While the cells in your body contain identical genetic information, the regulated expression of genes in different cell types or in response to environmental triggers allows cells to survive, take on different morphologies and functions, differentiate, and respond to stress. While we are still figuring out all the mechanistic details of this process, at a fundamental level, gene expression is coordinated by transcription factor proteins which bind sequence-specific motifs in the genome and coactivator protein complexes which interact with these transcription factors as well as components of the transcriptional machinery to integrate cellular signals and direct expression of specific genes in a timely, regulated manner.
During my PhD in Biophysics, I studied a fundamental coactivator complex, the human SAGA complex, using high resolution cryo-EM in partnership with the Nogales Lab at UC Berkeley. Using structural data, we identified how SAGA incorporates unique subunits in the human complex as compared to yeast SAGA and how subunits shared with the coactivator TFIID are incorporated differently within SAGA. Finally, we investigated human genetic mutations within the large subunit of SAGA, TRRAP, which are associated with neurodevelopmental disorders and could map them onto the 3D structure of SAGA allowing for interpretation of their likely etiology.
Structure of the human SAGA coactivator complex.
Herbst & Esbin et al. NSMB 2021
Now as a postdoc, I am investigating how transcription factors and coactivators control differentiation in stem cells of the placenta. Development of the placenta during pregnancy is a crucial mammalian phenomenon which supports fetal development during pregnancy. A subset of fetal stem cells undergoes an early fate specification into placental trophoblasts. Importantly, in humans, a subset of these cells (syncytiotrophoblasts) undergo a dramatic morphological differentiation process whereby they fuse to become a multi-nucleated syncytium which constitutes the maternal-fetal barrier during pregnancy. Defects in syncytiotrophoblast differentiation are hallmarks of deadly pregnancy diseases such as preeclampsia where patient placentas show impaired trophoblast cell fusion and decreased expression of endogenous retroviral fusogens such as syncytin-2, that correlate with disease severity. However, to date, few molecular regulators of this important cell fusion process have yet been found. Using cellular models of syncytiotrophoblast formation, CRISPR genome editing, high content imaging, and single molecule tracking, my research aims to identify new transcriptional regulators of placental differentiation and uncover their biophysical mechanisms in placental cells.
Seeking new regulators of transcription within placental development – our goal is to identify transcription factors which influence the expression of key genes, for example the fusogenic Syncytin genes in human cells, and to biophysically and biochemically characterize how they work.