Developmental Genomics Section
The Developmental Genomics Section strives to understand how complex genotypes and environmental interactions result in disease. Researchers in the section use the fruit fly, Drosophila melanogaster, as a model system. The section’s long-term goal is to develop predictive models of gene function based on gene network analysis in fruit flies. In this work, it is important to identify all the genes, mRNA isoforms, and regulatory elements encoded in the genome. It is also important to determine genetic function across the genome and to develop connectivity maps. Our approach relies on a combination of high-throughput techniques to profile biological processes—such as expression, promoter occupancy, and chromatin status—in conjunction with computational analysis of genomic sequence. The section’s work also addresses a number of interesting questions highly amenable to genome-wide analysis. For example, we are studying lipid storage and the transcriptional response to altered gene copy number.
Gene Regulation and Development Section
The Gene Regulation and Development Section studies how enhancers activate transcription. Research focuses on the mouse and human beta-globin gene families that are regulated in a tissue and developmental-stage-specific fashion by a complex enhancer, the locus control region (LCR). We use biochemical, genetic, genomic, and computational approaches in cell lines, embryonic stem cells, and mice to (1) identify proteins involved in chromatin looping between the LCR and globin genes, (2) investigate the role of long non-coding RNAs in LCR function, and (3) determine how chromosome folding influences enhancers. The studies contribute to gene therapy efforts by revealing the complex interplay between genes and their modulators in the nucleus.
Jurrien Dean, M.D.
The Mammalian Developmental Biology Section investigates female gonadogenesis and early embryogenesis. Research emphasizes events that define the maternal to embryonic transition in mammals by developing models and testing their predictions with mouse transgenesis. One investigative focus is on genetic hierarchies that control follicle formation and expression of maternal effect genes within the ovary. Another is on the molecular basis of sperm-egg recognition that results in fertilization and the intricately orchestrated events that effectively prevent polyspermy. Lastly, we investigate the role of maternal gene products in the activation of the embryonic genome progression through cleavage-stage development and establishment of initial embryonic cell lineages.
Molecular Mechanisms of Development Section
The Molecular Mechanisms of Development Section investigates molecular processes required for establishing a terminally differentiated organism from a homogeneous population of totipotent cells. Work in the section focuses on receptor-mediated signal transduction pathways, as well as nuclear targets to identify mechanisms that specify multicellular differentiation, developmental cell fate, and pattern formation. Approaches include genetic screens, cell imaging, biochemical assay, and deep sequencing with computational analyses. Recent data have defined novel regulatory pathways for mTOR, tyrosine kinase, and presenilin signaling, and demonstrated an essential role for gene-specific chromatin remodeling for developmental induction.
The Lei laboratory seeks to understand how higher-order chromatin structure influences gene expression. Our main goal is to elucidate mechanisms and regulation of chromatin insulators, which are DNA-protein complexes situated throughout the genome that define distinct transcriptional domains. One area of particular interest is the contribution of RNA and RNA-related mechanisms to chromatin organization. Approaches used in the laboratory include genetics, biochemistry, cell biology, molecular biology, and computational analysis of genome-wide datasets. Our work promotes understanding of the intricately orchestrated transcriptional programs needed for proper development and differentiation.