Researchers reveal hidden features in mycobacterial genomes that control stress adaptation

New research led by Qingyun Liu, Ph.D., assistant professor in the Department of Genetics at UNC, has discovered a genetic trait called “transcriptional plasticity” that plays a key role in controlling the transcriptional response of mycobacteria to stress conditions.

Bacterial cells must rapidly regulate the expression of their genes in response to sudden changes in the external environment. However, the extent to which certain genes can change their expression in response to environmental changes, rather than maintaining stable expression levels, has long puzzled scientists. Understanding how bacteria regulate these different transcriptional processes and the genetic signatures underlying them remains a challenge.

Lead researcher Qingyun Liu, Ph.D., working with researchers at the University of North Carolina at Chapel Hill, Harvard University, and Fudan University, set out to unravel the complex factors that control the transcriptional response of Mycobacterium tuberculosis (Mtb), the bacterial pathogen that causes tuberculosis. It remains the leading cause of death from a single infectious source, with more than 10.6 million new cases and 1.6 million deaths annually.Their study, titled “Gene-encoded transcriptional plasticity underlies stress adaptation in Mycobacterium tuberculosis,” is published in the journal nature communications.

The researchers analyzed a comprehensive dataset of 894 RNA-Seq samples from 73 different conditions that were generated in previous studies and compiled by the researchers for the purpose of meta-analysis.

The researchers studied transcriptional plasticity (TP) of each M. tuberculosis gene as a proxy for variability in gene expression in response to environmental changes. Their analysis revealed significant TP variation among Mtb genes, related to gene function and essentiality. Furthermore, they found that key genetic characteristics, such as gene length, GC content, and operon size, independently impose constraints on TP beyond the scope of trans -regulation.

For example, genes with shorter lengths generally exhibit higher TP compared to genes with longer lengths. Furthermore, genes with the lowest TP profiles were concentrated in groups whose GC content was closely related to the genome-wide average (65%).

“These features, previously unrelated to transcriptional regulation in mycobacteria, are now thought to be factors in the evolution of Mtb to form its genetic TP,” Liu said.

Using genetic signatures identified as causing TP, the researchers were able to use machine learning models to partially predict TP levels in the Mtb gene. However, Liu noted that while the model showed promise, it was not perfect at predicting target price levels. This suggests that there may still be unknown factors affecting TP that deserve further study.

By extending the analysis to two other mycobacterial species, Mycobacterium smegmatis and Mycobacterium abscessus, the researchers demonstrated striking conservation of the TP landscape across different mycobacterial species, implying that TP acts as a Conserved adaptive strategies in mycobacteria have evolutionary implications.

The researchers emphasize that TP can now serve as a useful complement to gene necessity and vulnerability to understand bacterial physiological processes. This information can help prioritize candidate genes for pharmaceutical purposes or mechanical dissection. Additionally, the researchers showed that TP could serve as a baseline factor for future transcriptional studies, helping to identify differentially expressed genes. This highlights the broader significance of TP in advancing our understanding of bacterial gene regulation and adaptation mechanisms.

The National Institutes of Health funded the research.

Media Contact: Mark Drewitch