title: Loss of neuronal 3D chromatin organization causes transcriptional and behavioural deficits related to serotonergic dysfunction.
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.
authors.affiliation: 1] Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Avenida Santiago Ramón y Cajal s/n, Sant Joan d'Alacant, 03550 Alicante, Spain [2] [3].
authors.forename: Satomi
authors.initials: S
authors.lastname: Ito
authors.affiliation: 1] Nencki Institute of Experimental Biology, Pasteura 3, 02-093 Warsaw, Poland [2].
authors.forename: Adriana
authors.initials: A
authors.lastname: Magalska
authors.affiliation: Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Avenida Santiago Ramón y Cajal s/n, Sant Joan d'Alacant, 03550 Alicante, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Alcaraz-Iborra
authors.affiliation: Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Avenida Santiago Ramón y Cajal s/n, Sant Joan d'Alacant, 03550 Alicante, Spain.
authors.forename: Jose P
authors.initials: JP
authors.lastname: Lopez-Atalaya
authors.affiliation: Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Avenida Santiago Ramón y Cajal s/n, Sant Joan d'Alacant, 03550 Alicante, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Rovira
authors.affiliation: Laboratory of Computational Biology, Estación Experimental de Aula Dei (Consejo Superior de Investigaciones Científicas) and Fundación ARAID, Avenida Montañana 1.005, 50059 Zaragoza, Spain.
authors.forename: Bruno
authors.initials: B
authors.lastname: Contreras-Moreira
authors.affiliation: Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Avenida Santiago Ramón y Cajal s/n, Sant Joan d'Alacant, 03550 Alicante, Spain.
authors.forename: Michal
authors.initials: M
authors.lastname: Lipinski
authors.affiliation: Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Avenida Santiago Ramón y Cajal s/n, Sant Joan d'Alacant, 03550 Alicante, Spain.
authors.forename: Roman
authors.initials: R
authors.lastname: Olivares
authors.affiliation: Instituto de Investigación en Discapacidades Neurológicas (IDINE), Departamento de Ciencias Médicas, Facultad de Medicina, Universidad de Castilla-La Mancha, Campus Biosanitario, C/Almansa, 14, Albacete 02006, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Martinez-Hernandez
authors.affiliation: Nencki Institute of Experimental Biology, Pasteura 3, 02-093 Warsaw, Poland.
authors.forename: Blazej
authors.initials: B
authors.lastname: Ruszczycki
authors.affiliation: Instituto de Investigación en Discapacidades Neurológicas (IDINE), Departamento de Ciencias Médicas, Facultad de Medicina, Universidad de Castilla-La Mancha, Campus Biosanitario, C/Almansa, 14, Albacete 02006, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Lujan
authors.affiliation: Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Avenida Santiago Ramón y Cajal s/n, Sant Joan d'Alacant, 03550 Alicante, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Geijo-Barrientos
authors.affiliation: Nencki Institute of Experimental Biology, Pasteura 3, 02-093 Warsaw, Poland.
authors.forename: Grzegorz M
authors.initials: GM
authors.lastname: Wilczynski
authors.affiliation: Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Avenida Santiago Ramón y Cajal s/n, Sant Joan d'Alacant, 03550 Alicante, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Barco
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D002843:Chromatin / Q000737:chemistry / Q000235:genetics / Q000648:ultrastructure*; D044127:Epigenesis, Genetic; D022041:Euchromatin / Q000378:metabolism / Q000648:ultrastructure; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006570:Heterochromatin / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D016548:Prosencephalon / Q000378:metabolism / Q000473:pathology; D011985:Receptors, Serotonin / Q000235:genetics; D012701:Serotonin / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D022041:Euchromatin; D006570:Heterochromatin; D006657:Histones; D011985:Receptors, Serotonin; D049452:Green Fluorescent Proteins; D012701:Serotonin