Molecular events arise from random collisions between molecules, which cause cell-to-cell variability in gene expression over time. This is especially true for processes involving small numbers of molecules (e.g. DNA) or slow processes (e.g. protein binding to DNA), where the systems cannot average over a large ensemble or over time. Here, we present a method of analysis, known as a piecewise deterministic Markov process, that accurately describes stochastic gene dynamics in the limit of large mRNA and protein levels (i.e. eukaryotic cells). We use this method to provide modeling insights on several titration-based oscillators commonly found in circadian clocks and immune signaling. This has been a wonderful long-distance collaboration with Yen Ting Lin, a Fellow at the Center for Nonlinear Studies at Los Alamos National Laboratory. Read more about his research here!
Lin YT, Buchler NE. Efficient analysis of stochastic gene dynamics in the non-adiabatic regime using piecewise deterministic Markov processes. J. R. Soc. Interface (2018)
Single-molecule RNA fluorescence in situ hybridization (smFISH) provides unparalleled resolution in the measurement of the abundance and localization of nascent and mature RNA transcripts in fixed, single cells. Mariana developed a computational pipeline (BayFish) to infer the kinetic parameters of gene expression from smFISH data at multiple time points after gene induction. Given an underlying model of gene expression, BayFish uses a Monte Carlo method to estimate the Bayesian posterior probability of the model parameters and quantify the parameter uncertainty given the observed smFISH data. This has been a fun and fruitful collaboration with the Anne West lab in Neuroscience at Duke!
Gomez-Schiavon M, Chen LF, West AE, Buchler NE. BayFish: Bayesian inference of transcription dynamics from population snapshots of single-molecule RNA FISH in single cells. Genome Biology 18: 164 (2017)
Read our latest work that builds upon our growing expertise in cell cycle genomics and the evolution of the G1/S regulatory network in Fungi. This manuscript studied the evolution of duplicated G1/S transcription factors (SBF and MBF) in the budding yeast S. cerevisiae by examining 16 different chimeric transcription factor complexes containing the DNA binding domains from different fungi species. Our data shows that while SBF is the likely ancestral regulatory complex, the ancestral DNA binding element is more MCB-like. G1/S network expansion after gene duplication took place by both cis– and trans– co-evolutionary changes in closely related but distinct regulatory sequences. This was a fun collaboration with Amir Aharoni (Ben Gurion University) and Rob de Bruin (University College London)
Hendler A, Medina EM, Kishkevich A, Abu-Qarn M, Klier S, Buchler NE, de Bruin RAM, Aharoni A. Gene duplication and co-evolution of G1/S transcription factor specificity in fungi are essential for optimizing fitness. PLoS Genetics 13: e1006778 (2017)