Gonçalo Castelo-Branco Group - Research and publications
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/nuclei cell RNA-Seq and identified several cell states within the oligodendrocyte lineage in development and disease (Science 2015, Science 2016, Dev Cell 2018, Nature Medicine 2018, Nature 2019). We generated several webresources from our single-cell and bulk transcriptomic datasets, compiled in our OligoInternode interface, where you can enter your gene of interest and investigate its expression pattern in the identified oligodendrocyte lineage populations/states or how your genes of interest are differentially expressed.
Altered human oligodendrocyte heterogeneity in multiple sclerosis
Sarah Jäkel, Eneritz Agirre, Ana Mendanha Falcão, David van Bruggen, Ka Wai Lee, Irene Knuesel, Dheeraj Malhotra, Charles ffrench-Constant, Anna Williams and Gonçalo Castelo-Branco.
Nature, online 23 januari 2019
Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis.
Falcão AM, van Bruggen D, Marques S, Meijer M, Jäkel S, Agirre E, et al
Nat. Med. 2018 12;24(12):1837-1844
Transcriptional Convergence of Oligodendrocyte Lineage Progenitors during Development.
Marques S, van Bruggen D, Vanichkina DP, Floriddia EM, Munguba H, Väremo L, et al
Dev. Cell 2018 08;46(4):504-517.e7
RNA velocity of single cells.
La Manno G, Soldatov R, Zeisel A, Braun E, Hochgerner H, Petukhov V, et al
Nature 2018 08;560(7719):494-498
Birth, coming of age and death: The intriguing life of long noncoding RNAs.
Samudyata , Castelo-Branco G, Bonetti A
Semin. Cell Dev. Biol. 2018 07;79():143-152
Single-cell transcriptomic analysis of oligodendrocyte lineage cells.
van Bruggen D, Agirre E, Castelo-Branco G
Curr. Opin. Neurobiol. 2017 12;47():168-175
Open Access at CON
Oligodendrocyte heterogeneity in the mouse juvenile and adult central nervous system.
Marques S, Zeisel A, Codeluppi S, van Bruggen D, Mendanha Falcão A, Xiao L, et al
Science 2016 Jun;352(6291):1326-1329
News article at KI
Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq.
Zeisel A, Muñoz-Manchado AB, Codeluppi S, Lönnerberg P, La Manno G, Juréus A, et al
Science 2015 Mar;347(6226):1138-42
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, et al
Neurobiol. Dis. 2014 Nov;71():220-33
Open Access Publication at Elsevier.
Neural stem cell differentiation is dictated by distinct actions of nuclear receptor corepressors and histone deacetylases.
Castelo-Branco G, Lilja T, Wallenborg K, Falcão AM, Marques SC, Gracias A, et al
Stem Cell Reports 2014 Sep;3(3):502-15
Open Access Publication at Cell Press.
Citrullination regulates pluripotency and histone H1 binding to chromatin.
Christophorou MA, Castelo-Branco G, Halley-Stott RP, Oliveira CS, Loos R, Radzisheuskaya A, et al
Nature 2014 Mar;507(7490):104-8
News article at ki.se.
The non-coding snRNA 7SK controls transcriptional termination, poising, and bidirectionality in embryonic stem cells.
Castelo-Branco G, Amaral PP, Engström PG, Robson SC, Marques SC, Bertone P, et al
Genome Biol. 2013 ;14(9):R98
News article at KI.
The epigenetics of cancer: from non-coding RNAs to chromatin and beyond.
Castelo-Branco G, Bannister AJ
Brief Funct Genomics 2013 May;12(3):161-3
Editorial, article at bfg.oxfordjournals.org