Which came first: the chicken or the egg? This metaphor describes situations where it is not clear which of two events should be considered the cause and which should be considered the effect. There exists a similar question in biology during early animal development. Animal development begins when a sperm fertilizes an egg and the resulting fertilized egg creates a single cell with enormous differential potential because it is able to develop into all cell types. In frogs, within the first few hours after fertilization, a fertilized egg divides several times and develops into three cell types with distinct functions. These differentiated cells express different genes. The dilemma here is - What regulates the gene expression to give the cell identity? One idea is that DNA-binding proteins are the major drivers and these directly control gene expression. In this scenario, the expression patterns of the DNA-binding proteins are critical. Another idea is that the early embryonic DNA is very restrictive and only limited regions of DNA are accessible to DNA-binding proteins. Thus, the configuration of DNA is important. This project will address which of these two models is important. A combination of cutting edge technologies will be applied during the course of this research. In addition, this project has an outreach component, and will train undergraduates to become familiar with the latest science concepts and technology affecting biomedical sciences.

The activation of gene transcription in the embryo relies on maternal transcription factors, which sit high in the regulatory hierarchy to coordinate the gene regulatory cascades that lead to stereotypical development of embryos. The goal of this project is to examine the earliest lineage restriction events of germ layer specification (ectoderm, mesoderm, endoderm) using Xenopus and to address how maternal transcription factors regulate embryonic genome programming. Since transcription factors drive gene expression programs by binding Cis-Regulatory Modules (CRMs) dispersed throughout the genome, a major unanswered question is how maternal transcription factors bind specific CRMs to endow the transcriptional responses. This important question can be addressed by going back to the earliest stages of embryonic development when transcription from the embryonic genome has not yet begun, the number of different cell types is small, and the genome appears relatively na?ve. Three maternal transcription factors (Otx1, VegT and Sox7) were recently identified and shown to be involved in endoderm specification. Using a combination of genomic approaches together with genetic methods, both gain- and loss-of-function mutants of these maternal transcription factors will be analyzed to determine the mechanisms by which individual CRM activities are coordinately activated, and ensure subsequent epigenetic modifications of the genome.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

National Science Foundation (NSF)
Division of Integrative Organismal Systems (IOS)
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Steven Klein
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University of California Irvine
United States
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