26 Mar 2021
Hao Yuan Kueh
Department of Bioengineering
University of Washington, Seattle
During development, progenitors follow timetables for cell lineage specification over timescales spanning many cell divisions. These developmental timetables are robustly encoded by the embryo, yet flexibly adjustable by evolution, facilitating variation in organism size and form. Epigenetic mechanisms, acting in cis at individual genomic loci, influence the expression of lineage-specifying genes, and could control the timing of their activation and ensuing cell differentiation. In this talk, I will first discuss our studies of T cell development, where we define a timed epigenetic switching mechanism, involving the histone 3 lysine-27 trimethylation (H3K27me3) modification, that generates time delays in the activation of the T cell lineage-specifying transcription factor Bcl11b. Activation delays in this epigenetic switch span multiple cell generations, and are tunably controlled by both transcription factors and chromatin modifiers. Next, I will present theoretical work, where we show that the gene regulatory networks composed of these tunable epigenetic switches can uphold autonomous developmental timetables that enable the generation of multiple cell types in precisely defined numbers and fractions. Mutations in the components of these epigenetic switching regulatory networks can readily alter the timing of individual events within a developmental timetable, or alter the overall pace at which timetables unfold, allowing sizes of differentiated populations to be controlled in a scalable manner. With their robust, yet flexibly adjustable nature, epigenetic switching networks could represent central targets on which evolution acts to manufacture diversity in size and form.