Our Mission:

Research in our laboratory integrates molecular, cell, developmental, genetic and genomic data to understand fundamental processes related to DNA packaging, transcriptional regulation and epigenetic inheritance in the context of early vertebrate development and disease.

Our Model:

We primarily use the zebrafish as a model for our research. Most processes are well conserved between zebrafish and other vertebrates (including humans). The large numbers of synchronously dividing, externally fertilized embryos produced from zebrafish crosses enable molecular and genomic studies of early embryogenesis that can be difficult to perform in mammalian systems. At the same time the small size, rapid development and clarity of the zebrafish embryo facilitates imaging based approaches to monitor chromatin dynamics in vivo across all stages of development.

Current Research Focuses:

Chromatin regulation in early embryogenesis:

Segregation of eukaryotic genomes into open regions of euchromatin and condensed regions heterochromatin represents one of the most fundamental processes in eukaryotic biology. Failure to package DNA into these distinct states has profound consequences for transcriptional regulation, genome stability and normal development. Yet, despite its fundamental importance, the mechanisms that drive the fractionation of genomes into these distinct domains remain unclear.

In many metazoan species, early embryonic nuclei lack condensed chromatin ultrastructure and have nearly undetectable levels of many histone modifications associated with both euchromatic and heterochromatic domains. Although the exact timing varies between species, features of euchromatic and heterochromatic domains appear to be rapidly established following the onset zygotic genome activation.

Current research in our laboratory is aimed at understanding the mechanisms that drive the de novo segregation of genomes into these distinct compartments, and the developmental consequences of shifting the timing of this event.

DNA methylation loss in disease (Cancer and ICF syndrome):

The epigenetically modified DNA base 5-methylcytosine (DNA methylation, 5mC) is essential for vertebrate development and aberrant DNA methylation patterns are common in diseases. In particular, the pericentromeric satellite repeats that flank chromosome centromeres are highly enriched in 5mC. Specific loss of 5mC at these sequences is very common in cancer and is a hallmark of the rare human disease, Immunodeficiency, Centromere and Facial abnormalities (ICF) syndrome.

While the general importance of 5mC is well-established, the specific functions of 5mC at pericentromeres are less clear. Our laboratory has generated the first viable animal models that faithfully recapitulate selective hypomethylation of pericentromeres and hallmarks of ICF syndrome.

Current research in our laboratory uses these models to understand relationship between pericentromeric methylation loss and cancer, how pericentromeric methylation loss contributes to ICF syndrome pathology and the mechanisms that regulate methylation at pericentromeres.

In vivo reporters of Heterochromatic silencing:

The small size, rapid development and clarity of the zebrafish larvae make it ideally suited for in vivo monitoring of heterochromatic silencing. Our lab is working to develop transgenic zebrafish lines that allow us to monitor repression of fluorescent reporters that are normally silenced by heterochromatin across all cells and tissues over the entirety of zebrafish development. Our lab will use these lines in screens to identify genes required for heterochromatin silencing and conditions that disrupt this silencing.

Impact of Early Toxicant exposure on heterochromatin formation:

Epidemiological and experimental evidence suggest that early life exposure to environmental stress can have long-term health consequences. Epigenetic changes represent one mechanism linking prenatal exposures to latent health outcomes. However, despite the clear public health relevance, our understanding of the relationship between environmental stress, epigenetic mechanisms, and latent disease remains limited. Most studies probing environmental stress and the epigenome focus on changes near genes. Yet, the bulk of vertebrate DNA is made up of repetitive sequences including transposons and satellite DNA. Loss of epigenetic repression at these repeats causes genome instability, transposon mobilization and aberrant activation of the innate immune system. Therefore, it is imperative that we understand the potential for embryonic stresses to interfere with silencing of repeats.

Projects in the lab will probe the hypothesis that embryonic exposure to environmental stress can disrupt heterochromatic repression by testing a broad panel of environmental challenges including heavy metals, endocrine disruptors and DNA damaging agents for their impact on epigenetic silencing at repetitive sequences.