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Mikel Zaratiegui
Assistant
Professor
Rutgers University
Dept. Molecular Biology & Biochemistry
Nelson Biological Labs. Room A139
Piscataway. NJ 08854
(732) 445-1497
FAX - 2447
zaratiegui@dls.rutgers.edu |
Chromatin Dynamics, Heterochromatin, RNA interference,
Transposons, Silencing, Replication, Genome Integrity, Fission Yeast
genetics
The combination of DNA with the protein complement that
regulates it is known as chromatin. Depending on the degree of compaction of
chromatin we can distinguish two forms of organization, Euchromatin and
Heterochromatin. While Euchromatin is open and accessible, Heterochromatin
is a specialized form of chromatin with a highly compacted structure. It
covers regions of the genome that are highly repetitive, and by ensuring a
high degree of compaction it prevents transcription as well as recombination
of the repeat elements. These are very important functions because most
repetitive parts of the genome are derived from transposons, selfish genetic
elements capable of moving within the genome and increasing their copy
number. These potentially harmful parasitic sequences must be silenced to
avoid their rampant spread and the mutation and genomic instability that it
can cause. The other main types of sequences coated by heterochromatin are
highly repetitive arrays of elements called satellite DNA. Over the course
of evolution, heterochromatic satellite regions have gained new roles in the
chromosome. For example, the pericentric satellite DNA is necessary for
proper chromosome segregation through its participation in centromere
formation. Since repetitive DNA constitutes a large proportion of eukaryotic
genomes, heterochromatin plays a key role in their function and evolution,
and loss of its regulation can lead to cancer and aging-related diseases.
We study the mechanisms by which the cell recognizes repetitive and
parasitic elements and compacts them into heterochromatin, and how this
heterochromatic structure is maintained through mitosis. In particular, we
are interested in the interaction of DNA replication and epigenetic
inheritance. We have shown that repetitive regions pose impediments to the
progression of the replication fork, and the DNA damage signaling and
repair-like reaction that this elicits can recruit chromatin remodeling
factors that deposit heterochromatic marks. In this manner, epigenetic
inheritance of heterochromatin can be directly coupled to DNA replication by
reestablishment of silencing marks in the wake of the replication fork. This
provides an explanation to why these widely varied sequences are silenced by
heterochromatin despite exhibiting no sequence conservation.
To study these phenomena, we use the small genome of the fission yeast
Schizosaccharomyces pombe as a model, because it exhibits silencing
mechanisms that are similar to those found in higher eukaryotes. We study
the involvement if RNA interference in the formation of heterochromatin at
pericentric repeats, and the role of the family of domesticated transposases
CENP-B in the silencing or retrotransposons. Both pathways display
interactions with the DNA replication machineries and affect the progression
of the replication fork. Ultimately, we aim to discover the conserved
principles that underlie epigenetic inheritance.
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