Abstract
In a recent study published in Nature, Zhang, Rubio Rodríguez-Kirby and colleagues accurately recorded temporal, dynamic changes during brain development revealing the program underlying chromatin accessibility of genes involved in myelination and axonogenesis.1 By developing an in situ spatial tri–omics platform – spatial ARP-seq and spatial CTRP-seq – at a near single-cell resolution that simultaneously profiles the genome-wide chromatin state, the whole-transcriptome RNA and the proteome, the study unravels the spatiotemporal dynamics of brain development and neuroinflammatory responses, with an atlas of the mouse postnatal brain benchmarked to corresponding regions of the developing human visual cortex.1
Brain development and demyelinating injury are regulated across layers of cellular information: chromatin accessibility and epigenetic modifications (e.g., H3K27me3 repression) shape transcriptional potential, while RNA and protein outputs can diverge, making the in situ tri–omics co-profiling essential for resolving the temporal scale. Leveraging this approach, Zhang et al. identified in the wild type cortex layer-defining transcription factors whose chromatin accessibility persists in time and spreads across layers even after their RNA expression declines, consistent with an “epigenetic trailing” of developmental states. In the corpus callosum, myelin genes were epigenetically primed before full transcriptional and protein-level myelination, with patterns organised across callosal subregions in coordination with layer-specific projection neuron tracts.1 Conversely, in a lysolecithin-induced focal white-matter demyelination mouse model, the spatial tri–omics platform reveals coordinated changes in chromatin accessibility, H3K27me3-associated silencing, RNA expression, and protein abundance for oligodendrocyte and myelin genes across de- and re-myelination, together with delayed microglial activation and neuroinflammatory responses in distal white-matter tracts. Within primary and distal lesion-like regions, microglia occupy distinct multimodal states with gene modules overlapping with known disease- and injury-associated programs, while the overall neuroinflammatory response follows similar spatial and temporal trajectories.1