Current Research and Scholarly Interests
GENETIC AND EPIGENETIC PRINCIPLES OF DEVELOPMENTAL GENE REGULATION
Interactions between the genome and its cellular and signaling environments, which ultimately occur at the level of chromatin, are the key to comprehending how cell-type-specific gene expression patterns arise and are maintained during development or are misregulated in disease. Research in our laboratory is focused on understanding how cis-regulatory information encoded by the genome is integrated with the transcriptional machinery and epigenetic regulation to allow for emergence of form and function during embryogenesis.
Central to the cell type-specific transcriptional regulation are distal cis-regulatory elements called enhancers, which function in a modular way to provide exquisite spatiotemporal control of gene expression during development. We are using a combination of genomic, genetic, biochemical, and single-cell approaches to investigate how enhancers are activated in response to developmental stimuli, how they communicate with target promoters over large genomic distances to regulate transcriptional outputs, and what is the role of chromatin modification and remodeling in facilitating or restricting enhancer activity.
MECHANISMS OF DEVELOPMENTAL PLASTICITY
Interest in understanding how developmental plasticity and commitment are governed at the chromatin level led us to studies of cell types with an unusually broad differentiation potential, such embryonic stem cells (ESCs) and neural crest cells. For example, we have focused on the mechanisms of pluripotency, a property that ESCs share with an early embryo, which endows these cells with the ability to give rise to the three germ layers (endoderm, ectoderm and mesoderm) and, consequently, all tissues represented in the adult organism. Interestingly, pluripotency can have different 'flavors' (e.g. growth factor requirements, properties of the transcriptional network, epigenetic states) depending on which state of the peri-implantation embryo has been captured by the in vitro conditions and which species the embryo originated from. We are investigating regulatory principles that govern these stage- and species-specific differences. In particular, we want to uncover aspects of early embryonic gene regulation that are unique to humans and other primates.
MAKING FACES: DEVELOPMENT, EVOLUTION AND VARIATION OF THE HUMAN CRANIAL NEURAL CREST
From Galapagos finches to anteaters, the remarkable diversity of craniofacial structures within the vertebrate species is a testament to the plasticity of development and resourcefulness of evolution. While craniofacial development requires interactions between multiple embryonic cell types, Cranial Neural Crest Cells (CNCCs) play a major role in establishing the central plan of facial morphology as well as determining its species-speci?c variation. Craniofacial disorders, which involve a large number of syndromes as well as non-syndromic manifestations, account for a third of all human malformations.
To overcome the inability to obtain CNCCs directly from primate embryos, we have previously established an in vitro model in which speci?cation, migration and differentiation of human CNCCs are recapitulated in the dish. The goal of our ongoing research effort is to understand how variation in CNCC gene expression translates into differences in cellular behavior, leading to the emergence of normal-range and disease-associated morphological diversity in the human craniofacial form. This expression variation can result both from the trans-regulatory differences, such as those associated with mutations of transcriptional and chromatin regulators in craniofacial syndromes, and from the variation in cis-regulatory sequences. To understand both mechanisms of variation and their impact on disease and morphology, we are combining in vitro models of primate CNCC formation with the in vivo work in a variety of organisms including Xenopus, chick and mouse.