It?s All In the Packaging
25 Jun, 2007 04:43 pm
Remember how the best chefs pay as much attention to the packaging and presentation of a dish as the food itself. It turns out that the human genome believes as much in its packaging. Our DNA does not lie naked in the cell, but is wrapped up in proteins that constitute the packaging called chromatin. In the ENCODE pilot project a multinational team of investigators analyzed 1% of the human genome for a wide array of functional signatures. They studied which portions are expressed as RNA, which portions get copied early or late in the life of a cell and which portions are covered by different types of proteins. To their surprise, the results from the different experiments, looking at different things, in different parts of the world, dovetailed to yield a very simple message: packaging is king!
Another surprise from the study is the difference in packaging of the two copies of genes in a cell. All of us have two copies of genes residing on two copies of a given chromosome: one from Mom and the other from Dad. It is widely believed that both copies of a gene are treated equally by a cell: if a gene is to be expressed, both copies of the gene will be in the active chromatin and will be copied early in the cell cycle and expressed equally. The reverse is true if a given gene is to be silenced. The University of Virginia team discovered, however, that in a cancer cell as much as 20% of the genome is in an asymmetric environment. The two (or sometimes more) copies of a given gene are not in the same chromatin environment. One copy is in active chromatin and replicated early, while the other copy is in repressed chromatin and replicated late. Such asymmetry was known to occur in a handful of genes known as imprinted genes, and indeed one of the imprinted loci in the ENCODE region revealed this expected asymmetry. The surprise was that in a cancer cell, as much as 20% of the genome revealed such asymmetry. If this result is reproduced in other cancer cells, there is the distinct possibility that a cancer cell can silence a gene that deters cancer cell growth by such asymmetric packaging. If both copies of a gene are expressed a cancer cell needs to be struck twice by lightning. Mutation is a rare event and yet the cancer cell has to mutate both copies of an anti-cancer gene to break free. If 20% of the genome in a cancer cell has asymmetric packaging, however, it is entirely possible that a cancer cell has to mutate only the single active copy of an anti-cancer gene to break free: the other copy of the gene would be silenced by asymmetric repressive chromatin packaging.
Thus, although the sequence of letters revealed by the human genome sequence is clearly important, equally important is the packaging in which this sequence is vested in our cells. The sequence of letters remains the same from cell to cell, yet the packaging changes resulting in the expression of different genes in different cells to produce the gorgeous mosaic that is the human body. Unfortunately, cancer cells can subvert the packaging mechanism to inactivate the back-up copy of anti-cancer genes without having to hope for a rare mutation to inactivate the back-up copy. There is good news in this: a new class of drugs are being pursued that can change the packaging of chromatin. Such drugs could selectively change the packaging and activate the back-up copy of the anti-cancer gene to rein in the cancer.
Karnani N., et al, Pan-S replication patterns and chromosomal domains defined by genome-tiling arrays of ENCODE genomic areas, Genome Research, June 2007