Gonçalo Castelo-Branco Group
September 2016: Gonçalo receives grant under the Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet’s new research centre for regenerative medicine.
June 2016: Paper in Science on oligodendrocyte heterogeneity, by Sueli and Amit (Linnarsson’s lab) et al.
January 2016: Gonçalo receives ERC Consolidator Grant
Our research group is interested in the molecular mechanisms defining the epigenetic state of stem/progenitor cells. We are particularly focused on how interplay between transcription factors, non-coding RNAs and chromatin modifying enzymes contributes to the transition between epigenetic states in oligodendrocyte precursor cells, with the aim to design epigenetic based-therapies to induce regeneration (remyelination) in demyelinating diseases, such as multiple sclerosis.
All cells in a given organism are derived from a single cell (zygote) and thereby share an identical genome. Additional layers of epigenetic information overlaid on the genome achieve the plethora of cellular phenotypes present in development and in the adult body. This epigenetic information is stored at the level of chromatin, the complex where nuclear DNA is packaged together with histones. DNA methylation and post-translational modifications at histones define the epigenetic state of a cell and ultimately cell fate, by controlling key processes, including transcription. Non-coding RNAs have also emerged recently as key regulators of chromatin and cell fate.
Oligodendrocytes insulate neuronal axons through their myelin containing membranes. Myelin allows the fast and efficient impulse transmission between neurons through saltatory conduction and is important for axonal integrity, thereby being essential for the proper functioning of the central nervous system. Several diseases, such as multiple sclerosis (MS), are characterized by abnormal or defective myelination. Spontaneous remyelination occurs at initial stages of MS, promoted by endogenous oligodendrocyte precursor cells (OPCs). However, this process progressively starts occurring with less efficiency, until it eventually fails. Oligodendrocyte precursors (OPCs) start to be specified early during embryogenesis, in different areas of the embryonic brain, but their terminal differentiation and functional maturation occurs only at post-natal stages. The epigenetic state of OPCs define their ability to remain as a precursor cell, differentiate or even de-differentiate into a stem cell state or a glioma initiating cell state.
The main focus of our research group is to investigate how different epigenetic states in OPCs are established, by identifying key chromatin modifying complexes and non-coding RNAs that are involved in epigenetic transitions, using technologies such as RNA-Seq (single-cells and in FACS sorted OPCs) and quantitative proteomics, among others. We have so far uncover the role of specific histone deacetylases in the differentiation of neural stem cells into the oligodendrocyte lineage (Stem Cell Reports 2014), investigated the use of HDACs inhibitors and thyroid hormone in models of multiple sclerosis (Neurobiology of Disease 2014). We also performed single cell RNA-Seq and identified several cell states within the oligodendrocyte lineage (Science 2015, Science 2016, in press). We generated a web-interface, in collaboration with Sten Linnarson’s lab, where all the data can be browsed (Oligodendrocyte Single Cell RNA-Seq 2016).
Our research group is based at the Department of Medical Biochemistry and Biophysics (MBB), at the Karolinska Institutet (KI), Stockholm, Sweden, within the Laboratory of Molecular Neurobiology. This Research Division has presently 8 research groups, focused on several aspects of development, stem cell biology, neuroscience and cancer, providing a unique critical mass and expertize, and vibrant scientific environment. Our research group has access to state-of-the-art resources in molecular and cell biology, biochemistry, and cell imaging within the unit, at the MBB department and the National Core Facility SciLifeLab at the KI campus. Furthermore, KI is a university focused on biomedical sciences and the Nobel Assembly at KI annually awards the Nobel Prize in Physiology or Medicine. KI ranks as one of the world's leading medical universities, with around 600 research groups covering all medical fields.
“Oligodendrocyte heterogeneity in the mouse juvenile and adult central nervous system”
Sueli Marques†, Amit Zeisel†, Simone Codeluppi, David van Bruggen, Ana Mendanha Falcão, Lin Xiao, Huiliang Li, Martin Häring, Hannah Hochgerner, Roman A. Romanov, Daniel Gyllborg, Ana Muñoz Manchado, Gioele La Manno, Peter Lönnerberg, Elisa M. Floriddia, Fatemah Rezayee, Patrik Ernfors, Ernest Arenas, Jens Hjerling-Leffler, Tibor Harkany, William D. Richardson, Sten Linnarsson*, Gonçalo Castelo-Branco*
SCIENCE 2016, in press
*Co-corresponding and senior author
Publication in Science
News article at KI
“Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq”
Amit Zeisel†, Ana B. Muñoz Manchado†, Simone 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*
SCIENCE 2015, 347 (6226), 1138-1142
Publication at sciencemag.org.
"Acute treatment with valproic acid and l-thyroxine ameliorates clinical signs of experimental autoimmune encephalomyelitis and prevents brain pathology in DA rats."
Castelo-Branco G*, Stridh P, Guerreiro-Cacais AO, Adzemovic MZ, Falcão AM, Marta M, Berglund R, Gillett A, Hamza KH, Lassmann H, Hermanson O, Jagodic M*.
NEUROBIOL. DIS. 2014 Nov; 71:220-33 (number of citations: 3)
*Co-corresponding and senior author
Open Access Publication at Elsevier.
"Neural stem cell differentiation is dictated by distinct actions of nuclear receptor corepressors and histone deacetylases"
Gonçalo Castelo-Branco*, Tobias Lilja, Karolina Wallenborg, Ana M. Falcao, Sueli Marques, Aileen Gracias, Derek Solum, Ricardo Paap, Julian Walfridsson, Ana I. Teixeira, Michael G. Rosenfeld, Kristen Jepsen, and Ola Hermanson*
STEM CELL REPORTS 2014, 3(3):502-15 (number of citations: 10)
*Co-corresponding and senior author
Open Access Publication at Cell Press.
"Citrullination regulates pluripotency and Histone H1 binding to chromatin"
Maria Christophorou*, Gonçalo Castelo-Branco*, Richard Halley-Stott, Clara Slade Oliveira, Remco Loos, Aliaksandra Radzisheuskaya, Kerri A. Mowen, Paul Bertone, José Silva, Magdalena Zernicka-Goetz, Michael L. Nielsen, John Gurdon, Tony Kouzarides
NATURE 2014, 507(7490):104-8
* equal contribution, co-first author
Publication at nature.com.
News article at ki.se.
“The non-coding snRNA 7SK controls transcriptional termination, poising and bidirectionality in embryonic stem cells”
Gonçalo Castelo-Branco, Paulo Amaral, Pär Engström, Sam Robson, Sueli Marques, Paul Bertone, and Tony Kouzarides
Genome Biology, 2013, 14:r98
Abstract at genomebiology.com
News article at KI
The epigenetics of cancer: from non-coding RNAs to chromatin and beyond
Castelo-Branco G, Bannister A.
Briefings in Functional Genomics, 2013, 12 (3), 161-163
Article at bfg.oxfordjournals.org
Doctoral courses and Conferences
Our lab has organized in 2013, 2014 and 2015 a doctoral course in Regulatory RNAs in Development, Disease and Evolution, together with Dr. Andrea Hinas and Dr. Paulo Amaral. The 2013 edition took place at Karolinska and included a KI conference on the same topic. The 2014 edition took place at the University of Uppsala, Sweden, while the 2015 edition took place at Karolinska Institutet and included a KI conference on Regulatory RNAs and Chromatin.
The Developing Brain
Gonçalo has been co-organising a doctoral course on the topic "The Developing Brain", together with Dr. Jens Hjerling-Leffler and Dr. Ulrika Marklund. This course has been associated with KI conferences on the same topic in 2014, 2015 and 2016.
EMBO Workshop "RNA structure meets function"
Vad är RNA? (in Swedish)
Talk at TEDxCoimbra: I only know that I know nothing: the importance of research in basic science (YouTube, in portuguese)
Research in our laboratory is funded/supported by:
European Research Council (Consolidator grant, Horizon 2020)
Swedish Research Council
Marie Curie Actions European Union 7th Framework Programme (FP7)
Swedish Brain Foundation
Åke Wibergs Foundation
Clas Groschinsky Foundation
Swedish Society of Medicine
European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)
Petrus och Augusta Hedlunds Foundation
Bioinformatics Long Term Support (WABI)
Ming Wai Lau Centre for Reparative Medicine
November 2016: Applications for a post-doctoral fellow with expertise in oligodendrocyte/myelin biology and/or rodent models of demyelination/multiple sclerosis are welcome. Please find the ad at: https://ki.mynetworkglobal.com/en/what:job/jobID:120966/where:4/
|Goncalo Castelo-Branco||Principle Investigator|
|Mandy Meijer||PhD student|
|Sueli Marques||Post-doctoral fellow|
|Ana Mendanha Falcao||Post-doctoral fellow|
|David van Bruggen||PhD student|
|Elisa Floriddia||Post-doctoral fellow|
|Diana Hernandez||Biomedicine student|
|Rashid Holtinkoski||Project student|
|João Santos||Master student, University of Lisbon, Portugal|
|Abeer Heskol||Research Assistant|