Acquisition and maintenance of DNA methylation in genomic imprinting

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DESCRIPTION (provided by applicant): Genomic imprinting is essential for mammalian development. Dysregulation of imprinting genes can lead to cancer, diabetes, cardiovascular diseases and other kinds of human diseases. Although genomic imprinting was identified in mammals almost three decades ago, it is still unclear if genomic imprinting plays a role in late embryonic development. Many unanswered questions persist about the nature of genomic imprinting memory and about how genomic imprints are established and maintained. This proposal aims to uncover the underlying molecular mechanisms of establishment, maintenance and acquisition of DNA methylation imprints in mouse embryos and in cell culture. These objectives can be reached now because we have discovered an important regulator in DNA methylation imprints. Our preliminary results indicate that ZFP57 appears to be required for cardiovascular development. ZFP57 can target DNA methyltransferases to imprinting control regions to initiate and maintain DNA methylation imprints. Our proposed experiments will examine whether ZFP57 regulates LIN-12/Notch signaling in cardiovascular development via its target imprinted gene, thereby linking genomic imprinting to late stages of embryonic development. The expected outcome from this research will further our understanding of the establishment and maintenance of DNA methylation imprints, setting the stage for future studies to unravel the molecular nature of genomic imprinting memory. Successful completion of these experiments will also provide proof of principle for manipulating DNA methylation imprints in pluripotent stem cells for future therapeutic applications. PUBLIC HEALTH RELEVANCE: Dysregulation of genomic imprinting are associated with a variety of human diseases including metabolic diseases, cardiovascular diseases and cancer. Indeed, it was just published that mutations in human Zfp57 result in hypomethylation at multiple imprinted regions and are associated with transient neonatal diabetes and congenital heart defects.