Splicing Factor RBM22 Broadly Affects RNA Polymerase II 5' Pausing, Elongation Rate and Termination and Prevents Genome Instability [ChIP-seq]

Splicing factors are vital for the regulation of RNA splicing, but the underlying molecular mechanisms of their involvement in transcriptional processes remain poorly understood. Here, we describe a direct role of splicing factor RBM22 in coordinating multiple steps of RNA Polymerase II (RNAPII) transcription in human cells. The RBM22 protein widely occupies the RNAPII-transcribed gene locus in the nucleus. Loss of RBM22 promotes RNAPII pause release, reduces elongation velocity and provokes transcriptional readthrough genome-wide, coupled with downstream-of-gene (DoG) transcript production and genome instability. RBM22 preferentially binds to the hyperphosphorylated, transcriptionally engaged RNAPII and coordinates its dynamics by regulating the homeostasis of the 7SK-P-TEFb complex and the association between RNAPII and SPT5 at the chromatin level. Our results uncover the multifaceted role of RBM22 in orchestrating the transcriptional program of RNAPII, and provide evidence implicating a splicing factor in both RNAPII elongation kinetics and termination control.