TAF3 is a subunit of the TFIID basal transcription factor complex that plays a central role in RNA polymerase II transcription initiation. As part of the TFIID-A module alongside TBP and TAF5, TAF3 recognizes promoters and promotes pre-initiation complex assembly. TAF3 functions as a histone reader through its plant homeodomain (PHD) finger, which binds H3K4me3 with enhanced affinity when combined with the serotonylation mark H3Q5ser 1. This H3K4me3–TAF3 interaction directs TFIID recruitment to active genes and stimulates transcription, particularly of p53 target genes during genotoxic stress 2. Beyond its role in basal transcription, TAF3 participates in specialized developmental processes: it forms a complex with TBPL2 required for myoblast-to-myocyte differentiation, and a selective interaction between TRF3 and TAF3 is essential for early zebrafish development and hematopoiesis 3. TAF3 also mediates long-range chr10 interactions through CTCF/cohesin complexes to regulate pluripotency genes in embryonic stem cells 4. TAF3 acts as a negative regulator of p53 transcription function 5. Clinically, TAF3 variants associate with red blood cell traits; in a Northern Italian founder population, TAF3 variants were linked to mean corpuscular hemoglobin concentration and may influence erythropoiesis through regulation of SPTA1 6. Recent evidence suggests TAF3 participates in oncogenic processes, identified in a pediatric mesenchymal tumor with an MN1::TAF3 fusion 7.