ABSTRACT
Both transcription and three-dimensional (3D) architecture of the mammalian genome play critical roles in neurodevelopment and its disorders. However, 3D genome structures of single brain cells have not been solved; little is known about the dynamics of single-cell transcriptome and 3D genome after birth. Here, we generated a transcriptome (3,517 cells) and 3D genome (3,646 cells) atlas of the developing mouse cortex and hippocampus by using our high-resolution multiple annealing and looping-based amplification cycles for digital transcriptomics (MALBAC-DT) and diploid chromatin conformation capture (Dip-C) methods and developing multi-omic analysis pipelines. In adults, 3D genome "structure types" delineate all major cell types, with high correlation between chromatin A/B compartments and gene expression. During development, both transcriptome and 3D genome are extensively transformed in the first post-natal month. In neurons, 3D genome is rewired across scales, correlated with gene expression modules, and independent of sensory experience. Finally, we examine allele-specific structure of imprinted genes, revealing local and chromosome (chr)-wide differences. These findings uncover an unknown dimension of neurodevelopment.
Subject(s)
Brain/growth & development , Genome , Sensation/genetics , Transcription, Genetic , Alleles , Animals , Animals, Newborn , Cell Lineage/genetics , Chromatin/metabolism , Gene Expression Regulation, Developmental , Gene Ontology , Gene Regulatory Networks , Genetic Loci , Genomic Imprinting , Mice , Multigene Family , Neuroglia/metabolism , Neurons/metabolism , Transcriptome/genetics , Visual Cortex/metabolismABSTRACT
Sensory neurons in the mouse eye and nose have unusual chromatin organization. Here we report their three-dimensional (3D) genome structure at 20-kilobase (kb) resolution, achieved by applying our recently developed diploid chromatin conformation capture (Dip-C) method to 409 single cells from the retina and the main olfactory epithelium of adult and newborn mice. The 3D genome of rod photoreceptors exhibited inverted radial distribution of euchromatin and heterochromatin compared with that of other cell types, whose nuclear periphery is mainly heterochromatin. Such genome-wide inversion is not observed in olfactory sensory neurons (OSNs). However, OSNs exhibited an interior bias for olfactory receptor (OR) genes and enhancers, in clear contrast to non-neuronal cells. Each OSN harbored multiple aggregates of OR genes and enhancers from different chromosomes. We also observed structural heterogeneity of the protocadherin gene cluster. This type of genome organization may provide the structural basis of the 'one-neuron, one-receptor' rule of olfaction.
Subject(s)
Olfactory Receptor Neurons/metabolism , Animals , Autophagy-Related Proteins/genetics , Autophagy-Related Proteins/metabolism , Female , Male , Mice , Mice, Inbred C57BL , Mutation/genetics , Olfactory Mucosa/cytology , Olfactory Mucosa/metabolism , Phospholipids/metabolism , Principal Component Analysis , Receptors, Odorant/genetics , Receptors, Odorant/metabolism , Schizosaccharomyces/metabolism , Sensory Receptor Cells/metabolismABSTRACT
A 36-year-old woman presented with right shoulder weakness after a left parotid tumor resection. The overall clinical presentation included severe paralysis and atrophy of the right sternocleidomastoid and upper trapezius, an absent right gag reflex, and diminished right posterior tongue pinprick sensation. A diagnosis of right-sided Vernet syndrome (cranial nerve IX, X, XI lesions) was made, presumably from compression of cranial nerves by internal jugular vein phlebectasia. To our knowledge, this is the first case report of spontaneous Vernet syndrome associated with internal jugular vein phlebectasia in the absence of other lesions of the jugular foramen.