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Loss of Neuronal 3D Chromatin Organization Causes Transcriptional and Behavioural Deficits Related to Serotonergic Dysfunction

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Loss of Neuronal 3D Chromatin Organization Causes Transcriptional and Behavioural Deficits Related to Serotonergic Dysfunction ARTICLE Received 22 Jan 2014 | Accepted 18 Jun 2014 | Published 18 Jul 2014 DOI: 10.1038/ncomms5450 Loss of neuronal 3D chromatin organization causes transcriptional and behavioural deficits related to serotonergic dysfunction Satomi Ito1,*,w, Adriana Magalska2,*, Manuel Alcaraz-Iborra1, Jose P. Lopez-Atalaya1, Victor Rovira1, Bruno Contreras-Moreira3, Michal Lipinski1, Roman Olivares1, Jose Martinez-Hernandez4, Blazej Ruszczycki2, Rafael Lujan4, Emilio Geijo-Barrientos1, Grzegorz M. Wilczynski2 & Angel Barco1 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. 1 Instituto de Neurociencias (Universidad Miguel Herna´ndez—Consejo Superior de Investigaciones Cientı´ficas), Avenida Santiago Ramo´n y Cajal s/n, Sant Joan d’Alacant, 03550 Alicante, Spain. 2 Nencki Institute of Experimental Biology, Pasteura 3, 02-093 Warsaw, Poland. 3 Laboratory of Computational Biology, Estacio´n Experimental de Aula Dei (Consejo Superior de Investigaciones Cientı´ficas) and Fundacio´n ARAID, Avenida Montan˜ana 1.005, 50059 Zaragoza, Spain. 4 Instituto de Investigacio´n en Discapacidades Neurolo´gicas (IDINE), Departamento de Ciencias Me´dicas, Facultad de Medicina, Universidad de Castilla-La Mancha, Campus Biosanitario, C/Almansa, 14, Albacete 02006, Spain. * These authors contributed equally to this work. w Present address: Information Processing Biology Unit, Okinawa Institute of Science and Technology (OIST) Graduate University, 1919-1 Tancha, Onna-son, Kunigami, Okinawa 904-049, Japan. Correspondence and requests for materials should be addressed to A.B. (email: [email protected]). NATURE COMMUNICATIONS | 5:4450 | DOI: 10.1038/ncomms5450 | www.nature.com/naturecommunications 1 & 2014 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms5450 esearch over the last decade indicates that epigenetic specific layers of the cortex and striatum (Fig. 1b). Reverse dysregulation importantly contributes to the aetiology transcription–quantitative PCR (RT–qPCR) and western blot Rof neuropsychiatric disorders1–3. Among the different assays indicated that the chimeric histone is expressed at a epigenetic mechanisms of regulation of gene expression, the comparable level to endogenous histone H2B and is functionally modulation of higher-order chromatin structures is one of the integrated into chromatin (Fig. 1c–e). Nissl staining and least understood. The interior of the eukaryotic cell nucleus is a immunostaining for different neuronal proteins demonstrated highly organized 3D structure in which regions of the genome that H2BGFP did not cause neuronal death nor gross alterations that are millions of bases apart, even belonging to different in brain anatomy (Supplementary Fig. 1). chromosomes, work together and define specialized sub- In the course of these initial experiments, we observed that structures with dedicated functions4,5. Thus, in most interphase H2BGFP accumulated in discrete structures in the interior of the somatic cells, pericentromeric regions are organized in clusters neuronal nucleus that were strongly labelled with the DNA stain referred to as chromocenters that consist of transcriptionally 4’,6-diamidino-2-phenylindole (DAPI). Although DAPI staining silent DNA and exhibit species- and cell type-specific features6–8. in the nucleus of CA1 neurons typically delineates the nuclear Chromatin architecture may have particular importance in envelope and accumulates in a few large chromocenters, in neurons, because these long-living cells are permanently arrested bitransgenic animals DAPI fluorescence overlapped with GFP in interphase and the structures formed during neuronal and provided a distinctive subnuclear pattern with numerous foci differentiation are probably irreversible9–11. During neuronal and without peripheral heterochromatin attached to the nuclear maturation, the nuclear architecture of neural precursors membrane (Fig. 1f). Similar but less pronounced differences were undergoes dramatic changes and passes from a small, also observed in other neuronal types expressing H2BGFP, such heterochromatic nucleus with many small chromocenters to the as granular neurons in the dentate gyrus, and cortical and striatal large euchromatic nucleus with a few large chromocenters neurons (Fig. 1g). Quantitative 3D analysis confirmed the characteristic of mature neurons12. Although the functional increase in the number of intranuclear DAPI-stained foci in consequences of these changes are obscure, the conserved pattern CA1 pyramidal neurons and revealed that these structures were in terminally differentiated neurons suggests that they are larger and more irregular in bitransgenic than in control mice physiologically relevant. For instance, studies in Purkinje (Fig. 1h–j and Supplementary Movies 1 and 2). neurons have revealed a precise assembly process in which To confirm these observations using a different approach that specific chromosomes always cluster together and adjacent provides better spatial resolution, we used electron microscopy neurons have similar spatial distribution of centromeric and (EM). The comparison of EM images corresponding to the telomeric clusters13,14. Furthermore, recent studies have shown stratum pyramidale in the CA1 subfield revealed dramatic that gene mutations associated with intellectual disability in differences between H2BGFP and control littermates. In ultrathin humans affect chromatin compactation and the number and size sections, the nucleus of CA1 pyramidal neurons in control of chromocenters in cortical neurons15,16. The reported changes animals showed none or, at most, one to two heterochromatic in the spatial distribution of satellite DNA and active loci in regions (Fig. 1k), whereas bitransgenic mice exhibited multiple hippocampal neurons after seizures or experimentally induced discrete heteropycnotic regions (Fig. 1l). Moreover, whereas the long-term potentiation also support a role for higher-order nuclei of control neurons show heterochromatin attached to the chromatin structures in neuronal function17–19. Also consistent inner nuclear envelope, in H2BGFP mice this was detached with this view, a recent study has revealed chromosomal (compare Fig. 1m,n). In fact, some neurons in bitransgenic mice conformation changes in the chromatin of the prefrontal cortex exhibited nuclear body-like circular membranous structures that of schizophrenic patients that specifically affected the GAD1 may have originated from invaginations of the nuclear lamina locus20. during heterochromatin detachment. We also observed a Serendipitously, the generation of bitransgenic mice that reorganization of the interchromatin compartment, which express a histone H2B tagged with green fluorescent protein appeared much emptier in H2BGFP mice than in control (H2BGFP) in an inducible manner in principal neurons of the animals (Fig. 1m,n, insets). These changes of nuclear ultra- forebrain provided us with an unexpected and valuable approach structure did not alter the number or structure of synapses to examine the consequences of interfering with 3D chromatin in the stratum radiatum (Fig. 1o,p: Control ¼ 0.285 and organization in neuronal gene expression and physiology. We H2BGFP ¼ 0.272 syn mm À 2). found that the accumulation of H2BGFP causes dramatic changes To characterize the extent of the nuclear disorganization, we in the nuclear architecture of pyramidal neurons, including next conducted co-localization experiments with proteins or chromocenter declustering and loss of peripheral heterochroma- protein modifications that are known to be enriched in specific tin. These changes are accompanied by highly specific transcrip- nuclear sub-structures. In agreement with EM images, the tional defects and behavioural abnormalities, including alterations nucleolar proteins fibrillarin and nucleolin revealed that nucleoli associated with serotonin (5-HT) dysfunction. Our results suggest were normal in H2BGFP-expressing neurons (Fig. 2a). The a new role for perinuclear heterochromatin and chromocenter spliceosome protein Sam68 and the Cajal body protein coilin also organization in the epigenetic regulation of neuronal gene revealed a normal staining pattern, indicating that these expression that may have relevance in the aetiology of mental structures were preserved in bitransgenic mice (Fig. 2b,c). Lamina illness. staining was also not affected, except for the occasional invaginations reported above (Fig. 2d,e). In contrast, fluorescence in situ hybridization (FISH) using a pancentromeric
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