Systematic assessment of the mouse TATA-box binding protein-associated factor 1 locus reveals novel messenger RNA isoforms and differential protein distribution across brain regions

Abstract TATA-box binding protein-associated factor 1 (TAF1) is the largest component of transcription factor IID, a fundamental multi-protein complex for RNA polymerase II-mediated transcription. TAF1 is essential for promoter recognition, coactivator interaction and normal development. Mutations in TAF1 cause developmental disorders and the lethal neurodegenerative disease X-linked dystonia-Parkinsonism. Our previous work suggested that this approximately 170 kb gene has a more complex set of transcripts than currently catalogued. We therefore undertook a systematic assessment of Taf1 transcription in mouse, given its widespread use as a model organism and its high genetic homology with humans. Using targeted nanopore sequencing, we reveal extensive transcriptional diversity and differential abundance of Taf1 messenger RNAs across brain and body regions. We identified 19 novel transcript variants and multiple novel exons, and we predicted their protein domain architectures and modelled them using AlphaFold. Notably, we observed elevated RNA and protein expression in the cerebellum compared with other brain regions. These findings substantially expand the transcriptional landscape of Taf1 and provide crucial insights to guide the investigation of transcript-specific mechanisms in neurodevelopmental and neurodegenerative disorders, enabling the creation of more accurate disease models.