We aim to directly visualize human mega-Dalton size activator/TFIID-mediated transcription assemblies during transcription initiation involved in tumor suppression, embryonic stem cell differentiation, and ovarian development. To tackle this challenging task, we utilize a combination of advanced single particle cryo-electron microscopy (cryo-EM), high-precision single molecule fluoresce microscopy, and a number of biochemical assays. We are one of the few labs in the world that are conducting these structural studies on those low abundant, very large, asymmetric, highly flexible human transcriptional protein co-complexes. Our structural insights will provide the mechanistic underpinnings for future nanoscale-targeting therapeutics that modulate the actions of these critical factors. More importantly, the techniques and knowledge developed can be applied to interrogate other protein complexes that result in abnormal gene expression.