Research in the Smith Lab

Our lab encompasses diverse research topics that are being pursued by passionate young scientists, unified by our desire to understand forms of genome regulation that support developmental processes and protect against disorder or malignancy. We believe that complex challenges are best solved creatively and in collaboration, allowing us to remain at the leading edge of technical and analytical innovation as we push for new breakthroughs in foundational biological problems. In particular, we are always looking to ask new questions related to the following areas.

Fertilization

Is a singular moment where an entire genome is effectively “resurrected.” Sperm DNA is delivered as a highly condensed, inert structure and must be rapidly reorganized to enable cellular functions. The scale, kinetics and mechanisms of this process are extremely elusive. We study these reprogramming mechanisms through combinations of experimental transgenesis, genomic profiling, and high-resolution microscopy. Simultaneously, we study parasitic genetic elements that are naturally active in the early embryo, but can be reactivated within some cancers. To understand their functionality and behavior, we are inventing new methods to track retrotransposons as they evade host repression and copy their progeny into the zygotic genome.

Embryo implantation and placental development

Placental biology depends upon a novel form of genome regulation resembling that in human cancers.  We seek to understand the biochemical, molecular, and physiological purpose of this “epigenetic landscape” and its evolutionary origin. We explore how organisms evolve epigenetic mechanisms to support novel reproductive functions, and the potential costs of these innovations to long term health. To do so, we are optimizing tools that allow us to identify context-specific biochemical interactions that support this landscape, perturb them and interpret their holistic impact on fetal progression and morphology. We use this model to pinpoint key molecular features of genome regulation in cancer, as well as translate our findings to understand when and how genome-scale regulatory changes act to support tumorigenesis.  

Epigenetic control of early organogenesis

A rapid burst of differentiation and proliferation that requires exquisite control to prevent long term birth defects.  Many congenital disorders are determined early, exhibit variable penetrance, and impact multiple organ systems. The rapid dynamics of early development and the ambiguous molecular nature of core drivers have obscured our ability to explain, detect, or intervene in congenital birth defects and adverse pregnancy outcomes. We are addressing these limitations through novel experimental platforms designed to examine complex mutant embryo phenotypes across multiple tiers of clinically and biologically relevant information.  Our primary system combines mouse zygotic perturbation with single cell analysis to evaluate embryo replicates, allowing us to identify key moments, tissues, and molecules that translate environmental insults to developmental defects. For proof of concept, we are defining the developmental and molecular origins of classic models of maternal diet that impact fetal health, including of folic acid on neural tube defects, a prevalent birth defect presumed to operate through an undetermined epigenetic mechanism.