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CpG Islands Tackle Chromatin Remodeling Project

April 28, 2010 Researchers have known about CpG Islands (CGIs) for decades, but there are still more questions than answers when it comes to this heavily studied genomic real-estate. Hypermethylated CGIs seem to get a lot of attention for their apparent involvement in transcriptional silencing, but most CGIs stay unmethylated. So what’s going on in these unmethylated CGIs? Two recent studies took on that question, and in the process showed that CGIs are involved in more (chromatin) remodeling than a home improvement show.

Both papers illustrate separate mechanisms by which CGIs maintain their hypomethylation status and keep a chromatin structure that permits transcription.

The first study led by John Thomson from Adrian Bird’s lab (Nature, April 2010) casts the CpG binding protein Cfp1 in a lead role in chromatin’s re-design special. Their study shows how Cfp1 works to establish active chromatin as follows:

• They found Cfp1 to be enriched in unmethylated CGI pools, created through methyl-CpG-sensitive restriction digestion of fractionated chromatin.
• They showed selective binding of Cfp1 to unmethylated CGIs both in vitro and in vivo using the mono-allelically methylated Xist locus in mice. This binding was verified by ChIP-bisulfite sequencing.
• Additionally, they found that H3K4me3, a classic mark of active chromatin at unmethylated CGIs, colocalized with Cfp1 binding.  Furthermore, this modification is drastically reduced in Cfp1-depleted cells.
• Finally, they integrated synthetic, promoter-free CGIs into the mouse genome to test the functional interplay of Cfp1 binding and H3K4me3.  They found that, despite the lack of promoters, the CGI inserts recruited Cfp1 and showed extensive H3K4me3 modifications.

This evidence led the Bird lab to conclude that Cfp1 is a major factor in maintaining an open chromatin structure at unmethylated CpG Islands.

The second paper from Robert Klose’s team at the University of Oxford (Molecular Cell, April 2010), identified a histone H3 lysine 36 demethylase, called KDM2A, that gets recruited to CGIs in order to remove H3K36 methylation and create open chromatin structure. Some other findings include:

• KDM2A binds only non-methylated DNA, and in fact only interacts with single CpG dinucleotides.
• KDM2A is found in CGIs throughout the genome.
• Depletion of KDM2A leads to H3K36me2 spreading.

Taken together, this evidence suggests that CGI DNA might act to differentiate CGI chromatin from other chromatin and to create chromatin structure that permits transcription, but doesn’t drive transcription.

“Importantly, this work describes a new paradigm by which a generic underlying DNA element is translated into a defined epigenetic chromatin architecture. It appears that this chromatin marking mechanisms doesn’t directly impinge on activated transcription but instead creates regulatory elements that are potentially more permissive to transcription factor and RNApolII nucleation.” says Klose.

Check out all of the behind the scenes remodeling in Nature, April 2010 and Molecular Cell, April 2010