Soren Impey, Ph.D.
Research Interests The Impey lab utilizes functional genomic approaches to characterize the transcriptional and epigenetic networks that regulate stem cell self-renewal and neural differentiation. We recently developed a novel technology, termed Serial Analysis of Chromatin Occupancy (SACO), that enables the identification of transcription factor target sites or epigenetic marks across entire mammalian genomes. The lab also relies on bioinformatics approaches to extract novel biology from our functional genomic and transcriptome screens. Neurogenesis and neuronal maturationOur initial SACO screen profiled targets of the transcription factor CREB, an important regulator of neurogenesis, neuronal maturation, and synaptic plasticity. Additional screens revealed a network of ~10,000 high-confidence CREB binding sites in a neural cell line, neuronal progenitors, and cortical neurons. We have recently utilized SACO and transcriptome data to identify hundreds of novel CREB target genes that are potently regulated by neurotrophins and neuronal activity. Remarkably, a significant fraction of inducible CREB-dependent genes are not predicted to code for proteins. Thus, a major focus of the lab is the characterization of these novel non-coding genes and microRNAs. Indeed, our lab was the first to identify a neurotrophin and activity-regulated microRNA that controls neuronal differentiation and synaptogenesis. More recent studies seek to gain additional insight into neurogenesis via screens for developmentally-regulated transcriptional regulators. NIH-supported research Epigenetic control of embryonic stem cell pluripotency and self-renewalEmbryonic stem (ES) cells isolated from the inner cell mass of murine blostocysts are pluripotent, capable of indefinite symmetric cell division, and can be differentiated into all cellular lineages. The recent isolation of human ES cells holds great promise for the treatment of a variety of degenerative disorders including, but not limited to, Parkinson's disease and diabetes. The homeodomain transcription factors, Oct3/4 and Nanog, are believed to play critical roles in sustaining ES cell pluripotency. Surprisingly, few Oct3/4 or Nanog targets have been linked to pluripotency and it is also not clear how these factors regulate transcription. Initial studies have identified over ~4,000 predicted Nanog target sites in mouse embryonic stem cells. Remarkably, we find that all tested Nanog targets are co-occupied by Oct3/4. More recent studies show that the Oct3/4-Nanog complex recruits a histone-methylation complex associated with active chromatin. We are also characterizing novel Nanog targets that directly regulate the Polycomb and Trithorax epigenetic pathways. These studies suggest that Nanog and Oct3/4 regulate embryonic stem cell self-renewal, at least in part, by controlling epigenetic remodeling. We believe that our studies will reveal epigenetic networks that may facilitate the re-programming of adult cells into pluripotent, ES-like cells. NIH-supported research
Summary of Current Research
Neuroscience Neuronal Differentiation Stem Cell Epigenetics Transcription Chromatin Genomics Embryonic Stem Cell Developmental biology MicroRNA Noncoding RNA
"Foxa3 induces goblet cell metaplasia and inhibits innate antiviral immunity,"
"Leptin induces hippocampal synaptogenesis via CREB-regulated MicroRNA-132 suppression of p250GAP,"
"Targeting inhibitors of the tumor suppressor PP2A for the treatment of pancreatic cancer,"
"The environmental neurotoxicant PCB 95 promotes synaptogenesis via ryanodine receptor-dependent miR132 upregulation,"
"A Genome-Wide Screen of CREB Occupancy Identifies the RhoA Inhibitors Par6C and Rnd3 as Regulators of BDNF-Induced Synaptogenesis,"