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LABORATORY
OF MOLECULAR GROWTH REGULATION
|
Bruce H. Howard, MD, Chief The
Laboratory of Molecular Growth Regulation (LMGR) conducts research on the
control of cell proliferation, DNA replication, and gene regulation. With respect
to the latter, independent groups work in complementary areas, including
regulation of the developing immune system, gene expression during early
embryogenesis, chromatin-mediated gene silencing, and transcription of small
RNA-encoding genes. Keiko Ozato’s group, the Section
on Molecular Genetics of Immunity, studies transcription factors that
control cell proliferation and differentiation in the immune system. Studies
on IRF-8 have revealed its importance for the proper development of
macrophages, granulocytes, and dendritic cells. Defects in these cell
lineages have severe consequences for innate immunity. Both IRF-8 and Brd4,
another transcription factor under investigation, were shown to function by
regulating the activity of chromatin. IRF-8 recruits the chromatin remodeling
protein BRG1. Brd4 recognizes acetylated histones in live cells and remains
bound to chromosomes during mitosis. Investigations
carried out by the Section on Eukaryotic Gene Regulation, led
by Mel DePamphilis,
concern control of gene expression during early mouse embryogenesis, which
has been linked to the transcription factor mTEAD-2. Experiments have
identified YAP65 as a long sought-after co-activator of the TEAD family of
transcription factors. Current experiments focus on the identification of
target genes for the TEAD-YAP65 complex. An independent project led by
investigators working on mTEAD-2 concerns cell cycle control and the role of
the ORC complex in DNA replication. ORC1, which is ubiquitinated and released
from chromatin during S phase, is a key component in the ORC cycle as well as
a link between DNA replication and cell metabolism. Still
another area of study relates to the multifunctional factor known as human La
antigen. Work in the Section on Molecular and Cell Biology, under the
direction of Richard Maraia, has
indicated that La antigen is essential for development. The protein is a
regulatory chaperone for nascent RNAs and is required for proper nuclear
trafficking and the successful processing of tRNAs. Phosphorylation of La
modulates its interaction with nascent transcripts as well as its
localization to the nucleolus. A
major effort of the Human Genetics Section, led by Bruce Howard, focuses on
higher-order chromatin structure, in particular how defects in the
maintenance of such structures may underlie developmental disorders and
age-related diseases. Random genome sampling, customized search algorithms
for genome comparisons, and genomics-style high-throughput approaches facilitate
the detection and mapping of age-related areas of chromatin remodeling. A
research group led by David Clark, the
Unit on Chromatin and Gene Expression, brings to the LMGR expertise in
both yeast genetics and the characterization of purified chromatin
structures. Studies with the latter have revealed unexpected and intriguing
properties of chromatin-remodeling machines. |