TY - JOUR T1 - Slow transcriptional elongation causes embryonic lethality and perturbs kinetic coupling of long neural genes JF - bioRxiv DO - 10.1101/426577 SP - 426577 AU - Magdalena M. Maslon AU - Ulrich Braunschweig AU - Stuart Aitken AU - Abigail R. Mann AU - Fiona Kilanowski AU - Chris J. Hunter AU - Benjamin J. Blencowe AU - Alberto R. Kornblihtt AU - Ian R. Adams AU - Javier F. Cáceres Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/11/04/426577.abstract N2 - The rate of RNA Polymerase II (RNAPII) elongation has an important role in the control of Alternative splicing (AS); however, the in vivo consequences of an altered elongation rate are unknown. Here, we generated mouse embryonic stem cells (ESCs) knocked-in for a slow elongating form of RNAPII. We show that a reduced transcriptional elongation rate results in early embryonic lethality in mice and impairs the differentiation of ESCs into the neural lineage. This is accompanied by 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. ER -