History of Our Research

The Full Story

Discovering Layers of Ribosome Heterogenity

For many decades, ribosomes were viewed as uniform and passive machines—molecular entities that translate mRNA into protein with little regulatory input. This view provided a powerful and simplifying framework for understanding gene expression. However, it also left open an important question: how can a single, invariant machine generate the extraordinary diversity of protein expression programs observed across cell types, developmental stages, and disease states?

Our work has sought to explore this question. Over the past years, together with many talented trainees and collaborators, we have contributed to a growing body of evidence suggesting that ribosomes are not uniform, but instead exist in diverse and functionally specialized forms. These studies have uncovered multiple layers of heterogeneity—spanning composition, associated factors, RNA features, and dynamic regulation—that collectively shape how genetic information is expressed at the level of translation.

From Uniform Machines to Specialized Regulators

One of the earliest insights from our work was that ribosomal proteins—long considered “core” and invariant—can be differentially expressed and utilized. By studying specific ribosomal proteins in developmental systems, we found that altering ribosome composition can lead to selective translation of distinct subsets of mRNAs, rather than global changes in protein synthesis.

These findings suggested that ribosomes themselves can encode regulatory information—what we and others have described as a form of “ribosome specialization.” Rather than acting as passive readers of mRNA, ribosomes can actively influence which messages are translated, when, and in which cellular contexts.

Importantly, this work was carried out in physiological settings, including embryonic development, where even subtle shifts in translational control can have profound consequences for cell fate decisions. These studies helped establish the idea that translation is not simply downstream of gene expression—but an active and selective layer of regulation.

Compositional Heterogeneity: Ribosomes Are Not Identical

A key layer of heterogeneity lies in the composition of the ribosome itself.

We and others have shown that:

Ribosomal protein levels can vary across tissues and developmental stages
Specific ribosomal proteins are required for the translation of particular mRNA subsets
Alterations in ribosome composition can lead to highly selective phenotypes, rather than global defect
These findings challenged the longstanding assumption that all ribosomes are identical. Instead, they support a model in which cells assemble functionally distinct ribosomes tailored to specific biological needs

This concept has important implications for human disease. For example, mutations in ribosomal proteins lead to disorders such as ribosomopathies, where only specific cell types are affected despite the universal requirement for ribosomes. Our work has contributed to understanding how ribosomes can underlie tissue-specific disease phenotypes.

rRNA Variation: An Overlooked Source of Functional Diversity

While much of the early work in the field focused on ribosomal proteins, an additional and often overlooked layer of heterogeneity lies within ribosomal RNA (rRNA) itself.

rRNA forms the structural and catalytic core of the ribosome, yet it has traditionally been viewed as invariant. Our work has helped highlight that rRNA can exhibit:

Sequence variation across genomic rDNA copies
Differential expression of rRNA variants across tissues and developmental states
Diverse chemical modifications that influence ribosome function

These features suggest that ribosomes may differ not only in their protein composition, but also in the very RNA scaffold that defines their architecture.

Importantly, variation in rRNA has the potential to directly impact:

Ribosome structure and conformational dynamics
Interactions with mRNA and tRNA
Recruitment of regulatory factors

By developing and applying new approaches to study rRNA sequence diversity and modification landscapes, our work has begun to uncover how rRNA heterogeneity contributes to specialized translation programs. This represents an important expansion of the field, shifting attention toward the ribosome as an RNA-driven regulatory machine, not solely a protein-defined complex. More recently, we have causally linked rRNA variation and copy number to a wide array of human traits and phenotypes by carrying out GWAS analysis of the rDNA loci. This loci have been hidden from prior analysis and limited our understanding of the genetics of human health and disease.

Expansion Segments: Structural Platforms for Regulation

Eukaryotic ribosomes contain large insertions within rRNA known as expansion segments, which extend from the ribosome surface and are among the most variable regions across species and cell types.

Historically, expansion segments were thought to be largely structural or evolutionary additions. However, emerging evidence, including our work, suggests that they may serve as functional platforms for regulatory interactions.

Expansion segments can:

Provide binding interfaces for RNA-binding proteins and regulatory complexes
Create spatially distinct microenvironments on the ribosome surface
Potentially influence ribosome localization within the cell

Because these regions are highly flexible and variable, they offer a unique opportunity for cell type–specific and context-dependent regulation.

We are particularly interested in how expansion segments may:

Scaffold specialized ribosome-associated factors
Mediate selective translation of specific mRNA subsets
Contribute to spatial regulation of translation in cells (e.g., localized translation)

These ideas point to a model in which ribosome structure itself, particularly its most variable regions,plays an active role in shaping gene expression. These are also the sites where the majority of rRNA variation is evident and causally linked to human traits and disease, ranging from cancer to myocardial infarction.

Ribosome-Associated Factors and Regulatory Networks

Beyond the core ribosome, another major layer of heterogeneity arises from ribosome-associated proteins (RAPs) and RNA-binding factors.

We have found that ribosomes interact with a wide range of regulatory proteins that:

Modulate translation initiation and elongation
Influence ribosome recruitment to specific mRNAs
Coordinate translation with signaling pathways and cellular states

These interactions create ribosome-centered regulatory hubs, where signaling, RNA biology, and protein synthesis converge.

In this framework, the ribosome is not an isolated machine but part of a larger dynamic and context-dependent network. Different combinations of RAPs can tune translational output in highly specific ways, allowing cells to rapidly adapt to changing conditions.

mRNA Features and Selective Translation

A further layer of specificity is encoded within the mRNAs themselves.

Our work has highlighted how specific features of mRNAs—particularly within untranslated regions (UTRs) can determine their translational behavior. These features include:

Structured RNA elements, we term "IRES-like"
Upstream open reading frames (uORFs)
Sequence motifs that recruit regulatory proteins

Through these elements, mRNAs can be selectively recognized by particular ribosomes or translation complexes, enabling highly selective gene expression programs.

This selectivity becomes especially important in contexts such as development, stress responses, and disease, where cells must rapidly reprogram protein synthesis without necessarily altering transcription.

Dynamic and Context-Dependent Translation

Ribosome heterogeneity is not static—it is highly dynamic.

In our more recent work, we have explored how translation is rapidly remodeled in response to environmental and physiological cues. For example, during tissue injury and regeneration, we found that cells can activate a program of selective translation from pre-existing mRNAs, enabling rapid protein production without requiring new transcription.

These findings suggest that translational control provides a temporal advantage, allowing cells to respond within minutes to hours. We have also found that during the step-wise differentiation of stem cells down the endoderm and mesoderm layers, ribosomes are remodeled. In this context, ribosome heterogeneity becomes a mechanism for:

Rapid adaptation
Control of cell fate
Regeneration and repair

Importantly, these dynamic changes are often invisible at the level of the transcriptome, underscoring the importance of directly studying translation.

Integration with Metabolism and Signaling

Another emerging theme in our work is the integration of ribosome function with cellular metabolism and signaling pathways.

We have shown that pathways such as mTOR play a central role in regulating translation, linking:

Nutrient availability
Cellular energy status
Protein synthesis capacity

More recently, we have found that evolutionary changes in signaling pathways can alter how translation is regulated, enabling distinct biological outcomes such as enhanced regenerative capacity.

These findings point to a broader principle: translation sits at the intersection of gene regulation, metabolism, and cell signaling, acting as a key integrator of cellular state.

A Multi-Layered View of Ribosome Heterogeneity

Taken together, our work supports a model in which ribosome heterogeneity operates across multiple, interconnected layers:

Compositional diversity – variation in ribosomal proteins
rRNA variation – sequence diversity and chemical modification
Structural diversity – expansion segments as regulatory platforms
Associated factors – interaction with regulatory proteins and complexes
mRNA selectivity – encoded features that direct translation
Dynamic regulation – rapid changes in response to cellular signals
Signaling integration – coupling to pathways such as mTOR and metabolism

Rather than a single mechanism, ribosome heterogeneity emerges from the integration of these layers, enabling precise and context-dependent control of gene expression.

Looking Forward

While much has been learned, this field is still in its early stages. Many important questions remain:

How are specialized ribosomes assembled and regulated?
How do rRNA variants and expansion segments contribute to specificity?
What defines ribosome–mRNA selectivity in different contexts?
Can these mechanisms be harnessed therapeutically?

Our ongoing work aims to address these questions by combining experimental and computational approaches, as well as developing new technologies to directly visualize and manipulate translation in cells.

A Shift in Perspective

Perhaps the most important outcome of this work is a shift in how we think about gene expression.

Rather than viewing translation as a uniform, downstream process, it is increasingly clear that it represents a central and highly regulated layer of control. Ribosomes are not simply machines—they are participants in gene regulation, capable of shaping biological outcomes in precise and sometimes unexpected ways.

We are grateful to the many students, postdocs, and collaborators who have contributed to these discoveries, and we look forward to continuing to explore this evolving landscape together.