Cell-type specialization in the brain is encoded by specific long-range chromatin topologies
Cell-type specialization in the brain is encoded by specific long-range chromatin topologies
Abstract Neurons and oligodendrocytes are terminally differentiated cells that sustain cascades of gene activation and repression to execute highly specialized functions, while retaining homeostatic control. To study long-range chromatin folding without disturbing the native tissue environment, we developed Genome Architecture Mapping in combination with immunoselection (immunoGAM), and applied it to three cell types from the adult murine brain: dopaminergic neurons (DNs) from the midbrain, pyramidal glutamatergic neurons (PGNs) from the hippocampus, and oligodendroglia (OLGs) from the cortex. We find cell-type specific 3D chromatin structures that relate with patterns of gene expression at multiple genomic scales, including extensive reorganization of topological domains (TADs) and chromatin compartments. We discover the loss of TAD insulation, or ‘TAD melting’, at long genes (>400 kb) when they are highly transcribed. We find many neuron-specific contacts which contain accessible chromatin regions enriched for putative binding sites for multiple neuronal transcription factors, and which connect cell-type specific genes that are associated with neurodegenerative disorders such as Parkinson’s disease, or specialized functions such as synaptic plasticity and memory. Lastly, sensory receptor genes exhibit increased membership in heterochromatic compartments that establish strong contacts in brain cells. However, their silencing is compromised in a subpopulation of PGNs with molecular signatures of long-term potentiation. Overall, our work shows that the 3D organization of the genome is highly cell-type specific, and essential to better understand mechanisms of gene regulation in highly specialized tissues such as the brain.
Harabula Izabela、Szabo Dominik、Serebreni Leonid、Bianco Simona、Musella Francesco、Paul Eleanor J.、Franke Vedran、Dechant Georg、Nicodemi Mario、Teichmann Sarah A.、Fiorillo Luca、Castelo-Branco Gon?alo、Winick-Ng Warren、Thieme Christoph J.、Abentung Andreas、Kempfer Rieke、Welch Lonnie、Chiariello Andrea M.、Kukalev Alexander、Irani Ehsan、Zhang Yingnan、Redondo Luna Zea、Triglia Elena Torlai、Meijer Mandy、Apostolova Galina、Akalin Altuna、Kolodziejczyk Aleksandra A.、Pombo Ana、Ungless Mark A.、Irastorza-Azcarate Ibai
Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbr¨1ck Centre for Molecular Medicine||Humboldt-Universit?t zu BerlinEpigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbr¨1ck Centre for Molecular Medicine||Humboldt-Universit?t zu BerlinEpigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbr¨1ck Centre for Molecular MedicineDipartimentio di Fisica, Universit¨¤ di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant?ˉAngeloDipartimentio di Fisica, Universit¨¤ di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant?ˉAngeloInstitute of Clinical Sciences, Imperial College LondonBioinformatics and Omics Data Science Platform, Berlin Institute for Medical Systems Biology, Max-Delbr¨1ck Centre for Molecular MedicineInstitute for Neuroscience, Medical University of InnsbruckDipartimentio di Fisica, Universit¨¤ di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant?ˉAngelo||Berlin Institute of HealthCavendish Laboratory, University of Cambridge||Wellcome Sanger Institute, Wellcome Genome CampusDipartimentio di Fisica, Universit¨¤ di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant?ˉAngeloLaboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet||Ming Wai Lau Centre for Reparative Medicine Karolinska InstitutetEpigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbr¨1ck Centre for Molecular MedicineEpigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbr¨1ck Centre for Molecular MedicineInstitute for Neuroscience, Medical University of InnsbruckEpigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbr¨1ck Centre for Molecular Medicine||Humboldt-Universit?t zu BerlinSchool of Electrical Engineering and Computer Science, Ohio UniversityDipartimentio di Fisica, Universit¨¤ di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant?ˉAngeloEpigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbr¨1ck Centre for Molecular MedicineEpigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbr¨1ck Centre for Molecular Medicine||Berlin Institute of HealthSchool of Electrical Engineering and Computer Science, Ohio UniversityEpigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbr¨1ck Centre for Molecular Medicine||Humboldt-Universit?t zu BerlinEpigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbr¨1ck Centre for Molecular MedicineLaboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska InstitutetInstitute for Neuroscience, Medical University of InnsbruckBioinformatics and Omics Data Science Platform, Berlin Institute for Medical Systems Biology, Max-Delbr¨1ck Centre for Molecular MedicineCavendish Laboratory, University of Cambridge||Wellcome Sanger Institute, Wellcome Genome CampusEpigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbr¨1ck Centre for Molecular Medicine||Humboldt-Universit?t zu Berlin||Berlin Institute of HealthInstitute of Clinical Sciences, Imperial College LondonEpigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbr¨1ck Centre for Molecular Medicine
细胞生物学遗传学分子生物学
Harabula Izabela,Szabo Dominik,Serebreni Leonid,Bianco Simona,Musella Francesco,Paul Eleanor J.,Franke Vedran,Dechant Georg,Nicodemi Mario,Teichmann Sarah A.,Fiorillo Luca,Castelo-Branco Gon?alo,Winick-Ng Warren,Thieme Christoph J.,Abentung Andreas,Kempfer Rieke,Welch Lonnie,Chiariello Andrea M.,Kukalev Alexander,Irani Ehsan,Zhang Yingnan,Redondo Luna Zea,Triglia Elena Torlai,Meijer Mandy,Apostolova Galina,Akalin Altuna,Kolodziejczyk Aleksandra A.,Pombo Ana,Ungless Mark A.,Irastorza-Azcarate Ibai.Cell-type specialization in the brain is encoded by specific long-range chromatin topologies[EB/OL].(2025-03-28)[2025-06-08].https://www.biorxiv.org/content/10.1101/2020.04.02.020990.点此复制
评论