Cell Bio-Gilliam Travel Award Recipients

Cell division is a highly conserved essential process that is tightly regulated by various mechanisms, particularly post-translational modification pathways such as ubiquitination and phosphorylation. Furthermore, cell-cycle dysregulation may cause genetic instability in diseases such as cancer. My goal is to evaluate the ubiquitin system during the cell cycle and to better understand how ubiquitin system controls cell division. To achieve this, we designed an in vitro screening assay based on Xenopus egg extract to detect functional differences between the ubiquitin pathway during interphase and mitosis. Our findings revealed that the activity of the E2 enzyme UBE2H was strongly reduced during mitosis as a result of mitotic CDK-dependent phosphorylation. Cells expressing non-phosphorylatable UBE2H showed persistent E2 activity during mitosis, reduced several proteins in abundance and exhibited mitotic defects. Our results indicates that CDK-dependent UBE2H regulation is important for normal cell division. Moreover, this investigation enhances our understanding of the interplay between ubiquitination and phosphorylation, in particular highlighting how regulation of E2 activity can be an important point of regulation in ubiquitin-dependent protein degradation.

Internal states, such as hunger and thirst, are powerful motivational states that shape sensory perception, enhancing attention to need-relevant cues. Here, we investigate how thirst differentially influences odor perception, selectively heightening attraction to drink odors while sparing responses to other attractive cues, such as pheromones. The mouse olfactory system detects diverse odors that drive behaviorally specific responses, yet how distinct physiological states modulate sensory pathways to drive state-appropriate behaviors remains unclear. Our studies aim to uncover the molecular and circuit mechanisms by which thirst selectively modulates odor responses, providing insight into how internal states dynamically influence sensory processing and behavior.

Chromatin remodeling governs DNA accessibility, orchestrating fundamental biological processes such as gene expression, DNA replication, and DNA repair. Chromatin remodelers exhibit distinct periods of interspersed pausing during remodeling, which are hypothesized to serve as regulatory checkpoints, allowing the remodelers to sense entry- and exit-side DNA to achieve directional remodeling outcomes. Additionally, auxiliary elements of the chromatin remodeler and interactions with nucleosomal features have been implicated in regulating the recruitment to nucleosomes and sensing of DNA during pausing. However, the structural basis of remodeler recruitment, pausing, and DNA sensing remains poorly understood. My project focuses on using cryo-EM to reveal paused and recruitment states of the human chromatin remodeler CHD1 to understand how directional remodeling outcomes are regulated. This work will expand our model of chromatin remodeling and explain how DNA is sensed to achieve precise directionality during remodeling.

Cells have evolved mechanisms that can compensate for loss of function mutations in some genes by upregulating their paralogs. Recently, a novel genetic compensation mechanism was proposed to maintain gene expression in the actin gene family where the degradation of mutant actin mRNA leads to increased transcription of its paralogs in mouse embryonic stem cells. I investigated this genetic compensation mechanism in β-actin (Actb) mutants in mouse and human embryonic stem cells. My experiments show that genetic compensation in this system occurs through a classical pathway that senses changes in Actb protein levels and increases the transcription of Actb and its paralogs. Genetic compensation in Actb mutants is therefore mediated by a protein feedback mechanism independent of mutations that produce unstable Actb mRNA. Beyond genetic compensation, I am interested in the multifaceted roles of nascent RNA processing in gene regulation and genomic stability, especially how nascent RNA degradation contributes to maintaining transcriptional silencing.