Cornelia de Lange Syndrome (CdLS) is a multisystem genetic disorder caused by
mutations in the cohesin complex. It is believed that cohesin is able to regulate gene
expression with CTCF by holding chromatin in topological complexes, such as
active chromatin hubs, and that CdLS is caused by loss of these complexes causing
aberrant gene expression.
In order to determine if loss of these complexes in CdLS resulted in a general
change in the compaction of chromatin, I undertook a series of analyses of the
nucleus in CdLS patient lymphoblastoid cell lines (LCLs), compared to wildtype,
and later in RNAi knockdown models of CdLS. By fluorescent in situ hybridisation
(FISH) I studied the chromatin compaction of different regions of the genome, and
found that in some, but not all, CdLS cell lines, gene-rich regions have less compact
chromatin compared to wildtype. RNAi knockdown of two proteins that are mutated
in CdLS, NIPBL and SMC1, also resulted in decompaction of regions of the genome,
however these were different regions than in the patient LCLs, perhaps due to
variation between cell lines. This change was not due to the interaction between
cohesin and CTCF, as I found that knockdown of CTCF did not result in changes in
chromatin compaction. I have also looked at the published data for gene expression
in CdLS, and in mouse and Drosophila models of CdLS, and have found no
correlation between the genes misexpressed in CdLS in the three species, nor
between three cell lines of the same species.
These data suggest that the variation in chromatin compaction observed in CdLS
may not be due to an interaction between cohesin and CTCF, and that cohesin can
act independently of CTCF to regulate gene expression