Talpa senza pelo, genoma senza più segreti

Sequenziato il genoma dell'eterocefalo glabro, naked mole rat, l'animale longevo (30 anni) che resiste allo sviluppo dei tumori...
fonte
"http://www.physorg.com/news/2011-07-scientists-sequence-dna-cancer-resistant-rodent.html"

• Scientists at the University of Liverpool, in partnership with The Genome Analysis Centre, Norwich, have generated the first whole-genome sequencing data of the naked mole-rat, a rodent that is resistant to cancer and lives for more than 30 years.</p>

si attende di scoprire qualche meccanismo / pathway / antioncogene, la cui attività regoli altri modificatori attivatori / guardiani del genoma / regulatori chiave /controllori epigenetici.

Nel frattempo, ecco il sito del progetto genoma della talpa senza pelo, animale sociale ( una regina fertile, caste) capace di utilizzo di strumenti da lavoro (maschere in legno per tenere lontana la polvere)

Foto: Neil Bromhall, OSF, Getty. Dal sito

Naked Mole-Rat Genome Resource 2011.

http://naked-mole-rat.org

Aggiornamento (Biotechniques)

• the naked mole rat’s genome which contains an estimated 2.47 Gb and 22,561 genes. Comparatively, the mouse genome has 23,317 genes, and the rat genome has 22,841.

• In their analysis of cancer resistance, the researchers looked at the genes that encode the tumor-suppressor proteins p16Ink4a and p27Kip1. In humans and mice, tumor suppression is primarily mediated by p27Kip1, but previous research has proposed that p16Ink4a plays a role in the naked mole rat’s heighten tumor resistance. Although the naked mole rat’s and the mouse’s p16 gene both consist of three exons, the last exons are not very similar. Furthermore, two early stop codons in the second exon result in a significantly smaller protein. These sequence differences could affect the tumor suppressing function of these proteins.

• To study longevity, the team analyzed RNA sequencing data from the brain, kidney, and liver of newborns, young, and older naked mole rats. As a result, the researchers found that gene expression did not change significantly during the rodent’s lifespan, particularly in the brain. Specifically, the researchers found stable expression during its lifetime of the gene SMAD3, which may regulate the rate of cell death in the naked mole rat and help prevent the development of cancer.

• Aside from to SMAD3, 30 other genes had stable expression during the naked mole rat’s lifetime. For example, mitochondrial functions and telomerase reverse-transcriptase (TERT) were expressed well maintained during the organism’s lifespan.

• Likewise, the researchers found genetic modifications that could explain the naked mole rat’s pain insensitivity. Previous research had found that the rodent’s skin and cutaneous C-fibers lack neuropeptide Substance P, which is involved with pain signaling in other mammals. While the genethat encodes this peptide is intact in the naked mole rat genome, it had a deletion in the core promoter that could possibly alter its expression.

• ”Evolutionarily, pain insensitivities of animals is a novel system. It can respond to systems, it can increase survival or reproductive chance. It’s considered an evolutionary advantage, says Zhang.

• Small eyes and poor visual function in the naked mole rat were traced to two missing vertebrate opsin genes when compared with the genomes of mice, rats, and guinea pigs. However, the genes that encode the photopigments rhodopsin and melanopsin are intact in the genome, allowing the rodent to adapt to their dark environment.

“The blind mole rat cells recognized when they were over proliferating and that would induce cell death of an entire culture,” explained study author Vera Gorbunova, professor of biology and associate professor of oncology at the University of Rochester. “We started to think maybe this is how they fight cancer in vivo. That when the cells sense that they are pre-cancerous, they just trigger cell death in a very efficient way.”

To simulate cancer, Gorbunova’s lab rapidly grew primary fibroblast cells that were isolated from the rodent in culture. Her team expected to find an anticancer mechanism similar to the one that they recently described in the African naked mole rat called early contact inhibition. That mechanism prevents overcrowding in cell populations by arresting the cancerous cells with uncontrolled growth and proliferation while allowing others to survive.

Instead, Gorbunova and colleagues found that their entire culture died. “We had never seen the entire culture dish die at once before. Within three days, there were no more live cells on the plate,” said Gorbunova. 

To investigate the possible biological processes behind their observation, the researchers measured the levels of the protein interferon, which is released by an organism’s cells to initiate an immune system response to pathogens. The team found that interferon was secreted in the cells in the culture in response to the cancer stimulation. As a result, all the cells in the culture died.

The blind mole rat may have evolved this unique use of interferon to protect itself against oxygen deprivation and flooding in its natural underground tunnel habitat. So, the blind mole rats and naked mole rats seem to have evolved two different anti-cancer mechanisms to meet the survival needs of their underground environments. 

“Surprisingly, when the same scenario was repeated on different continents, evolution came to two different decisions. It just happened independently, two different solutions to the same problem,” said Gorbunova.

Now, Gorbunova plans to conduct more tests to understand how the blind mole rat’s cells actually sense hyperproliferation and how to use interferon to activate similar pathways in human cells for cancer prevention.

“I do believe that this is very applicable, and I would like to see more cancer researchers actually using those cancer resistance models because it’s a staple organism to use mice that are cancer prone," said Gorbunova. "But if we want to understand cancer resistance, mice are not very useful. It is better to look at species that are cancer resistant.”

Reference

1. Gorbunova, V., C. Hine, X. Tian, J. Ablaeva, A.V. Gudkov, E. Nevo, and A. Seluanov. 2012. Cancer resistance in the blind mole rat is mediated by concerted necrotic cell death mechanism. PNAS Early Edition. Published online October 3, 2012.
2.  Kim, E.B., X. Fang, A.A. Fushan, Z. Huang, A.V. Lobanov, L. Han, S.M. Marino, X. Sun, A.A. Turanov, et al. 2011. Genome sequencing reveals insights into physiology and longevity of the naked mole rat. Nat. [Published online October 12, 2011]
3. Edrey YH, Park TJ, Kang H, Biney A, Buffenstein R. Endocrine function and neurobiology of the longest-living rodent, the naked mole-rat Exp Gerontol 2011 Feb;46(2-3):116-123.
Proposal to Sequence an Organism of Unique Interest for Research on Aging: Heterocephalus glaber, the Naked Mole-Rat, genomics.senescence.info, 26/04/2011