Marisa S. Bartolomei, Ph.D.

Description of Research Expertise

Research Interests

The research in my laboratory focuses on the study of genomic imprinting and X inactivation in mice.

Key words: genomic imprinting, X inactivation, DNA methylation, epigenetics.

Description of Research

One aspect of the research in my laboratory focuses on the study of genomic imprinting in mice. While affecting only a subset of genes in mammals, genomic imprinting results in the unequal expression of the maternal and paternal alleles of a gene. As a consequence, the maternal and paternal genomes are functionally non-equivalent and both are required for normal mammalian development. One imprinted gene, H19, is exclusively expressed from the maternally-derived allele in mice and humans. There are a number of important questions concerning the control of imprinting that are being addressed using the mouse H19 gene. These questions include how and when the inactive and active alleles are differentiated, what sequences designate that a gene is to be imprinted, and what factors function to imprint the gene. One set of experiments in the laboratory tests the hypothesis that methylation of the cytosine residue in CpG dinucleotides is the signal that differentiates the two alleles. We also are testing the role of chromatin structure in conferring parental identity since it is likely that methylation and chromatin structure act coordinately to determine and regulate imprinted expression. Another set of experiments uses transgenic mice and homologous recombination in ES cells to determine the sequences responsible for imprinting a gene. The goal of these experiments is to identify the minimal elements required for imprinting and subsequently identify trans-acting factors involved in the imprinting process.

My laboratory also studies the process of X inactivation in mice. X inactivation is the dosage compensation mechanism that female mammals use to silence one X chromosome and to achieve equivalent X-linked expression to males. Certain aspects of this complex multi-step process have been well established, but the molecular and genetic mechanisms controlling this process remain poorly characterized. While all factors known to be involved in X inactivation map to the X chromosome, it is probable that unidentified autosomal factors are essential to the process. To isolate such factors, ENU mutagenesis in the mouse was used to select for mutations that affect X inactivation. In collaboration with Huntington Willard (Duke University), we have recovered two independent autosomal dominant mutations that perturb X inactivation patterns. Affected heterozygous females exhibit alterations in the proportion of cells expressing a given X chromosome. The observation that 6.5 day embryos are affected by the mutations suggests that we have disrupted autosomal factors that act early in the X inactivation pathway. Such factors may regulate the choice process of X inactivation. These results represent the first evidence of an autosomal mutation affecting any component of the X inactivation pathway. We have mapped the mutations and are currently refining their locations in addition to characterizing further the phenotype of the mutant animals.


Rotation Projects

1. Analysis (expression, DNA methylation and higher order chromatin structure) of mice harboring mutations at the endogenous H19/Igf2 locus.

2. Examination of the effects of various environmental perturbations on imprinting status, including environmental estrogens and procedures used in Assisted Reproductive Technologies.

3. Examination of noncoding RNAs at the H19/Igf2 locus.

4. Other projects available by speaking with PI.

Lab Personnel

Graduate students: Shu Lin, Jamie Weaver, Lara Abramowitz, Rob Plasschaert
Research Associate: Joanne Thorvaldsen
Postdoctoral Fellows: Folami Ideraabdullah, Sebastien Vigneau, Martha Susairjo, Winifred Mak
Research Assistants: Christopher Krapp
Undergraduates: Kristine Wong, Molly Reed, Benjamin Schneider