Nuclear exosome targeting complexes modulate 3D chromatin interactions genome-wide

Three-dimensional chromatin contacts are thought to be largely determined by loop exclusion driven by CTCF and the cohesin complex. Recent evidence also suggests a role for RNA in shaping genome architecture. Nuclear RNA exosome, together with targeting complexes, PAXT and NEXT, control the decay of noncoding RNAs (ncRNAs), notably enhancer-associated RNAs (eRNAs) and promoter upstream transcripts (PROMPTs). We mapped the chromatin recruitment sites of ZCCHC8 (NEXT), ZFC3H1 (PAXT) and MTR4 helicase, as well as the ncRNAs accumulating upon their depletion. While NEXT and PAXT map to both TSSs and enhancers, MTR4 was associated with enhancers that show preferential long-range contacts with promoters. Loss of MTR4 or ZFC3H1 led to the accumulation of cohesin at target enhancers and TSSs. Chromatin conformation capture analysis revealed that MTR4 modulates the 3D genome landscape. Contacts at anchor points were increased while intraloop contacts were decreased following loss of MTR4 suggesting that MTR4 facilitates loop extrusion. These data highlight a key interplay between cohesin-mediated enhancer-promoter interactions and the regulation of ncRNAs by nuclear RNA exosome that is consistent with a role for RNA in genome folding. Overall design: Long-range chromatin interactions were detected by Hi-C in control or MTR4 depleted cells