishing Scooping protection and rapid publication arlier in the year, we started a series of arti- These and other key procedures have been various steps to ensure rapid handling of the cles in EMBOencounters to inform readers included in a formal description of The EMBO manuscript and to avoid protracted revisions. Eabout some of the developments in scientif- Transparent Publishing Process for all four EMBO EMBO editors rapidly respond to submissions. ic publishing. The previous article described the publications (see Figure 1 and journal websites). The initial editorial decision ensures that only ‘Transparent Review’ process used by The EMBO Here, I describe the processes developed and those manuscripts enter full peer review that Journal, EMBO reports, Molecular Systems Biology used by the EMBO publications that allow have a high chance of acceptance in a timely and EMBO Molecular Medicine.
    [Show full text]
  • Quantitative Analysis Questions the Role of Mecp2 in Alternative Splicing
    bioRxiv preprint doi: https://doi.org/10.1101/2020.05.25.115154; this version posted August 31, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Quantitative analysis questions the role of MeCP2 as a global regulator of alternative splicing Kashyap Chhatbar1,2, Justyna Cholewa-Waclaw2, Ruth Shah2, Adrian Bird2, Guido Sanguinetti1,3* 1 School of Informatics, University of Edinburgh, Edinburgh, United Kingdom 2 The Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, United Kingdom 3 International School for Advanced Studies (SISSA), Trieste, Italy * To whom correspondence should be addressed: [email protected] Abstract MeCP2 is an abundant protein in mature nerve cells, where it binds to DNA sequences containing methylated cytosine. Mutations in the MECP2 gene cause the severe neurological disorder Rett syndrome (RTT), provoking intensive study of the underlying molecular mechanisms. Multiple functions have been proposed, one of which involves a regulatory role in splicing. Here we leverage the recent availability of high-quality transcriptomic data sets to probe quantitatively the potential influence of MeCP2 on alternative splicing. Using a variety of machine learning approaches that can capture both linear and non-linear associations, we show that widely different levels of MeCP2 have a minimal effect on alternative splicing in three different systems. Alternative splicing was also apparently indifferent to developmental changes in DNA methylation levels. Our results suggest that regulation of splicing is not a major function of MeCP2.
    [Show full text]
  • Publications from Rsrt-Funded Projects
    PUBLICATIONS FROM RSRT-FUNDED PROJECTS 2021 Shao, Yingyao, Yehezkel Sztainberg, Qi Wang, Sameer S. Bajikar, Alexander J. Trostle, Ying-Wooi Wan, Paymaan Jafar-nejad, et al. 2021. “Antisense Oligonucleotide Therapy in a Humanized Mouse Model of MECP2 Duplication Syndrome.” Science Translational Medicine 13 (583): eaaz7785. https://doi.org/10.1126/scitranslmed.aaz7785. Tillotson, Rebekah, Justyna Cholewa-Waclaw, Kashyap Chhatbar, John C. Connelly, Sophie A. Kirschner, Shaun Webb, Martha V. Koerner, et al. 2021. “Neuronal Non-CG Methylation Is an Essential Target for MeCP2 Function.” Molecular Cell 81 (6): 1260-1275.e12. https://doi.org/10.1016/j.molcel.2021.01.011. 2020 Aeby, Eric, Hun-Goo Lee, Yong-Woo Lee, Andrea Kriz, Brian C. Del Rosario, Hyun Jung Oh, Myriam Boukhali, Wilhelm Haas, and Jeannie T. Lee. 2020. “Decapping Enzyme 1A Breaks X-Chromosome Symmetry by Controlling Tsix Elongation and RNA Turnover.” Nature Cell Biology, August. https://doi.org/10.1038/s41556-020-0558-0. Bernardo, Pia, Stuart Cobb, Antonietta Coppola, Leo Tomasevic, Vincenzo Di Lazzaro, Carmela Bravaccio, Fiore Manganelli, and Raffaele Dubbioso. 2020. “Neurophysiological Signatures of Motor Impairment in Patients with Rett Syndrome.” Annals of Neurology 87 (5): 763–73. https://doi.org/10.1002/ana.25712. Boxer, Lisa D., William Renthal, Alexander W. Greben, Tess Whitwam, Andrew Silberfeld, Hume Stroud, Emmy Li, Marty G Yang, Benyam Kinde, Eric C Griffith, Boyan Bonev, Michael E Greenberg. 2020. “MeCP2 Represses the Rate of Transcriptional Initiation of Highly Methylated Long Genes.” Molecular Cell 77 (2): 294-309.e9. https://doi.org/10.1016/j.molcel.2019.10.032. Chhatbar, Kashyap, Justyna Cholewa-Waclaw, Ruth Shah, Adrian Bird, and Guido Sanguinetti.
    [Show full text]