Research in Dr. Mellissa Mann’s laboratory focuses on molecular mechanisms that regulate genomic imprinting during gametogenesis and early embryo development. Genomic imprinting is defined as a mechanism of transcriptional regulation that restricts expression to one parental allele. Imprinting is a multi-step process that begins in the gametes, where epigenetic modifications differentially mark the parental alleles. These marks must then be stably maintained in the developing embryo where they are translated into parental-specific expression. Errors in any of these stages can lead to genomic imprinting disorders, such as Beckwith-Wiedemann Syndrome, Angelman Syndrome, and Silver-Russell Syndrome. The Mann lab addresses how genomic imprinting is regulated in gametes, pre- and postimplantation embryos and the three stem lineages of the early embryo using a mouse model, and a combination of genetic, molecular, and cytological tools. There are four main projects in Dr. Mann’s lab:
Assisted Reproductive Technologies and Genomic Imprinting
Children conceived by assisted reproduction technologies are at increased risk of intrauterine growth retardation, premature birth, low birth weight, and possibly genomic imprinting disorders. Dr. Mann’s research has lead the field by producing extensive and novel data showing that preimplantation development is a critical period of imprint maintenance that is susceptible to epigenetic perturbation during oocyte and embryo manipulation. Our current work will determine how hormone stimulation or embryo culture perturbs imprint maintenance.
Imprinted domain regulation
Very little is known about mechanisms that regulate genomic imprinting during early development. Using an improved lentiviral transgene delivery system, an RNAi library for epigenetic modifiers and hybrid stem cells that that we generated, we conducted a positive selection, loss of function, RNA interference screen for epigenetic factors that regulate genomic imprinting, using the Kcnq1ot1 domain as a model imprinted domain. We have identified novel candidate factors involved in imprinted gene regulation as well as discovered a novel mechanism of imprinted domain regulation that we are currently investigating.
Role of the Kcnq1ot1 long noncoding in stem cells and early embryos
There is little information of how imprinted gene expression is established across an imprinted domain during preimplantation development and its maintenance during early postimplantation development. To better understand the regulatory events in early embryos, we are using genetic models to more precisely determine the timing of paternal allelic silencing of genes within the domain and whether the Kcnq1ot1 imprinting control region and/or the Kcnq1ot1 noncoding RNA are required for establishment and maintenance of paternal allelic silencing.
Identification of genomic imprinting control regions
An intriguing characteristic of imprinted genes is that they often cluster in large chromosomal domains that are co-ordinately regulated by cis-acting regions, known as imprinting control regions. To identify novel imprinting control regions, we have used extensive bioinformatics screening of publicly available database. Based on defined epigenetic profiles, we identified known and novel imprinting control regions. We are currently investigating these novel imprinting control regions and novel neighboring imprinted genes.
