A signature feature of Down syndrome (DS) cells with trisomy 21 (21T) is that thousands of genes throughout the genome are misexpressed, not just those on Chromosome 21. This paradox remains one of the major mysteries about DS. In this proposal we will test a new idea to account for global gene misregulation in DS. This model hypothesizes that fundamental steps in transcription by RNA polymerase II including how fast it moves, where it pauses, and where it terminates are globally altered in DS. These changes in RNA polymerase II function could be caused by abnormal activation of signalling pathways known to occur in DS or by elevated expression of the DYRK1A protein kinase encoded on Chr 21 which phosphorylates RNA polymerase II directly.