Incomplete transcripts dominate the Mycobacterium tuberculosis transcriptome

Xiangwu Ju, Shuqi Li, Ruby Froom, Ling Wang, Mirjana Lilic, Madeleine Delbeau, Elizabeth A. Campbell, Jeremy M. Rock () and Shixin Liu ()
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Xiangwu Ju: The Rockefeller University
Shuqi Li: The Rockefeller University
Ruby Froom: The Rockefeller University
Ling Wang: The Rockefeller University
Mirjana Lilic: The Rockefeller University
Madeleine Delbeau: The Rockefeller University
Elizabeth A. Campbell: The Rockefeller University
Jeremy M. Rock: The Rockefeller University
Shixin Liu: The Rockefeller University

Nature, 2024, vol. 627, issue 8003, 424-430

Abstract: Abstract Mycobacterium tuberculosis (Mtb) is a bacterial pathogen that causes tuberculosis (TB), an infectious disease that is responsible for major health and economic costs worldwide1. Mtb encounters diverse environments during its life cycle and responds to these changes largely by reprogramming its transcriptional output2. However, the mechanisms of Mtb transcription and how they are regulated remain poorly understood. Here we use a sequencing method that simultaneously determines both termini of individual RNA molecules in bacterial cells3 to profile the Mtb transcriptome at high resolution. Unexpectedly, we find that most Mtb transcripts are incomplete, with their 5′ ends aligned at transcription start sites and 3′ ends located 200–500 nucleotides downstream. We show that these short RNAs are mainly associated with paused RNA polymerases (RNAPs) rather than being products of premature termination. We further show that the high propensity of Mtb RNAP to pause early in transcription relies on the binding of the σ-factor. Finally, we show that a translating ribosome promotes transcription elongation, revealing a potential role for transcription–translation coupling in controlling Mtb gene expression. In sum, our findings depict a mycobacterial transcriptome that prominently features incomplete transcripts resulting from RNAP pausing. We propose that the pausing phase constitutes an important transcriptional checkpoint in Mtb that allows the bacterium to adapt to environmental changes and could be exploited for TB therapeutics.

Date: 2024
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DOI: 10.1038/s41586-024-07105-9

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