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Cell-type specialization is encoded by specific chromatin topologies

Warren Winick-Ng (), Alexander Kukalev, Izabela Harabula, Luna Zea-Redondo, Dominik Szabó, Mandy Meijer, Leonid Serebreni, Yingnan Zhang, Simona Bianco, Andrea M. Chiariello, Ibai Irastorza-Azcarate, Christoph J. Thieme, Thomas M. Sparks, Sílvia Carvalho, Luca Fiorillo, Francesco Musella, Ehsan Irani, Elena Torlai Triglia, Aleksandra A. Kolodziejczyk, Andreas Abentung, Galina Apostolova, Eleanor J. Paul, Vedran Franke, Rieke Kempfer, Altuna Akalin, Sarah A. Teichmann, Georg Dechant, Mark A. Ungless, Mario Nicodemi, Lonnie Welch, Gonçalo Castelo-Branco and Ana Pombo ()
Additional contact information
Warren Winick-Ng: Berlin Institute for Medical Systems Biology, Epigenetic Regulation and Chromatin Architecture Group
Alexander Kukalev: Berlin Institute for Medical Systems Biology, Epigenetic Regulation and Chromatin Architecture Group
Izabela Harabula: Berlin Institute for Medical Systems Biology, Epigenetic Regulation and Chromatin Architecture Group
Luna Zea-Redondo: Berlin Institute for Medical Systems Biology, Epigenetic Regulation and Chromatin Architecture Group
Dominik Szabó: Berlin Institute for Medical Systems Biology, Epigenetic Regulation and Chromatin Architecture Group
Mandy Meijer: Karolinska Institutet
Leonid Serebreni: Berlin Institute for Medical Systems Biology, Epigenetic Regulation and Chromatin Architecture Group
Yingnan Zhang: Ohio University
Simona Bianco: Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo
Andrea M. Chiariello: Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo
Ibai Irastorza-Azcarate: Berlin Institute for Medical Systems Biology, Epigenetic Regulation and Chromatin Architecture Group
Christoph J. Thieme: Berlin Institute for Medical Systems Biology, Epigenetic Regulation and Chromatin Architecture Group
Thomas M. Sparks: Berlin Institute for Medical Systems Biology, Epigenetic Regulation and Chromatin Architecture Group
Sílvia Carvalho: Berlin Institute for Medical Systems Biology, Epigenetic Regulation and Chromatin Architecture Group
Luca Fiorillo: Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo
Francesco Musella: Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo
Ehsan Irani: Berlin Institute for Medical Systems Biology, Epigenetic Regulation and Chromatin Architecture Group
Elena Torlai Triglia: Berlin Institute for Medical Systems Biology, Epigenetic Regulation and Chromatin Architecture Group
Aleksandra A. Kolodziejczyk: University of Cambridge
Andreas Abentung: Medical University of Innsbruck
Galina Apostolova: Medical University of Innsbruck
Eleanor J. Paul: Imperial College London
Vedran Franke: Berlin Institute for Medical Systems Biology, Bioinformatics and Omics Data Science Platform
Rieke Kempfer: Berlin Institute for Medical Systems Biology, Epigenetic Regulation and Chromatin Architecture Group
Altuna Akalin: Berlin Institute for Medical Systems Biology, Bioinformatics and Omics Data Science Platform
Sarah A. Teichmann: University of Cambridge
Georg Dechant: Medical University of Innsbruck
Mark A. Ungless: Imperial College London
Mario Nicodemi: Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo
Lonnie Welch: Ohio University
Gonçalo Castelo-Branco: Karolinska Institutet
Ana Pombo: Berlin Institute for Medical Systems Biology, Epigenetic Regulation and Chromatin Architecture Group

Nature, 2021, vol. 599, issue 7886, 684-691

Abstract: Abstract The three-dimensional (3D) structure of chromatin is intrinsically associated with gene regulation and cell function1–3. Methods based on chromatin conformation capture have mapped chromatin structures in neuronal systems such as in vitro differentiated neurons, neurons isolated through fluorescence-activated cell sorting from cortical tissues pooled from different animals and from dissociated whole hippocampi4–6. However, changes in chromatin organization captured by imaging, such as the relocation of Bdnf away from the nuclear periphery after activation7, are invisible with such approaches8. Here we developed immunoGAM, an extension of genome architecture mapping (GAM)2,9, to map 3D chromatin topology genome-wide in specific brain cell types, without tissue disruption, from single animals. GAM is a ligation-free technology that maps genome topology by sequencing the DNA content from thin (about 220 nm) nuclear cryosections. Chromatin interactions are identified from the increased probability of co-segregation of contacting loci across a collection of nuclear slices. ImmunoGAM expands the scope of GAM to enable the selection of specific cell types using low cell numbers (approximately 1,000 cells) within a complex tissue and avoids tissue dissociation2,10. We report cell-type specialized 3D chromatin structures at multiple genomic scales that relate to patterns of gene expression. We discover extensive ‘melting’ of long genes when they are highly expressed and/or have high chromatin accessibility. The contacts most specific of neuron subtypes contain genes associated with specialized processes, such as addiction and synaptic plasticity, which harbour putative binding sites for neuronal transcription factors within accessible chromatin regions. Moreover, sensory receptor genes are preferentially found in heterochromatic compartments in brain cells, which establish strong contacts across tens of megabases. Our results demonstrate that highly specific chromatin conformations in brain cells are tightly related to gene regulation mechanisms and specialized functions.

Date: 2021
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DOI: 10.1038/s41586-021-04081-2

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