The genome organizer SMC1A mediates the gene expression response in inflammation by dissociating from nuclear-speckles and redistributing to the nuclear periphery

Abstract

Nuclear architectural proteins are increasingly recognized as multifunctional regulators whose roles extend well beyond static genome organization. Here we report that SMC1A, a core subunit of the cohesin complex, undergoes a striking redistribution upon inflammatory stimulation in human monocytes, dissociating from nuclear speckles and accumulating at genomic regions enriched for stress-response genes with distinct exon-intron architectural properties. Through integrative analysis of RNA-seq, chromatin organization, and nuclear spatial data, we demonstrate that this redistribution has functional consequences at multiple levels of gene expression. SMC1A dissociation from speckles is accompanied by a reduction in intron retention events -consistent with a transition from a poised, pre-loaded transcriptional state toward active, efficient co-transcriptional processing- and by selective engagement with genes whose exon-intron architecture favors exon definition splicing, shorter nuclear mRNA residence times, and peripheral radial positioning. Genes affected by SMC1A silencing, by contrast, occupy more central nuclear positions and display fundamentally different structural properties, demonstrating that the two modes of SMC1A perturbation -stress-induced redistribution and depletion- are functionally and spatially non-equivalent. These findings suggest a genome compartmentalization in which DNA compositional preferences, gene architecture, radial positioning, and splicing mode converge to define gene sets capable of rapid, precise activation. SMC1A navigates this pre-existing landscape upon inflammatory cues, coordinating transcriptional and post-transcriptional responses simultaneously. We propose that stress-induced redistribution of architectural proteins within a largely invariant nuclear compartmental framework represents a general regulatory mechanism, one whose logic is encoded in the structural organization of the genome itself.