Molecular insights into regulator-dependent transcription initiation pathways

The National Institute of General Medical Sciences awarded the University of California, Berkeley $152,300 on March 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to conduct structural and biochemical investigation of how regulatory factors modulate transcription factor IID (TFIID) and its role in gene expression control. The research applies structural biology and biochemical approaches to study two distinct TFIID interactors: E proteins such as E2A, which enhance TFIID promoter binding, and the DOT1L complex, a chromatin regulator that recruits TFIID to promoters through chromatin recognition. The mechanistic insights generated are intended to advance fundamental understanding of gene regulation and disease mechanisms, with potential applications to leukemogenesis and therapeutic development. Performance occurs at the Nogales Lab at UC Berkeley, Berkeley, California, with a period of performance extending from March 1, 2026, through February 28, 2029. This is a Project Grant assistance type.

Abstract

To choreograph the many processes required for life, cells maintain precise control of gene expression. Nuclear factors regulating transcription are linked to a wide spectrum of human cancers, and therefore understanding their functions is of great interest to human health. Many of these regulators function by modulating transcription factor IID (tfiid), a component of the core transcriptional apparatus. Tfiid plays a critical, fundamental role in transcriptional activation, being the molecular target of diverse transcription factors. Moreover, IT interacts with the DOT1L complex, a histone modifier and reader, thus linking gene activation to chromatin state. Despite decades of study, our molecular understanding of how regulatory factors modulate tfiid structure and function remains limited. This proposal seeks to address this GAP in understanding by applying structural and biochemical approaches to investigate the role of tfiid interactors in promoting transcription. Specifically, two distinct interactors will be studied: (1) e proteins, such as E2A, which are transcriptional activators that enhance tfiid promoter binding, and (2) the DOT1L complex, a chromatin regulator possessing several histone reader domains, which recruits tfiid to promoters via chromatin recognition. The structural and mechanistic insights generated by the proposed research will greatly enhance our fundamental understanding of gene regulation. Furthermore, both e proteins and DOT1L are linked to human diseases and play crucial roles in leukemogenesis, underscoring the potential of novel mechanistic insights to bolster our understanding of disease mechanisms and inspire new therapeutic approaches to benefit human health. The proposed research will be conducted in the nogales lab at the university of california, berkeley, which is a leader in the field of structural biology. The nogales lab has deep expertise in the technique of cryo-electron microscopy (cryo-EM), which is the primary structural technique used in the proposed work. The nogales lab is affiliated with the california institute for quantitative biosciences (QB3), which houses key facilities such as the CAL-cryo microscopy facility and the QB3/chemistry mass spectrometry facility, which will provide crucial instrumentation and experimental support. The fellowship proposal also encompasses a training plan tailored to gaining experience critical for a future career in academia. In addition to providing the opportunity to develop rich scientific expertise in structural biology and gene regulation, the proposed work will also provide crucial training in mentorship, project management, and scientific communication.