SUPT3H is a transcriptional coactivator and core component of the SAGA (Spt-Ada-Gcn5 Acetyltransferase) complex, conserved from yeast to humans 1. As a histone-fold domain-containing protein, SUPT3H contributes one histone-fold pair to the SAGA complex's octamer-like scaffold structure 2. While SUPT3H's yeast ortholog Spt3 interacts with TATA-binding protein (TBP) and regulates global RNA polymerase II transcription 2, mammalian SUPT3H functions distinctly. In mouse embryonic stem cells, SUPT3H is dispensable for SAGA assembly and global Pol II transcription but essential for cell growth and self-renewal, affecting only a specific subset of genes 2. Beyond transcription, SUPT3H variants associate with facial morphology variation in Eurasian populations 3 and knee osteoarthritis progression risk 4. SUPT3H also participates in bone metabolism: a long noncoding RNA derived from SUPT3H (lnc-SUPT3H-1:16) acts as a competing endogenous RNA regulating parathyroid hormone-stimulated osteoblast differentiation through miRNA-6797-5p sponging 5. Additionally, SUPT3H variants associate with ADAMTS13 activity levels 6, and the SUPT3H promoter physically interacts with the RUNX2-P1 bone-specific promoter during osteoblast differentiation 7. These findings demonstrate SUPT3H's multifaceted roles in transcriptional regulation and development beyond its SAGA complex function.