Input-Output Functions to Describe Gene Regulatory Networks
Can gene regulatory networks be described like electronic circuits? With Elizabeth Eck at UC Berkeley, I am developing an input-output functional description of gene regulatory networks in the context of the developing fruit fly embryo. By experimentally measuring both transcription factor (i.e. input) concentrations and transcription activity (i.e. output), we can compare our data with various theoretical descriptions and constrain the space of possible classes of models. Unlike previous work, which mainly relies on static data taken at fixed timepoints in embryonic development, our experiments capture the full spatiotemporal dynamics of the system, which have the capacity to reveal interesting underlying mechanisms that cannot be seen with static measurements.
Nonequilibrium Processes in Transcriptional Regulation and Chromatin Accessibility
With Elizabeth Eck at UC Berkeley, I am studying signatures of nonequilibrium behavior in transcription initiation and chromatin accessibility. Specifically, we investigated the applicability of the Monod-Wyman-Changeux (MWC) model of chromatin accessibility, a popular class of models of transcriptional regulation, in the context of the hunchback gene in the fruit fly. Under the lens of the MWC model, hunchback is regulated by the transcription factors Bicoid and Zelda, which passively push the equilibrium state of chromatin from an inaccessible state to an accessible state. Surprisingly, we found that the resulting dynamics of transcriptional onset could not be described by an equilibrium MWC model, or indeed even a nonequilibrium MWC model. This led us to propose an alternate nonequilibrium transcription factor-driven model, where Bicoid and Zelda, instead of regulating an equilibrium configuration of chromatin, actively drive a series of transitions of chromatin through intermediary, transcriptionally silent states, before resulting in transcriptional onset.
Dynamical Modeling of the Eukaryotic Transcription Cycle with Live Imaging
The eukaryotic transcription cycle is a complex process by which an RNA polymerase molecule loads onto a gene, initiates transcription, elongates through the body of the gene, produces an mRNA transcript, and then terminates to be recycled for future usage. Although the biochemical aspects of this process are well-known, dynamic investigations have been difficult to conduct, mainly due to the challenges involved in imaging transcription in real-time in vivo. Here, I used a novel experimental technique to visualize the transcription cycle in developing fruit fly embryos in real time. With a simple model, I developed a statistical methodology to simultaneously infer all of the effective parameters of the transcription cycle at single-cell resolution. Initial results agree with previous measurements and additionally suggest a biophysical coupling between transcriptional activity and polymerase termination rates.
DNA Accumulation at Heated Air-Water Interfaces and the Origins of Life
With Prof. Dieter Braun at the LMU in Munich, I discovered that DNA, when placed in microscale channels filled with water, spontaneously accumulates at air-water interface (e.g. bubbles) when the system undergoes heating. Further work showed that other biomolecules also accumulated, such as lipids and RNA precursors. In fact, vesicle structures can form as a result of this accumulation and trap nucleic acids inside in a protocell-like fashion. This surprising discovery holds implications for the origins of life, as many theories of early evolution require biomolecules such as DNA to somehow accumulate to chemically relevant concentrations amidst a lifeless Earth.