Cis-epigenetic control of developmental timing

Abstract

Development of a single multipotent progenitor into distinct cell-types of the correct number and proportion requires careful coordination of gene expression patterns over time. Within the context of these complex gene regulatory networks, lineage-specifying genes must be activated at a specific time and in order. Because these lineage-specifying events are unfolding within proliferating progenitors, variations in the relative timing of these activation events can alter the final numbers and relative proportions of each lineage. While extrinsic signals induce and guide these development processes, the temporal schedule of lineage-commitment events is frequently upheld in cell-autonomous manner. The mechanisms underlying cell-autonomous timing control and their role in regulating cell-type proportions remains unclear.In this dissertation, I first review our current understanding of cell-autonomous control of development timing by gene regulatory networks and provide an overview of early thymocyte development as a model system to study the fundamental principles of gene regulation and developmental cell fate control. In Chapter 2, I provide evidence for a cis-epigenetic switching mechanism that enables tunable temporal control of developmental gene activation and lineage- specification. In Chapter 3, I detail our approach to efficiently interrogate a collection of non- coding regulatory elements that separately control the timing, initiation and maintenance of the cis-epigenetic switch. Finally, in Chapter 4, I provide evidence that the timing of this cis-epigenetic switch is important for regulating the number and types of cells that emerge during thymocyte development.