Slow transcriptional elongation causes embryonic lethality and perturbs kinetic coupling of long neural genes

Abstract

Alternative splicing (AS) is a highly regulated process that increases protein diversity and is critical for cell differentiation and development. The rate of RNA Polymerase II (RNAPII) elongation has an important role in the control of AS. We generated mouse embryonic stem cells (ESCs) knocked-in for a slow elongating form of RNAPII and show that a reduced transcriptional elongation rate causes early embryonic lethality in mice and impairs the differentiation of ESCs into the neural lineage. The reduced elongation rate caused changes in splicing and in gene expression in ESCs and along the pathway of neuronal differentiation. In particular, we found a crucial role for RNAPII elongation rate in transcription and splicing of long neuronal genes involved in synapse signaling. The impact of the kinetic coupling of RNAPII elongation rate with AS is more predominant in ESC-differentiated neurons than in pluripotent cells. Our results demonstrate the requirement for an appropriate transcriptional elongation rate to ensure proper gene expression and to regulate AS during development.