EPIOPC · Role of chromatin-modifying enzymes in oligodendrocyte precursor state in development and multiple sclerosis

Role of chromatin-modifying enzymes inoligodendrocyte precursor statein development and multiple sclerosis

The main aim of the project “Role of chromatin-modifying enzymes in oligodendrocyte precursor state in development and multiple sclerosis” was to investigate the mechanisms of action of key transcription factors regulating oligodendrocyte development, with a focus on the interactions with chromatin modifying enzymes. We obtained considerable progress in the objectives of the project. Our group published 4 peer-reviewed papers in Science, Neurobiology of Disease and Stem Cell Reports, in which the support of this grant is acknowledged. Paper 1. Gonçalo Castelo-Branco*, Tobias Lilja, Karolina Wallenborg, Ana M. Falcao, Sueli C. Marques, Aileen Gracias, Derek Solum, Ricardo Paap, Julian Walfridsson, Ana I. Teixeira, Michael G. Rosenfeld, Kristen Jepsen, and Ola Hermanson* “Neural stem cell differentiation is dictated by distinct actions of nuclear receptor corepressors and histone deacetylases" STEM CELL REPORTS, 2014 *co-corresponding and senior authors In this paper, we found by chromatin immunoprecipitation (ChIP) coupled with Next Generation Sequencing that the chromating modifying enzymes histone deacetylase 2 (HDAC2) and HDAC3 bind to similar but also different subset of genes in neural stem cells (NSCs). The transcription factor Sox2 and HDAC2 are simultaneously present in the regulatory regions of myelin-related genes and HDAC2 actively repress OL differentiation from embryonic NSCs and oligodendrocyte precursor cells (OPCs). This is mediated by the direct inhibition of the transcription of Sox10. We also found that transcription factor Sox10 represses the expression of Sox2 and Sox9 in post-natal OPCs. I am co-senior and corresponding author of the paper, and 2 post-doctoral fellows in my group are also co-authors. Paper 2. Gonçalo Castelo-Branco*, Pernilla Stridh, Milena Z. Adzemovic, André Ortlieb Guerreiro-Cacais, Ana Mendanha Falcao, Monica Marta, Rasmus Berglund, Alan Gillett, Hamza KH, Hans Lassmann, Ola Hermanson and Maja Jagodic*. Acute treatment with valproic acid and L-thyroxine ameliorates clinical signs of experimental autoimmune encephalomyelitis and prevents brain pathology in DA rats” NEUROBIOLOGY OF DISEASE 2014 * co-corresponding and senior author As a follow-up of the Stem Cell Reports paper, I initiated a collaboration with Dr. Maja Jagodic, Karolinska Institutet, to investigate whether HDAC inhibition could be used in therapeutical approaches for multiple sclerosis. In work performed in my research group (by myself, Dr. Ana Falcao, post-doctoral fellow, and Kedir Hamza, a master student in my group) and Dr. Jagodic’s research group, we found that treatment with the HDAC inhibitor valproic acid and thyroid hormone leads to sustained amelioration of EAE in rats. Paper 3. Amit Zeisel†, Ana B. Manchado†, S. Codeluppi, Peter Lönnerberg, Gioele La Manno, Anna Juréus, Sueli Marques, Hermany Munguba, Liqun He, Christer Betsholtz, Charlotte Rolny, Gonçalo Castelo-Branco§, Jens Hjerling-Leffler* and Sten Linnarsson*, “Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq,” SCIENCE 2015, 347 (6226), 1138-1142 § senior author In a close collaboration with Dr. Sten Linnarsson and Dr. Jens-Hjerling Leffler’s labs, my research group performed single-cell RNA-Seq of OPCs and other populations within the oligodendrocyte lineage. Dr. Sueli Marques, a post-doctoral fellow in my group, run this project in our lab. Part of our collaborative effort was published in Science, 2015. I am a senior author in this publication. PAPER 4: Marques S, Zeisel A, Codeluppi S, van Bruggen D, Mendanha Falcão A, Xiao L, Li H, Häring M, Hochgerner H, Romanov RA, Gyllborg D, Muñoz-Manchado AB, La Manno G, Lönnerberg P, Floriddia EM, Rezayee F, Ernfors P, Arenas E, Hjerling-Leffler J, Harkany T, Richardson WD, Linnarsson S, Castelo-Branco G.* Oligodendrocyte heterogeneity in the mouse juvenile and adult central nervous system. SCIENCE. 2016 Jun 10;352(6291):1326-9. doi: 10.1126/science.aaf6463. PMID: 27284195 *Co-corresponding and senior author In this paper, we uncover an unexpected heterogeneity of cells of the oligodendrocyte lineages, which is an important resource to investigate the transcriptional states of oligodendrocytes. I am a co-corresponding and senior author in this publication, and several members of my group are co-authors. In association with this publication, my group and my collaborator Prof. Sten Linnarsson have made available for the scientific community a resource website: http://linnarssonlab.org/oligodendrocytes/ We have also generated additional extensive preliminary data on the 2 objectives of the grant proposal. We have currently one manuscript submitted for publication and another being finalized for submission. Updates on our current work can be found in my laboratory’s website at: http://ki.se/en/mbb/goncalo-castelo-branco-group: As such, we have successful fulfilled our objectives to uncover some of the key molecular mechanisms of oligodendrocyte differentiation and myelination and found novel chromatin targets for epigenetic-based therapies for demyelinating disease such as MS.

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