Loss of neuronal 3D chromatin organization causes transcriptional and behavioural deficits related to serotonergic dysfunction

Satomi Ito, Adriana Magalska, Manuel Alcaraz-Iborra, Jose P. Lopez-Atalaya, Victor Rovira, Bruno Contreras-Moreira, Michal Lipinski, Roman Olivares, Jose Martinez-Hernandez, Blazej Ruszczycki, Rafael Lujan, Emilio Geijo-Barrientos, Grzegorz M. Wilczynski and Angel Barco ()
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Satomi Ito: Instituto de Neurociencias (Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas)
Adriana Magalska: Nencki Institute of Experimental Biology
Manuel Alcaraz-Iborra: Instituto de Neurociencias (Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas)
Jose P. Lopez-Atalaya: Instituto de Neurociencias (Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas)
Victor Rovira: Instituto de Neurociencias (Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas)
Bruno Contreras-Moreira: Laboratory of Computational Biology, Estación Experimental de Aula Dei (Consejo Superior de Investigaciones Científicas) and Fundación ARAID
Michal Lipinski: Instituto de Neurociencias (Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas)
Roman Olivares: Instituto de Neurociencias (Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas)
Jose Martinez-Hernandez: Instituto de Investigación en Discapacidades Neurológicas (IDINE), Facultad de Medicina, Universidad de Castilla-La Mancha, Campus Biosanitario
Blazej Ruszczycki: Nencki Institute of Experimental Biology
Rafael Lujan: Instituto de Investigación en Discapacidades Neurológicas (IDINE), Facultad de Medicina, Universidad de Castilla-La Mancha, Campus Biosanitario
Emilio Geijo-Barrientos: Instituto de Neurociencias (Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas)
Grzegorz M. Wilczynski: Nencki Institute of Experimental Biology
Angel Barco: Instituto de Neurociencias (Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas)

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: Abstract The interior of the neuronal cell nucleus is a highly organized three-dimensional (3D) structure where regions of the genome that are linearly millions of bases apart establish sub-structures with specialized functions. To investigate neuronal chromatin organization and dynamics in vivo, we generated bitransgenic mice expressing GFP-tagged histone H2B in principal neurons of the forebrain. Surprisingly, the expression of this chimeric histone in mature neurons caused chromocenter declustering and disrupted the association of heterochromatin with the nuclear lamina. The loss of these structures did not affect neuronal viability but was associated with specific transcriptional and behavioural deficits related to serotonergic dysfunction. Overall, our results demonstrate that the 3D organization of chromatin within neuronal cells provides an additional level of epigenetic regulation of gene expression that critically impacts neuronal function. This in turn suggests that some loci associated with neuropsychiatric disorders may be particularly sensitive to changes in chromatin architecture.

Date: 2014
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DOI: 10.1038/ncomms5450

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