CTCF/cohesin organize the ground state of chromatin-nuclear speckle association

Abstract

The interchromatin space in the cell nucleus contains various membrane-less nuclear bodies. Recent findings indicate that nuclear speckles, a distinct nuclear body, exhibit preferential interactions with chromatin in a ground state, potentially priming specific genes for speckle-mediated gene expression and induction. Key questions are how this preferred ground state of chromatin-nuclear speckle association is established and what are the gene regulatory roles of this layer of nuclear organization. We report that chromatin structural factors CTCF and cohesin are required for full ground association between DNA and nuclear speckles. Disruption of ground state DNA-speckle contacts via CTCF or cohesin depletion had minor effects on ground expression of speckle-associated genes, however we found strong negative effects on stimulus-dependent induction of speckle-associated genes. In contrast, disruption of the cohesin releasing factor WAPL, which stabilizes cohesin on chromatin, led to enhanced inducibility of speckle-associated genes. Thus, our findings support a role of ground state chromatin-speckle association in promoting gene inducibility. We also observed similar disruption of the chromatin-nuclear speckle association in cell lines derived from patients with Cornelia de Lange syndrome (CdLS), a congenital neurodevelopmental disease, in which cohesin pathways are involved, here revealing nuclear speckles as a new potential avenue of therapeutic inquiry. In summary, our findings uncover a novel mechanism underlying a new layer of regulation of chromatin organization and gene expression, mediated by chromatin-nuclear speckle association with relevance to human disease.