Researchers map genome enhancers

Providing another tool to help to understand gene regulation on a global scale, a US research team has identified and mapped 55,000 enhancers, short regions of DNA that act to enhance or boost the expression of genes. The map, published 18 March in the advance online edition of the journal Nature, will help scientists understand how cells control expression of genes specific to their particular cell type.

“Our studies show that enhancers play much more prominent role than previously appreciated in cell-type-specific gene expression, helping to explain what causes cells to differentiate into liver or brain or skin cells, or why these cells might become cancerous,” said principal investigator Bing Ren, PhD, associate professor of Cellular and Molecular Medicine at the University of California, San Diego School of Medicine and head of the Laboratory of Gene Regulation at the Ludwig Institute for Cancer Research (LICR).

Enhancers are one of several types of regulatory elements, along with promoters and insulators, which are scattered across the genome and act to assemble proteins that regulate the transcription of individual genes.

By systematically analysing more than 14 million DNA probes corresponding to the entire human genome, the team created a new genomicscale map of enhancers.

Stem cells show promise as treatment for deafness

Deafness affects more than 250 million people worldwide. It typically involves the loss of sensory receptors, called hair cells, for their “tufts” of hairlike protrusions, and their associated neurons. The transplantation of stem cells that are capable of producing functional cell types might be a promising treatment for hearing impairment, but no human candidate cell type has been available to develop this technology.

A new study led by Dr Marcelo N. Rivolta of the University of Sheffield has successfully isolated human auditory stem cells from foetal cochleae (the auditory portion of the inner ear) and found they had the capacity to differentiate into sensory hair cells and neurons. The study is published in the April 2009 issue of Stem Cells.

The researchers painstakingly dissected and cultured cochlear cells from 9-11 weekold human foetuses. The cells were expanded and maintained in vitro for up to one year, with continued division for the first 7 to 8 months and up to 30 population doublings, which is similar to other non-embryonic stem cell populations, such as bone marrow. Gene expression analysis showed that all cell lines expressed otic markers that lead to the development of the inner ear as well as markers expressed by pluripotent embryonic stem cells, from which all tissues and organs develop.

They were able to formulate conditions that allowed for the progressive differentiation into neurons and hair cells with the same functional electrophysiological characteristics as cells seen in vivo.

“The results are the first in vitro renewable stem cell system derived from the human auditory organ and have the potential for a variety of applications, such as studying the development of human cochlear neurons and hair cells, as models for drug screening and helping to develop cell-based therapies for deafness,” say the authors.

New tumour suppressor gene discovered

Researchers in the US have identified a gene that suppresses tumour growth in melanoma, the deadliest form of skin cancer.

The study was part of a systematic genetic analysis of a group of enzymes implicated in skin cancer and many other types of cancer and was reported 29 March in the journal Nature Genetics. The analysis found that onequarter of human melanoma tumours had mutations in genes that code for matrix metalloproteinase (MMP) enzymes. The findings lay the foundation for more individualised cancer treatment strategies where MMP and other key enzymes play a functional role in tumour growth.

Tumour suppressor genes encode proteins that normally serve as a brake on cell growth. When such genes are mutated, the brake may be lifted, resulting in the runaway cell growth known as cancer. In contrast, oncogenes are genes that encode proteins involved in normal cell growth. When such genes are mutated, they also may cause cancer, but they do so by activating growth-promoting signals. Cancer therapies that target oncogenes usually seek to block or reduce their action, while those aimed at tumour suppressor genes seek to restore or increase their action.

The new study may help to explain the disappointing performance of drugs designed to treat cancer by blocking MMP enzymes. Because members of the MMP gene family were thought to be oncogenes and many tumours express high levels of MMP enzymes, researchers have spent decades pursuing MMPs as promising targets for cancer therapies. However, when MMP inhibitors were tested in people with a wide range of cancers, the drugs failed to slow – and in some cases even sped up – tumour growth.

Now, it turns out that one of the most often mutated MMP genes in melanoma is not an oncogene at all. In its study, the team led by researchers from the National Human Genome Research Institute (NHGRI) found that MMP-8 actually serves as a tumour suppressor gene in melanoma. Consequently, in the estimated 6% of melanoma patients whose tumours harbour a mutated MMP-8 gene or related tumour suppressor(s), it may not be wise to block all MMPs. The study suggests that a better approach may be to look for drugs that restore or increase MMP-8 function or for drugs that block only those MMPs that are truly oncogenes. 

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