Tomoko Yamada | Search PubMed

PubMed2026

Mega-enhancers compartmentalize transcriptionally active long genes in the brain.

Exceptionally long genes and cis-regulatory enhancers are selectively activated in mammalian brain neurons, and these loci are mutation hotspots in neurological disorders. However, the organization of these large genomic elements at the level of chromosome folding, beyond local enhancer-promoter interactions, remains poorly understood. Here we report the discovery of a genomic subcompartment in the mouse cerebellum formed by near-megabase-long enhancers and their associated long genes encoding synaptic or signalling proteins. Genomic regions within this subcompartment are enriched in the outer half of the nucleus, whereas other transcriptionally active structures are enriched in the nuclear interior. Using an in vivo CRISPR genetic mini screen, we uncover a specific role for the transcription factor Etv1 in coupling the compartmentalization of neuronal long genes with their expression. Together, our study defines mechanisms that organize transcriptionally active genes across chromosomes in the mammalian brain.

Animals↗

PubMed2023

Mega-Enhancer Bodies Organize Neuronal Long Genes in the Cerebellum.

Dynamic regulation of gene expression plays a key role in establishing the diverse neuronal cell types in the brain. Recent findings in genome biology suggest that three-dimensional (3D) genome organization has important, but mechanistically poorly understood functions in gene transcription. Beyond local genomic interactions between promoters and enhancers, we find that cerebellar granule neurons undergoing differentiation in vivo exhibit striking increases in long-distance genomic interactions between transcriptionally active genomic loci, which are separated by tens of megabases within a chromosome or located on different chromosomes. Among these interactions, we identify a nuclear subcompartment enriched for near-megabase long enhancers and their associated neuronal long genes encoding synaptic or signaling proteins. Neuronal long genes are differentially recruited to this enhancer-dense subcompartment to help shape the transcriptional identities of granule neuron subtypes in the cerebellum. SPRITE analyses of higher-order genomic interactions, together with IGM-based 3D genome modeling and imaging approaches, reveal that the enhancer-dense subcompartment forms prominent nuclear structures, which we term mega-enhancer bodies. These novel nuclear bodies reside in the nuclear periphery, away from other transcriptionally active structures, including nuclear speckles located in the nuclear interior. Together, our findings define additional layers of higher-order 3D genome organization closely linked to neuronal maturation and identity in the brain.

Journal Article↗