About Dr. Schmidt's research

Mammalian organisms inherit one copy of each chromosome from their mother and one copy from their father. Therefore for the two alleles of an autosomal gene there exists a “maternal” allele and a “paternal” allele. The majority of mammalian genes are expressed equivalently from each allele. A subset of genes defies this rule, however, being expressed from only one of the two parental alleles. These are referred to as imprinted genes, and the process that regulates their allele-specific expression is called genomic imprinting. To date over 30 imprinted genes have been described and it is predicted that there may be as many as 100 such genes in the mammalian genome.

We are only beginning to understand how imprinted genes are regulated. It is believed that an “imprint” marks each parental allele so that it can be identified by the cellular machinery and expressed or silenced appropriately. This imprint must be maintained throughout the life of an organism, but reset with each passage through the germline. Candidate regulators of imprinting include DNA methylation, histone acetylation and specialized chromatin structures. The proper regulation of imprinted genes also depends on their organization into large chromosomal clusters, with coordinate regulation of the genes within a cluster. For the H19, Igf2 and Ins2 genes on mouse chromosome 7, a single element controls the imprinting of all three genes. Imprinted genes appear to be major regulators of embryonic growth, and many encode growth factors or their receptors. Human disease syndromes and mouse mutations that result from loss of imprinting exhibit aberrant somatic growth and a predisposition to tumors.

The research in my laboratory centers on the study of two imprinted genes on mouse chromosome 12, Dlk1, which encodes a member of the Notch family of transmembrane proteins, and Gtl2, which produces a noncoding RNA. We have shown that these two genes are tightly linked in mice and humans and are oppositely imprinted, with Dlk1 expressed only from the paternally inherited chromosome while Gtl2 is expressed only from the maternally inherited chromosome. The mouse, Mus musculus, is being used as a model system to investigate the functions of Dlk1 and Gtl2, and to identify the mechanisms that regulate their imprinting. One area of research is the characterization of a potential imprinting control element located upstream of Gtl2 that appears to be required for the imprinting of both genes. Gene targeting in the mouse will allow us to analyze the effects on imprinting when this region is deleted in vivo. We are also dissecting the Dlk1-Gtl2 chromosomal region to look for additional genes; the clustering of known imprinted genes suggests other genes will exist in this domain as well. Finally, we are studying the role of Dlk1 and Gtl2 in embryonic growth. A combination of transgenic and gene targeting technologies is being employed to understand how these genes contribute to embryonic development.

Representative Publications

McMurray EN, Rogers ED, Schmidt JV. (2009) Imprinting analysis in the Acrodysplasia region of mouse chromosome 12. Bioscience Reports, Epub ahead of print.

Schmidt JV, Schmidt CL, Ozer F, Ernst RE, Feldheim KA, Ashley MV, Levine M. (2009) Low genetic differentiation across three major ocean populations of the whale shark, Rhincodon typus. PLoS One, 4:e4988.

Labialle S, Yang L, Ruan X, Villemain A, Schmidt JV, Hernandez A, Wiltshire T, Cermakian N, Naumova AK. Coordinated diurnal regulation of genes from the Dlk1-Dio3 imprinted domain: implications for regulation of clusters of non-paralogous genes. Human Molecular Genetics, 17:15-26.

Carr, MS, Yevtodiyenko, A, Schmidt, CL and Schmidt, JV. (2007) Allele-specific histone modifications regulate expression of the Dlk1-Gtl2 imprinted domain. Genomics, 89:280-290.

Steshina, EY, Carr, MS, Kalinina, E, Yevtodiyenko, A, Appelbe, OK and Schmidt, JV. (2006) Loss of imprinting at the Dlk1-Gtl2 locus caused by insertional mutagenesis in the Gtl2 5' region. BMC Genetics, 7:44.

Yevtodiyenko, A and Schmidt, JV. (2006) Dlk1 expression marks developing endothelium and sites of branching morphogenesis in the mouse embryo and placenta. Developmental Dynamics, 235:1115-1123.

Yevtodiyenko, A, Steshina, EY, Farner, SC, Levorse, JM and Schmidt, JV. (2004) A 178-kb BAC transgene imprints the mouse Gtl2 gene and localizes tissue-specific regulatory elements. Genomics, 84:277-287.