Cell-type specialization is encoded by specific chromatin topologies

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.

An epigenome atlas of neural progenitors within the embryonic mouse forebrain

“…As we only examined ~50 genes with Capture-C, the realm of region-specific interactions between genes and cREs in the developing forebrain is only beginning to be explored. Previous comparative analyses of chromatin structure have described organ and cell type-specific spatial configurations but have focused mostly on adult tissues 53 , 54 . Analysis of cell populations representing earlier stages of differentiation trajectories have been mostly restricted to the immune system 55 , 56 , limb differentiation 57 and other organisms 58 , 59 and have revealed lower variation of chromatin structure between different cell types.…”

Gene structure heterogeneity drives transcription noise within human chromosomes

“…Besides the link to transcriptional hubs and cohesin degron experiments, our results provide insight into other biological observations that are difficult to reconcile with a single existing model. First, ImmunoGAM suggests that chromatin topologies are cell-type specific 34 , at variance with TADs, which are largely cell-type insensitive 35 . Our results also suggest that the different behaviour may be due to the fact that topologies are closely related to transcription, hence are expected to be cell-type specific, but the structural heterogeneity is not so easily captured by Hi-C like approaches.…”

An epigenome atlas of neural progenitors within the embryonic mouse forebrain

“…As we only examined ~50 genes with Capture-C, the realm of region-specific interactions between genes and cREs in the developing forebrain is only beginning to be explored. Previous comparative analyses of chromatin structure have described organ and cell type-specific spatial configurations, but have focused mostly on adult tissues 54,55 . Analysis of cell populations representing earlier stages of differentiation trajectories have been mostly restricted to the immune system 56,57 , limb differentiation 58 and other organisms 59,60 and have revealed lower variation of chromatin structure between different cell types.…”