Gene regulation is a complex and highly dynamic process that underpins all forms of life. Ribosomes, the conserved macromolecular machines of protein translation, decode the three-nucleotide codons embedded in messenger RNA (mRNA) into amino acid sequences with remarkable efficiency and fidelity. Disruption of this finely tuned process is linked to a wide range of human diseases, including cancer and developmental disorders.

Ribosomes are composed of ribosomal RNAs (rRNAs) and ribosomal proteins (RPs), and function through coordinated interactions with mRNA and transfer RNAs (tRNAs). Chemical modifications of rRNAs, tRNAs, and RPs represent an evolutionarily conserved layer of regulation, yet their functional significance remains incompletely understood.

The long-standing view of ribosomes as static and uniform machines has been challenged by recent work from our group and others (Rajan et al., Cell Reports, 2024; Nature Communications, 2023 and 2026), suggesting instead that ribosomes can be heterogeneous and functionally specialized.

Emerging evidence from our group and others indicates that rRNA molecules are not uniformly synthesized or modified, raising the possibility that distinct ribosome populations may selectively regulate subsets of mRNAs. However, progress in this area has been limited by the lack of genetic tools to precisely manipulate rRNA modifications without altering the underlying nucleotide sequence.

Much of our current understanding is derived from yeast models with relatively simplified epitranscriptomes, whereas studies in human systems indicate that rRNA modifications are dynamically regulated in diseases such as cancer. In parallel, the molecular mechanisms by which non-coding RNAs (ncRNAs) regulate translating ribosomes remain poorly understood.

To address these questions, we employ eukaryotic pathogens such as Trypanosoma brucei and Leishmania spp., which serve as powerful model systems for RNA biology. These organisms experience diverse environmental stresses throughout their life cycles and predominantly rely on post-transcriptional regulation of gene expression.

They also harbor a rich and largely unexplored repertoire of ncRNAs, including small nucleolar RNAs (snoRNAs) and long non-coding RNAs (lncRNAs), and possess an epitranscriptomic landscape comparable in complexity to higher eukaryotes.

Our previous works have shown that perturbation of even a single rRNA modification can significantly impact ribosome function and selectively alter the translation of specific mRNAs, supporting the concept of modification-driven ribosome specialization (Rajan et al., Cell Reports, 2024; Nature Communications, 2023 and 2026).

Leveraging advances in genome editing, we systematically manipulate individual and multi-copy ncRNAs to dissect their roles in regulating RNA modifications, ribosome function, and translational control.

Research in our laboratory is built on a strong foundation of biochemical and molecular approaches, complemented by next-generation sequencing to quantitatively map RNA modifications and translation at high resolution (Figure A). These strategies enable us to link changes in RNA chemistry and ncRNA function to their consequences on gene expression.

In parallel, we incorporate cryo-electron microscopy as a complementary tool to obtain mechanistic insights into how specific RNA modifications and ncRNA interactions influence ribosome structure and function at near-atomic detail (Figure B-C).

Our long-term goal is to elucidate how RNA-based regulatory mechanisms shape translation and cellular physiology in health and disease. By integrating biochemical, genetic, and systems-level approaches, we aim to uncover fundamental principles of translational control and their implications for pathogen biology and human disease.