Teves, Sheila

Research Interest

The underlying theme that motivates my research is to understand the mechanisms that regulate cellular memory and cell fate decisions. How do cells maintain their state? What processes are required to change from one cell state to another? Central to these processes is precise yet tunable transcriptional regulation. Throughout the years, I have studied different aspects of transcriptional regulation and gained expertise in gene editing technology, genomics, and live-cell imaging.

1. Transcriptional memory through the cell cycle:

During mitosis, chromatin becomes highly condensed and transcription is shut off. How do the new daughter cells re-establish the original transcription program? One theory is that, while the vast majority of DNA-bound proteins become evicted from mitotic chromosomes, select transcription factors (TFs) remain bound to promote efficient reactivation following mitosis, a process termed mitotic bookmarking. During my postdoctoral work, I discovered that the decades’ worth of literature on the eviction of TFs arises largely as a consequence of a chemical cross-linking artifact. Instead, we established that many TFs remain associated with mitotic chromosomes in mESCs but in a more dynamic manner than with interphase chromatin (Teves et al. 2016). Furthermore, the transcriptional machinery itself acts as a mitotic bookmarker and facilitates transcriptional reactivation following mitosis (Teves et al. 2018). In my own research group, we have examined how some TFs bind to mitotic chromosomes while others do not. Specifically, we examined two highly conserved TFs with different mitotic behaviors, and found that non-DNA binding domains of TFs can influence their behaviors during mitosis (Price, Budzynski, et al. 2023). We have also published a review (Price et al. 2020) and a methods chapter (Kwan et al. 2019) related to this theme.

2. Mechanisms of Eukaryotic Transcription:

Transcription by the three main eukaryotic RNA Polymerases (Pol I, II, III) is initiated by the hierarchical assembly of general transcription factors (GTFs) onto promoter DNA. Decades of in vitro and yeast research have shown that the TATA-box binding protein (TBP) is the only common GTF among the three Pols, and is essential to the initiation of all transcription by triggering the binding of other GTFs to ensure proper Pol loading. In work from my own laboratory, we report instead that acute depletion of TBP in mouse embryonic stem cells (mESCs) has no global effect on ongoing Pol II transcription. Surprisingly, Pol II transcriptional induction through the Heat Shock Response or cellular differentiation also occurs normally in the absence of TBP. In contrast, acute TBP depletion severely impairs initiation by RNA Polymerase III. Taken together, our findings reveal an unexplored TBP-independent process in mESCs that points to a diversity in Pol II transcription initiation mechanisms (Kwan, Nguyen et al. 2023). Recently, we have also shown that Pol I transcription can occur independently of TBP, but that TBP plays a role in efficient reactivation of Pol I transcription following mitosis. This work is now posted as a preprint (Kwan et al. 2023).

3. Scholarly efforts in promoting equity, diversity, and inclusion in the sciences:

I am a strong proponent of equity, diversity, and inclusion within the department and throughout the scientific community. I am a faculty member of the EDI committee in the Biochemistry and Molecular Biology Department. I serves as an informal mentor to women and under-represented minorities through my advocacy work in social media (Twitter, >3000 followers), and I have published work on the benefits of inclusion in the workplace (Teves. Science, 2021). Together with my fellow Wall Scholars, we have published a book titled “Chromatic: Ten meditations on crisis in art and letters”. My contribution to this book is titled “The legacy of racism and sexism in the sciences”. Together, these represent the scholarly outputs of my ongoing outreach to promote EDI in the sciences.