Research Interests:
The research in the Bartolomei laboratory uses the
mouse as a model system to study the mechanisms that
control genomic imprinting and X inactivation. Both
phenomena employ genetic and epigenetic strategies to
distinguish and stably inactivate parental alleles or
chromosomes. Genomic imprinting affects a small number of
genes and results in the unequal expression of the maternal
and paternal alleles of these genes. The majority of
projects in the Bartolomei laboratory focus on a cluster of
imprinted genes on the distal end of mouse chromosome 7,
where the maternally expressed H19 and the paternally
expressed Igf2 genes reside.
The Bartolomei laboratory is using gene targeting and
transgenic experiments to identify critical factors and
sequence involved in the imprinting of these two genes.
Additionally, RNAi approaches are being used to ablate
candidate factors that are mediating genomic imprints in
the germline and early embryo. The laboratory is also using
various physiological and developmental perturbations such
as embryo culture, DNA methyltransferase mutant mice and
mouse somatic cell cloning to investigate critical
imprinting processes. While genomic imprinting regulates
the parental expression of specific genes throughout the
genome, X inactivation results in the silencing of most
genes on one of the two X chromosomes in females to achieve
dosage compensation between males and females.
For the study of X inactivation, the laboratory has
employed chemical mutagenesis to identify factors involved
in the choice of which chromosome is to be active/inactive
and has isolated autosomal mutations with dominant effects
on X inactivation patterns. These mutations are currently
being characterized, mapped and identified.
Recent
Representative Publications:
Engel, N., West, A.G., Felsenfeld, G., and M.S.
Bartolomei. (2004). Antagonism between DNA hypermethylation
and enhancer-blocking activity at the H19 DMD is uncovered
by CpG mutations. Nature Genetics, 36:883-888.
Mann, M.R.W., Lee, S.S., Doherty, A.S., Verona, R.I.,
Nolen, L.D., Schultz, R.M., and M.S. Bartolomei. (2004).
Selective loss of imprinting in the placenta following
preimplantation development in culture. Development,
131:3727-3735.
Nolen, L.D., Gao, S., Han, Z., Mann, M.R.W., Chung, Y.G.,
Otte, A.P., Bartolomei, M.S. and Latham, K.E. (2005). X
Chromosome Reactivation and Regulation in Cloned Embryos.
Developmental Biology, 279:525-540.
Mager, J. and M.S. Bartolomei. (2005). Strategies for
dissecting epigenetic mechanisms in the mouse. Nature
Genetics, 37:1194-1200.
Thorvaldsen, J.L., Fedoriw, A.M., Nguyen, S., and M.S.
Bartolomei. (2006). Developmental profile of H19 DMD
deletion alleles reveals multiple roles of the DMD in
regulating allelic expression and DNA methylation at the
imprinted H19/Igf2 locus. Molecular and Cellular Biology,
26: 1245-1258.
Chadwick, L.H., Pertz, L.M., Broman, K.W., Bartolomei,
M.S., and H.F. Willard. (2006). Genetic control of X
chromosome inactivation in mice: definition of the Xce
candidate interval. Genetics, 173:2103-2110.
Maatouk, D.M., Kellam, L.D., Mann, M.R.W., Lei, H., Li, E.,
Bartolomei, M.S. and J.L. Resnick. (2006). DNA methylation
is a primary mechanism of silencing postmigratory
primordial germ cell genes in both germ cell and somatic
cell lineages. Development, 133:3411-3418.
Mager, J., Schultz, R.M., Brunk, B.P., and M.S. Bartolomei.
(2006). Identification of candidate maternal-effect genes
through comparison of multiple microarray data sets.
Mammalian Genome, 17:941-949.
Engel, N., Thorvaldsen, J.L. and Bartolomei, M.S. (2006)
CTCF binding sites promote transcription initiation and
prevent DNA methylation on the maternal allele at the
imprinted H19/Igf2 locus. Human Molecular Genetics,
15:2945-2954.
Reese K.J., Lin S., Verona R.I., Schultz R.M. and M.S.
Bartolomei (2007). Maintenance of paternal methylation and
repression of the imprinted H19 gene requires MBD3, PLoS
Genetics, 3:e137.
Rivera, R.M., Stein, P., Weaver, J.R., Mager, J., Schultz,
R.M. and M.S. Bartolomei. (2007). Manipulations of mouse
embryos prior to implantation result in aberrant expression
of imprinted genes on day 9.5 of development. Human
Molecular Genetics, doi: 10.1093/hmg/ddm280.
Thorvaldsen, J.L. and M.S. Bartolomei. (2007). SnapShot:
Imprinted gene clusters. Cell, 130:958-959.
Verona, R.I., Thorvaldsen, J.L., Reese, K.J. and M.S.
Bartolomei. The transcriptional status but not the
imprinting control region determines allele-specific
histone modifications at the imprinted H19 locus. Molecular
and Cellular Biology, In Press.