Gonçalo Castelo-Branco Group – research and publications

Our research group is interested in the molecular mechanisms defining the transcriptomic and epigenomic states of oligodendrocyte lineage 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 oligodendroglia, with the aim to design epigenetic based-therapies to induce regeneration/remyelination and prevent neuroinflammation in demyelinating diseases, such as MS.

Illustration of oligodendocyte progenitor cells.
Binary choices of oligodendrocyte progenitor cells (OPCs), differentiation/myelination or transition to an immune state. Illustration: Amagoia Agirre.

Research area

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), including an immune state that might be relevant for the etiology and/or progression of MS. We generated several web resources 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.

Selected latest publications

Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosis susceptibility
Mandy Meijer*, Eneritz Agirre*, Mukund Kabbe, Cassandra A. van Tuijn, Abeer Heskol, Chao Zheng, Ana Mendanha Falcão, Marek Bartosovic, Leslie Kirby, Daniela Calini, Michael R. Johnson, M. Ryan Corces, Thomas J. Montine, Xingqi Chen, Howard Y. Chang, Dheeraj Malhotra, and Gonçalo Castelo-Branco
Neuron 2022 doi: 10.1016/j.neuron.2021.12.034

Single-cell CUT&Tag profiles histone modifications and transcription factors in complex tissues.
Bartosovic M, Kabbe M, Castelo-Branco G
Nat Biotechnol 2021 Apr;():
Access the article with SharedIT

Distinct oligodendrocyte populations have spatial preference and different responses to spinal cord injury.
Floriddia EM, Lourenço T, Zhang S, van Bruggen D, Hilscher MM, Kukanja P, et al
Nat Commun 2020 11;11(1):5860

Crossing boundaries: Interplay between the immune system and oligodendrocyte lineage cells.
Kirby L, Castelo-Branco G
Semin Cell Dev Biol 2020 Nov;():

Functionally distinct subgroups of oligodendrocyte precursor cells integrate neural activity and execute myelin formation.
Marisca R, Hoche T, Agirre E, Hoodless LJ, Barkey W, Auer F, et al
Nat Neurosci 2020 03;23(3):363-374

Gsta4 controls apoptosis of differentiating adult oligodendrocytes during homeostasis and remyelination via the mitochondria-associated Fas-Casp8-Bid-axis.
Carlström KE, Zhu K, Ewing E, Krabbendam IE, Harris RA, Falcão AM, et al
Nat Commun 2020 08;11(1):4071

PAD2-Mediated Citrullination Contributes to Efficient Oligodendrocyte Differentiation and Myelination.
Falcão AM, Meijer M, Scaglione A, Rinwa P, Agirre E, Liang J, et al
Cell Rep 2019 Apr;27(4):1090-1102.e10
Article at KI News: Protein composition changes stimulate brain development and neuronal communication

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. 2019 Feb;566(7745):543-547.

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
Full text

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

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
Article at KI News: Nerve-insulating cells more diverse than previously thought