Project: Research project

Project Details


DESCRIPTION (Taken from the applicant's Abstract)

We propose to study the mechanism of genomic imprinting, a genetic process
of importance in development, hormonal regulation and tumorigenesis. The
programme has been divided into 2 phases according to the guidelines for the
Mentored Clinical Scientist Development Award and will be completed over 5
years. The didactic element of the first phase will include laboratory
meetings, research conferences, journal clubs and seminars in the Department
of Genetics, as well as formal course work on the molecular genetics of
eukaryotes and the nucleus and cell cycle.

The research component of this proposal is a test of the hypothesis that
matrix-attachment regions (MARs) are involved in genomic imprinting. MARs
are DNA sequences which anchor chromatin to a fixed nuclear matrix. Many
nuclear factors (such as transcriptional and replication enzymes) are
associated with the nuclear matrix, which may explain the many effects in
cis found for MARs. As these effects include transcriptional enhancement,
DNA replication origination, methylation and chromatin structure
determination, they are candidates for controlling genomic imprinting. This
is because imprinted domains are characterized by differences in gene
expression, replication timing, methylation and chromatin structure between
homologous chromosomes. We propose that functional differences in MARs
between homologous imprinted regions determine these heterogenous
manifestations of imprinting. We describe two MARs from the imprinted
domain of distal mouse chromosome 7, the first described from an imprinted
region. Supporting our hypothesis that they are important regulatory
elements, they exhibit striking sequence conservation with rat.

Phase I of this proposal combines the didactic component described with the
comprehensive mapping of MARs from this domain. Phase II will concentrate
on the functional testing of the MARs by transfection into cultured cells of
appropriate constructs, laying the foundation for the production of
transgenic mice to fully test the role of these elements in genomic
Effective start/end date12/1/9611/30/02


  • Genetics
  • Molecular Biology


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