One of the most fundamental questions in biology is how cells become functionally distinct during development, even though they carry identical genome copies. We are particularly interested in the role played in the establishment of cell identity by the choice of which allele, maternal or paternal, will be expressed in a given cell lineage. Mechanisms of this type control genes coding for immunoglobulins and olfactory receptors, and are crucial for the generation of cell diversity in the immune and nervous systems. We have shown that this type of allelic choice occurs with many hundreds of human genes, creating an extraordinary epigenetic diversity in cell populations.
Currently, we use and develop a variety of approaches, including allele-specific arrays and whole-transcriptome next-gen sequencing, in order to build a comprehensive map of allele-specific expression and the correlated chromatin states. This effort is under way in both human and mouse cells to gain an insight into the evolutionary context of allelic silencing. Of particular interest to us is the contribution of allelic inactivation to progression of malignancy; an epigenetic silencing of one allele is a functional equivalent of loss of heterozygosity, even as the genome is still apparently intact.
Another line of research is identification of the molecular mechanisms underlying the choice of active and inactive alleles. We are using stem cells to characterize the developmental plasticity of allele-specific expression. We are also developing mouse knock-in models for high-throughput loss of function screening of pathways that are involved in establishment and maintenance of epigenetically controlled allele-specific expression.
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