Dark Matter, Rosetta Stones and Hordes of Beasties

Key regulatory roles are being identified for non-coding DNA sequences, once considered "junk".

The more you know, the more you find out about how much you still don’t know. So goes the old saying. A recent New York Times article nicely illustrated the practical outworking of this phenomenon in the context of cancer research. The article highlighted several recent papers and reviews showing how much progress has been made over the last ten years, and illustrating how the focus has changed to incorporate not only research on protein-coding sequences, but also the “dark matter” of noncoding RNAs and the potential contributions of genes from the millions of bacteria that colonize the human body.

In 2000, a review describing six key traits of cancer cells was published in the journal Cell, it is one of the most cited papers from that journal. In March of this year, the same authors published an update entitled Hallmarks of Cancer: The Next Generation describing current knowledge of the mechanisms underlying the same six traits, and adding two new ones. The updated list is as follows: 1) Sustained proliferative signaling; 2) Evading growth suppresors; 3) Resisting programmed cell death; 4) Limitless replicative potential; 5) Sustained angiogenesis; 6) Tissue invasion and metastasis; 7) Reprogramming energy metabolism; and 8.) Evading immune destruction. The review summarizes the basics of each characteristic, providing updated information on the cellular mechanisms involved and providing an overview of current research in each area. In their conclusions the authors briefly discuss epigenetic and microRNA studies, noting that such studies have already led to profound changes in our understanding of the genetic control mechanisms that operate in health and disease, but that it is still too early to tell whether advances in epigenetics will result in a fundamental change in understanding of cancer cell development per se, or will simply add detail to the already complex regulatory circuits involved.

The New York Times article highlighted the Cell review article and also provided a summary of how studies on the role of noncoding RNAs and on the genetic contributions of colonizing microorganisms are contributing to our understanding of growth control in both normal cells and tumor cells. The expansion of the field of study to include the potential contributions of noncoding sequences and microbial genes as well as protein-coding regions has constituted a major shift in perspective. The author describes this change as follows:

“These shifts in perspective, occurring throughout cellular biology, can seem as dizzying as what happened in cosmology with the discovery that dark matter and dark energy make up most of the universe.”

It is dizzying indeed to contemplate the added complexity of the roles of intergenic regions, pseudogenes, microRNAs and microbial colonists in health, disease and development, especially given the statistics that noncoding regions make up 98% of the human genome and that the number of microbial genes in the human body vastly outnumber the human ones. However, the body of work emerging from studies of noncoding RNAs and microbiome analysis makes fascinating reading. The following three reviews and papers highlight recent developments in these areas:

Dark Matter
Long noncoding RNAs are often referred to as the dark matter of the cell. This review, published in April 2011, provides an up-to-date summary of their roles–as identified so far. Topics covered include gene silencing, chromatin interactions, enhancer activity, and reprogramming of somatic cells to induced pluripotent stem cells.

A Rosetta Stone?
A ceRNA Hypothesis: The Rosetta Stone of a Hidden RNA Language, an essay published in the August issue of Cell, presents the idea that messenger RNAs, their pseudogenes, and long noncoding RNAs communicate using microRNA response elements in a large-scale regulatory network. Work showing that the tumor suppressor PTEN and its pseudogene PTENP1, and the gene:pseudogene partners KRAS and KRAS1P compete for the same miRNA elements is highlighted.

And Hordes of Beasties
Studies of the human microbiome are revealing hitherto unknown linkages between microbial flora and particular disease states. The paper Towards the human colorectal cancer microbiome, published in PLoS ONE in May 2011, compared the microbial genetic profile of normal colon tissue and adjacent colon tumor tissue. rRNA sequencing revealed striking differences in microbial colonization patterns between the two sites. The differences are intriguing, but the reasons for them remain to be defined.

Studies are just beginning to identify potential roles for colonizing bacteria in human health and disease.

I wonder how these and other studies will change our understanding of cancer cell development and growth regulation over the next ten years?

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Isobel Maciver

Isobel is a graduate of the University of Edinburgh and of Aston University in Birmingham, U.K. She is a technical writer and editor, and is also manager of the Scientific Communications group at Promega. She enjoys writing about issues in science and communication.

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