TAF2 condensation in nuclear speckles links basal transcription factor TFIID to RNA splicing

TFIID is an essential eukaryotic transcription factor, which is required for RNA polymerase II promoter recognition and activation. As a multiprotein complex, TFIID contains several intrinsically disordered regions (IDRs), but the functions of these IDRs are unknown. Here, we show that a conserved IDR drives the TFIID subunit TAF2 to nuclear speckles, where it forms biomolecular condensates, separate from the TFIID complex. Quantitative mass spectrometry analyses reveal that the TAF2 IDR is required for the interaction with the nuclear speckle and spliceosome-associated protein SRRM2, which is thereby recruited to TFIID. The formation of SRRM2-free TFIID complexes elicits a set of unique alternative splicing events. These include events in RNAs coding for proteins involved in transcription and transmembrane transport. Together, these data identify an IDR of the basal transcription machinery as a molecular switch between nuclear compartments to control protein complex composition and pre-mRNA splicing.