Scientists extend mechanism for cracking biochemical code

November 8, 2018, University of California - San Diego
Scientists extend mechanism for cracking biochemical code
Graphic showing sequences for peptide clusters. Credit: University of California San Diego

Since the time of ancient Egypt, humans have been making and breaking secret codes to retain and gain critical information. Human life itself is based upon a genetic code of DNA or RNA sequences which cells read and translate into proteins—the building blocks of life. Recent scientific discoveries have revealed the body's mechanisms for transcribing DNA regulated by the "histone code"—different chemical marks on the tails of histone proteins, which are macromolecules within cell nuclei responsible for packaging and structuring DNA.

After eight years of study, a team of researchers from the University of California San Diego and Johns Hopkins University published new findings about how to read the body's code in the Nov. 7 issue of Science Advances. The findings answer a key question in the dynamic research area of epigenetics—adding tags to DNA and histone proteins to alter cell functions without changing DNA sequence. Understanding the fundamental principles of how epigenetic information is transduced in the cell eventually could lead to developing new drugs for fighting diseases like cancer.

In the research article titled "Deciphering and engineering chromodomain-methyllysine peptide recognition," UC San Diego Professor of Chemistry and Biochemistry Wei Wang, postdoctoral scholars and his colleagues in the Departments of Pharmacology, Bioengineering, and Cellular and Molecular Medicine, as well as scientists at Johns Hopkins, provide a mechanistic explanation of how combinations of could be read by certain proteins—"reader proteins"—leading to changes of gene expression and interpretation of information coded in the DNA genome.

Chromodomain-peptide binding intensities on the microarray (shown as z scores; red, binding; green, nonbinding). Credit: University of California San Diego
"We developed a model to understand how reader proteins see through different combinations of histone modifications, which interpret and transduce the information encoded in tagging histone proteins without changing the DNA sequence," said Wang.

Applying a metaphor of makeup, Wang explained that if a person makes up his or her face, the makeup might change how the person looks, but he or she can still be identified as the same person. In the body, histone modifications can produce various combinations, like a person's makeup, that can change the chemical properties of the histone proteins. But Wang and colleagues found that reader proteins recognize those same chemical properties, even if they resulted from different combinations of histone modifications. According to Wang, because the number of possible combinations of different chemical tags is huge, the histone has not been well defined. The new findings, however, suggest a way to define the , a computational model depicting the chemical properties of . It is like seeing through a person's makeup and revealing the person's true identity.

"Based on the computational model, we are able to engineer the reader proteins to alter or enhance their binding to particular histone modifications," explained Wang. "If reader proteins with certain mutations are generated, we can use them as imaging probes to monitor the dynamics of histone modifications in live cells. This is something that cannot be done using antibodies."

Explore further: Energetic gene switch

More information: Ryan Hard et al. Deciphering and engineering chromodomain-methyllysine peptide recognition, Science Advances (2018). DOI: 10.1126/sciadv.aau1447

Related Stories

Energetic gene switch

August 31, 2018

Histones are proteins that regulate the unwinding of DNA in the cell nucleus and the expression of genes based on chemical modifications or "marks" that are placed on their tails. Understanding how the histone "code" regulates ...

Study ties protein 'reader' ENL to common leukemia

March 1, 2017

Anyone who uses an employee badge to enter a building may understand how a protein called ENL opens new possibilities for treating acute myeloid leukemia (AML), a fast-growing cancer of bone marrow and blood cells and the ...

YEATS protein potential therapeutic target for cancer

October 23, 2014

Federal Express and UPS are no match for the human body when it comes to distribution. There exists in cancer biology an impressive packaging and delivery system that influences whether your body will develop cancer or not.

Recommended for you

Earth's deep mantle flows dynamically

March 25, 2019

As ancient ocean floors plunge over 1,000 km into the Earth's deep interior, they cause hot rock in the lower mantle to flow much more dynamically than previously thought, finds a new UCL-led study.

Scientists solve mystery shrouding oldest animal fossils

March 25, 2019

Scientists from The Australian National University (ANU) have discovered that 558 million-year-old Dickinsonia fossils do not reveal all of the features of the earliest known animals, which potentially had mouths and guts.


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.