A slow transcription rate causes embryonic lethality and perturbs kinetic coupling of neuronal genes

MASLON, M.; BRAUNSCHWEIG, U.; AITKEN, S.; MANN, A.R.; KILANOWSKI, F.; HUNTER, C.H.; BLENCOWE, B.J.; KORNBLIHTT, A.R.; ADAMS, I.; CÁCERES, J.F.

EMBO JOURNAL

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2019

0261-4189

The rate of RNA polymerase II (RNAPII) elongation has an importantrole in the control of alternative splicing (AS); however, thein vivo consequences of an altered elongation rate are unknown.Here, we generated mouse embryonic stem cells (ESCs) knocked infor a slow elongating form of RNAPII. We show that a reducedtranscriptional elongation rate results in early embryonic lethalityin mice. Focusing on neuronal differentiation as a model, weobserved that slow elongation impairs development of the neurallineage from ESCs, which is accompanied by changes in AS and ingene expression along this pathway. In particular, we found acrucial role for RNAPII elongation rate in transcription and splicingof long neuronal genes involved in synapse signaling. The impactof the kinetic coupling of RNAPII elongation rate with AS is greaterin ESC-differentiated neurons than in pluripotent cells. Our resultsdemonstrate the requirement for an appropriate transcriptionalelongation rate to ensure proper gene expression and to regulateAS during development.