MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2.
- Martínez de Paz A Department of Biochemistry and Microbiology, University of Victoria, Petch Building 260, Victoria, BC, V8W 3P6, Canada.
- Khajavi L Unité de Mathématiques et Informatique Appliquées, Toulouse INRA, Auzeville, BP 52627, 31326, Castanet-Tolosan Cedex, France.
- Martin H Centre de Physiopathologie de Toulouse Purpan, INSERM, UMR 1043, CNRS, UMR 5282, Université Toulouse III Paul Sabatier, Toulouse, France.
- Claveria-Gimeno R Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI and GBsC-CSC-BIFI, Universidad de Zaragoza, 50018, Saragossa, Spain.
- Tom Dieck S Synaptic Plasticity Department, Max-Planck-Institute for Brain Research, Frankfurt/Main, Germany.
- Cheema MS Department of Biochemistry and Microbiology, University of Victoria, Petch Building 260, Victoria, BC, V8W 3P6, Canada.
- Sanchez-Mut JV School of Life Sciences, Brain Mind Institute, École Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland.
- Moksa MM Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada.
- Carles A Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada.
- Brodie NI University of Victoria-Genome British Columbia Proteomics Centre, Vancouver Island Technology Park, #3101-4464 Markham Street, Victoria, BC, V8Z7X8, Canada.
- Sheikh TI Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8, Canada.
- Freeman ME Department of Biochemistry and Microbiology, University of Victoria, Petch Building 260, Victoria, BC, V8W 3P6, Canada.
- Petrotchenko EV University of Victoria-Genome British Columbia Proteomics Centre, Vancouver Island Technology Park, #3101-4464 Markham Street, Victoria, BC, V8Z7X8, Canada.
- Borchers CH University of Victoria-Genome British Columbia Proteomics Centre, Vancouver Island Technology Park, #3101-4464 Markham Street, Victoria, BC, V8Z7X8, Canada.
- Schuman EM Synaptic Plasticity Department, Max-Planck-Institute for Brain Research, Frankfurt/Main, Germany.
- Zytnicki M Unité de Mathématiques et Informatique Appliquées, Toulouse INRA, Auzeville, BP 52627, 31326, Castanet-Tolosan Cedex, France.
- Velazquez-Campoy A Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI and GBsC-CSC-BIFI, Universidad de Zaragoza, 50018, Saragossa, Spain.
- Abian O Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI and GBsC-CSC-BIFI, Universidad de Zaragoza, 50018, Saragossa, Spain.
- Hirst M School of Life Sciences, Brain Mind Institute, École Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland.
- Esteller M Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Avinguda Gran Vía de L'Hospitalet 199-203. L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
- Vincent JB Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8, Canada.
- Malnou CE Centre de Physiopathologie de Toulouse Purpan, INSERM, UMR 1043, CNRS, UMR 5282, Université Toulouse III Paul Sabatier, Toulouse, France.
- Ausió J Department of Biochemistry and Microbiology, University of Victoria, Petch Building 260, Victoria, BC, V8W 3P6, Canada. jausio@uvic.ca.
- 2019-10-12
Published in:
- Epigenetics & chromatin. - 2019
Chromatin
Isoforms
MeCP2
Rett syndrome
Animals
Cell Line, Tumor
Chromatin
Circadian Rhythm
DNA
Humans
Methyl-CpG-Binding Protein 2
Mice
Mice, Knockout
Neurons
Protein Binding
Protein Domains
Protein Isoforms
Rats
Rats, Sprague-Dawley
Rett Syndrome
English
BACKGROUND
MeCP2-a chromatin-binding protein associated with Rett syndrome-has two main isoforms, MeCP2-E1 and MeCP2-E2, differing in a few N-terminal amino acid residues. Previous studies have shown brain region-specific expression of these isoforms which, in addition to their different cellular localization and differential expression during brain development, suggest that they may also have non-overlapping molecular mechanisms. However, differential functions of MeCP2-E1 and E2 remain largely unexplored.
RESULTS
Here, we show that the N-terminal domains (NTD) of MeCP2-E1 and E2 modulate the ability of the methyl-binding domain (MBD) to interact with DNA as well as influencing the turn-over rates, binding dynamics, response to neuronal depolarization, and circadian oscillations of the two isoforms. Our proteomics data indicate that both isoforms exhibit unique interacting protein partners. Moreover, genome-wide analysis using ChIP-seq provide evidence for a shared as well as a specific regulation of different sets of genes.
CONCLUSIONS
Our study supports the idea that Rett syndrome might arise from simultaneous impairment of cellular processes involving non-overlapping functions of MECP2 isoforms. For instance, MeCP2-E1 mutations might impact stimuli-dependent chromatin regulation, while MeCP2-E2 mutations could result in aberrant ribosomal expression. Overall, our findings provide insight into the functional complexity of MeCP2 by dissecting differential aspects of its two isoforms.
MeCP2-a chromatin-binding protein associated with Rett syndrome-has two main isoforms, MeCP2-E1 and MeCP2-E2, differing in a few N-terminal amino acid residues. Previous studies have shown brain region-specific expression of these isoforms which, in addition to their different cellular localization and differential expression during brain development, suggest that they may also have non-overlapping molecular mechanisms. However, differential functions of MeCP2-E1 and E2 remain largely unexplored.
RESULTS
Here, we show that the N-terminal domains (NTD) of MeCP2-E1 and E2 modulate the ability of the methyl-binding domain (MBD) to interact with DNA as well as influencing the turn-over rates, binding dynamics, response to neuronal depolarization, and circadian oscillations of the two isoforms. Our proteomics data indicate that both isoforms exhibit unique interacting protein partners. Moreover, genome-wide analysis using ChIP-seq provide evidence for a shared as well as a specific regulation of different sets of genes.
CONCLUSIONS
Our study supports the idea that Rett syndrome might arise from simultaneous impairment of cellular processes involving non-overlapping functions of MECP2 isoforms. For instance, MeCP2-E1 mutations might impact stimuli-dependent chromatin regulation, while MeCP2-E2 mutations could result in aberrant ribosomal expression. Overall, our findings provide insight into the functional complexity of MeCP2 by dissecting differential aspects of its two isoforms.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1186/s13072-019-0298-1
- PMID 31601272
- Persistent URL
- https://sonar.ch/global/documents/212352
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