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.
Competing Interest Statement
In the past 3 years, SAT has acted as a consultant for Genentech and Roche, and is a remunerated member of Scientific Advisory Boards of Biogen, GlaxoSmithKline and Foresite Labs. AP and MN hold a patent on Genome Architecture Mapping: Pombo, A., Edwards, P. A. W., Nicodemi, M., Beagrie, R. A. & Scialdone, A. Patent PCT/EP2015/079413 (2015).
Footnotes
To further explore the observation of large-scale decondensation (or melting) and loss of chromatin contacts at long genes (> 400kb), we have updated the manuscript to include new analyses. We have also added a new set of analyses to explore the presence of putative regulatory transcription factor motifs within the most cell-type specific contacts, and the types of genes present in these long-range contact loops.
