In A Rare Disorder, A Familiar Protein Disrupts Gene Function

As reported this week in the open-access journal PLoS Biology, an
international team of scientists studying a rare genetic disease has
discovered that
a bundle of proteins already known to be important for keeping chromosomes
together also plays an important role in regulating gene expression in
humans. In addition to shedding light on the biological roles of these
proteins, the research may lead to the development of better diagnostic
tools
for Cornelia de Lange syndrome (CdLS), a multisystem developmental
disease.



Ian D. Krantz, of The Children's Hospital of Philadelphia, and colleagues
investigated cohesin, a protein complex consisting of at least four
proteins that form a ring that encircles chromosomes during cell division.
Cohesin's long-established "canonical" role is to control
chromatids-the long strands that chromosomes form during DNA replication.
However, one open question in biology has been, "What does cohesin do
when cells are not dividing?" The paper from Krantz's team provides part
of the answer, as the first study in human cells to identify genes that
are dysregulated when cohesin doesn't work properly. Cohesin's role in
dysregulating gene expression has attracted considerable scientific
interest with a recent discovery that it may also be implicated in cancer.



Using DNA microarrays, Krantz and colleagues did a genome-wide analysis of
mutant cell lines from 16 patients with severe CdLS. All the cells had
mutations in the NIPBL gene, which plays a role in moving cohesin onto and
off chromosomes, or in genes encoding components of the cohesin complex
itself. The study team identified hundreds of genes that were dysregulated
in patient samples compared to samples from healthy individuals, and also
detected specific gene expression profiles that are unique to CdLS
patients. Importantly, said Krantz, the expression levels of dysregulated
genes
corresponded to the severity of the disease.



"We found that gene expression is exquisitely regulated by cohesin and the
NIBPL gene," said Krantz. "The gene expression patterns we found have
great potential to be used in a diagnostic tool for Cornelia de Lange
syndrome." He added that gene profiling arrays have the potential to be
developed as single-platform tools to diagnose, from a patient's blood
sample, not only CdLS, but also a variety of other developmental
disorders.



Funding: JL is supported by a CdLS Foundation Fellowship Grant; IDK is
supported by PO1 HD052860, NICHD; KS was supported in part by a grant of
the
Genome Network Project and Grant-in-Aid for Scientific Research (S) from
the MEXT, Japan. MAD. is supported by KO8 HD055488, NICHD. This project is
funded, in part, under a grant with the Pennsylvania Department of Health
(to NBS). The funders had no role in study design, data collection and
analysis, decision to publish, or preparation of the manuscript.

Competing interests statement: The authors declare that no competing
interests exist.



Citation:
"Transcriptional Dysregulation in NIPBL and Cohesin Mutant Human Cells."
Liu J, Zhang Z, Bando M, Itoh T, Deardorff MA, et al. (2009)

PLoS Biol 7(5):e1000119. doi:10.1371/journal.pbio.1000119


Source
Plos Biology