A human-specific TAF8 isoform diversifies the composition of the TFIID general transcription factor

Despite its central role in RNA polymerase II transcription, the composition and function of the TFIID general transcription factor can vary across tissues and developmental stages. Such variability may provide a substrate for evolutionary innovation and contribute to human-specific regulatory functions. Here, we identify a human-specific short isoform of TAF8 (TAF8s), a scaffold subunit of TFIID, generated through the use of an intronic polyadenylation site (iPAS). Comparative genomic analyses reveal that the genomic substrate for this isoform originated with the insertion of a FLAM-C Alu element into intron 5 in the common ancestor of anthropoid primates (Simiiformes), whereas subsequent small sequence changes at the Alu-associated iPAS coincide with the emergence of TAF8s expression in the human lineage. TAF8s lacks nearly half of the canonical TAF8 coding sequence, is widely expressed across human tissues, and accounts for a substantial fraction of TAF8 transcripts. It encodes a truncated protein lacking the canonical nuclear-localization signal and localizes predominantly to the cytoplasm. Despite retaining interactions with its histone-fold partner TAF10 and other core TFIID subunits, TAF8s loses interaction with TAF2, providing a molecular basis for alternative TFIID sub-complex formation. Together, our findings identify a recently evolved human-specific regulatory innovation at the TAF8 locus that diversifies the composition of a conserved general transcription factor. This example illustrates how evolution of transcript isoforms can generate new protein interactions and molecular complexity in essential cellular machineries, with potential implications for the functional diversification of TAF-containing complexes and the genetic basis of TAF-related developmental disorders.