What Are Transcription Errors' Role in Aging and Disease?

Why this study is important:

The human genome provides a precise, biological blueprint of life. To implement this blueprint correctly, the genome must be read with great precision, but it’s impossible for this process to be completely error-free. Mistakes during transcription — random errors in how DNA sequences are copied for a gene to be expressed — can happen any time in any number of ways. Research suggests that the error rate of transcription increases as cells age, yet how these transcription errors affect cellular health remains a mystery.

This study could reveal novel links between some of the most important forces in human aging and help explain why normal aging contributes to disease. Many age-related diseases, including Alzheimer’s and Parkinson’s, are characterized by the aggregation of toxic proteins. Error-prone transcription may trigger this accumulation of proteins and cellular toxicity associated with causes of age-related diseases.

Who is conducting the study:

Marc Vermulst, PhD, assistant professor of Pathology, whose lab is part of CHOP’s Center for Mitochondrial and Epigenomic Medicine, is leading this project.

How they plan to accomplish it:

Dr. Vermulst and his team will use a genetically engineered model to show error-prone transcription. In addition, they will use powerful new technology to identify the parameters that regulate the fidelity of transcription — the frequency of an “incorrect” event as compared with the “correct” event — throughout the genome.

What makes the study innovative:

The most notable innovation in the study rests with the use of a new sequencing technology developed by the research team. The technology is the first assay able to measure the fidelity of transcription across the genome and can now screen billions of base pairs in the genome. This analysis is expected to reveal how DNA sequence, damage, and expression level of a gene affects transcription and illuminate how these change as people age.

Ways the results could one day improve pediatric care (or lead to future research):

Most common diseases in Western society are age-related, so understanding the aging process has become one of the most important goals of medicine today. By understanding the process better, researchers and healthcare providers may be able to not only improve the quality of life for our aging population, but also protect people earlier — perhaps in childhood and adolescence — from age-related diseases.

Quick thoughts:

This new study builds upon Dr. Vermulst’s research aimed at understanding the role of “biological errors” in human aging and disease, including errors that occur during DNA replication and transcription. Transcription errors are especially fascinating to the team, because almost nothing is known about their effect on human health.

Who is providing the funding:

The National Institute on Aging provided funding for this research project.

Where to learn more:

A description of study is available on NIH’s Project Reporter. More information on Dr. Vermulst and his research focus is available on the CMEM website.