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Bradley Bernstein,
MD, PhD
Assistant Professor of Pathology, Harvard Medical
School
Assistant Pathologist, Massachusetts General Hospital
Molecular Pathology Unit
Massachusetts General Hospital
149 13th Street, 7th Floor
Charlestown, MA 02129
Phone: 617-726-5690
Fax: 617-726-5684
Email: bbernstein@partners.org
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With the availability
of the complete sequence of the human genome, a major
challenge becomes to understand its higher level organization
and function. Our laboratory studies how chromatin,
the structure that packages genomic DNA, contributes
to this process. Chromatin consists of DNA wrapped
around histone proteins and is regulated by post-translational
modifications that occur on the histones (e.g., acetylation
and methylation). Genomic regions that are highly
accessible and permissive to transcription tend to
be associated with acetylated and Lys4 methylated
histones. In contrast, inaccessible genomic regions
tend to be associated with Lys9 and Lys27 methylated
histones. Histone modifications can be maintained
through cell division and thus provide an "epigenetic"
memory that helps maintain lineage-specific gene expression
patterns in an organism. Chromatin deregulation can
result in inappropriate gene expression and contribute
to the pathogenesis of cancer and other diseases.
In an effort to understand how chromatin regulates
gene expression and genome function under normal and
pathologic conditions, we are mapping histone modifications
across entire chromosomes in various cell types. The
maps are generated by combining immunological methods
(chromatin immunoprecipitation) with high resolution
microarrays. Although most genomic sites associated
with modified histones are short (around 1 kilobase),
remarkably broad Lys4 methylated regions package the
HOX gene clusters (up to 60 kilobases). These regions
appear to represent expansive chromatin domains with
important roles in the epigenetic maintenance of HOX
gene expression. Currently, we are applying comparative
sequence analysis and mapping technologies to identify
and characterize chromatin domains elsewhere in the
genome. We believe that chromatin domains are a general
mechanism by which mammalian cells robustly regulate
developmental genes and ensure lineage fidelity. Mis-regulation
of such domains may represent one mechanism by which
MLL and other oncogenes lead to cancer. Future studies
aim to characterize the mechanisms by which these
domains are established and maintained under normal
and pathologic conditions.
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