A dual-module ECAS complex couples transcription elongation and RNA processing

Abstract

Faithful gene expression requires coordination between RNA polymerase II elongation and co-transcriptional RNA processing, yet the chromatin-associated assemblies supporting this coupling remain incompletely defined. Using native chromatin proteomics in human cells, we identify ECAS (elongation complex associated with splicing), a bipartite assembly linking an elongation module (AFF4-ELL2-EAF1) to a U2 snRNP-associated intron binding complex. ECAS occupies promoter-proximal chromatin and is molecularly distinct from canonical P-TEFb-containing super elongation complex (SEC). Acute perturbation of Aquarius (AQR)/XAB2-dependent ECAS functions impairs productive gene-body elongation without altering pause release, increases intron retention, and preferentially affects long genes. AQR loss also reduces capping-factor recruitment and nascent 5′ capping and increases promoter-proximal accumulation of cleavage/polyadenylation and RNA exosome factors. In mouse hematopoietic cells, Aqr is highly expressed, and its perturbation profoundly impairs leukemia initiation, maintenance, and leukemia stem cell function in MLL-rearranged leukemia. Together, these findings establish ECAS as a chromatin-associated assembly that couples productive elongation with RNA processing.