In the dancehall that is known as the nucleus, some stretches of DNA are very much in the swing of things, enjoying opportunities to pair with various proteins, executing all manner of dance moves—openings, closings, and the intricate business of transcription. Yet other stretches of DNA seem tethered to the nuclear margins, left out of the fun. These DNA wallflowers are epigenetically sidelined, almost as though they are marked for obscurity, bound to remain inactive.
In a way, the DNA that sticks close to the nuclear lamina is marked. Such DNA contains segments that are able to bind to a protein called Ying-Yang1 (YY1). Somehow, YY1 appears to have a part in consigning certain stretches of DNA to the nuclear lamina.
This finding emerged from studies led by Karen Reddy, Ph.D., a biochemist at Johns Hopkins University. Dr. Reddy and her colleagues also discovered two molecular tags that are needed for DNA to move to the lamina. The tags are found on the histone proteins that DNA coils around and are a classic form of epigenetic regulation. It seems likely that YY1 is involved in summoning the proteins that attach the molecular tags to the histones. But whether YY1 has additional roles, like acting as a magnet to bring the DNA to the lamina, is unclear.
These findings were presented January 5 in the Journal of Cell Biology, in an article entitled, “Directed targeting of chromatin to the nuclear lamina is mediated by chromatin state and A-type lamins.” The article describes how the Johns Hopkins researchers began by comparing immature, embryonic, skin-like cells to mature immune system cells from mice. When the researchers compared the segments of DNA clinging to the lamina in the two cell types, they found that differences occurred near genes that are used differently between the two. Additionally, the DNA regions that cling to the lamina were very consistent; there were no “grey areas” that were only sometimes associated with the lamina.
Next, the researchers chopped up the lamina-associated DNA segments and inserted individual pieces into the chromosomes of test cells, watching for the nearby chromosome segments to move to the lamina. They found that these segments were able to bind the protein YY1, and that YY1, when bound to a segment of DNA, was able to send the surrounding DNA to the lamina.
“Knockdown of YY1 or lamin A/C, but not lamin A, led to a loss of lamina association,” wrote the authors of the Journal of Cell Biology paper. “In addition, targeted recruitment of YY1 proteins facilitated ectopic LAD formation dependent on histone H3 lysine 27 trimethylation and histone H3 lysine di- and trimethylation. Our results also reveal that endogenous loci appear to be dependent on lamin A/C, YY1, H3K27me3, and H3K9me2/3 for maintenance of lamina-proximal positioning.”
Reflecting on the significance of these findings, Dr. Reddy said, “This is the first time a specific combination of epigenetic modifications has been implicated in tethering DNA to the lamina.” She added that researchers now “have a lot of interesting questions to answer about how different types of cells use this mechanism to regulate different sets of genes.”
Many of these questions will no doubt concern development, and how it is some stretches of DNA act like wallflowers in some kinds of cells, but are riotously active in others. The “wallflower mechanism,” which can turn off entire segments of the genome, may be especially useful during development, when each cell in the embryo takes on a different fate by making a different set of proteins, even though each contains the same set of genes.