Ying Xiang, Honghong Wang, Zhinang Yin, Ruijing Xiao, Zemin Song, Rui Lu, Rong Dai, Jiaqin Ye, Conghui Li, Yali Cui, Mengxuan Wang, Junhui Lv, Qiuzi Li, Fuqi Wang, Zhuoshi Li, Kaiwen Zhang, Yiming Zhang, Di Wu, Pingping Fang, Kaiwei Liang
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.