02:41am Wednesday 23 August 2017

New Understanding of Macrophage Gene Regulation Could Help Control Cancer, Other Diseases

A new database that maps how macrophage cells, which are important for blood vessel growth, regulate gene expression could help stop the development of tumors. This microscopic image shows macrophages (blue) isolated from mice that have taken up fluorescently labelled regulatory micro RNA molecules (red).
Image credit: Yi-Chien Lu

The study, published in Cell Reports on Dec. 18, identifies the locations where genetic regulatory micro RNA (miRNA) molecules bind to information-delivering molecules called messenger RNA, thereby controlling proteins expressed in the macrophage. At these sites, miRNA molecules influence whether the macrophage messenger RNA will be used for protein expression or degraded, ultimately determining which genes will be expressed. In the case of macrophages that are supporting tumor or cancer growth, interfering at these spots to make the cell degrade messenger RNA can help control the disease.

“If we understand the critical steps of gene expression, maybe we can do something about blocking genes that drive diseases such as cancer,” said senior author Dr. Timothy Hla, director of Weill Cornell’s Center for Vascular Biology and professor of pathology and laboratory medicine.

In addition to defining miRNA binding sites, the researchers also investigated RNA binding proteins, another component of gene expression. Their findings illuminate a delicate regulatory balance essential to healthy cell growth and activity.

The authors, led by Yi-Chien Lu, a post-doctoral fellow in Dr. Hla’s lab, found that the RNA binding protein that promotes protein expression, ELAVL1, and the binding protein that degrades RNA to prohibit protein expression, ZFP36, are synchronized, so that if one’s activity increases so does the other — and vice versa. This means the two proteins are regulated by the same miRNA, which in this study the researchers discovered to be miR-27. If the synchronization of these two binding proteins becomes unbalanced, the researchers predict that the disturbed functions of macrophages will contribute to diseases such as cancer and heart disease. Knowing the important role that miR-27 plays in this synchronization, scientists can study how to deliver miR-27 when the balance is off in order to achieve healthy synchronization and reduce the severity of disease.

The researchers were also able to map which miRNA control specific genes involved in blood vessel growth. The result is a database that all scientists can use to explore how interfering with different miRNAs can help stop tumor growth.

Collectively, this deeper understanding of macrophage regulation opens up numerous avenues to control cell function to regulate immunity, blood vessel and tissue functions.

“To be able to define in molecular terms a resource that many laboratories could then use to advance not only basic knowledge but also clinical application – that’s really exciting,” Dr. Hla said.

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