Research Directions

1. piRNAs and Ribosomes: How the Germline Repurposes Translation Machinery for RNA Defense

Adaptive Challenge

The genome is constantly challenged by internal genetic parasites, including transposable elements and endogenous retroviruses. These elements evolve rapidly and threaten genome integrity and fertility.

The germline must maintain genome stability while responding to continuously changing internal genomic threats.

Our View

We view PIWI-interacting RNAs, or piRNAs, as an RNA-mediated defense system of the germline. piRNAs allow organisms to protect their genomes against transposons, viruses, and other internal genomic threats.

Traditionally, ribosomes are viewed primarily as protein synthesis machines, while small RNA production is considered a separate RNA-processing pathway. Our work has introduced a new concept:

Ribosomes can directly participate in RNA fate selection and guide piRNA biogenesis.

This finding suggests that the translation machinery is not merely a passive reader of mRNAs. In germ cells, ribosomes can be repurposed as part of an RNA-processing and defense system. By recognizing, licensing, and directing selected RNAs into piRNA-producing pathways, ribosomes connect protein synthesis, RNA stability, small RNA processing, and genome defense.

We Study

- How piRNAs are generated;

- How new piRNAs arise and old piRNAs disappear;

- What piRNAs do beyond transposon silencing;

- How ribosomes participate in RNA fate selection and piRNA production;

- How translation, RNA stability, and small RNA processing are connected;

- How hosts use RNA mechanisms to respond to viruses, transposons, and other genomic threats;

- How reproductive systems across species use RNA mechanisms to adapt to genetic and environmental pressures.

Representative Discoveries

We discovered that ribosomes can actively guide piRNA biogenesis, revealing that the translation machinery itself can be repurposed as an RNA-processing and adaptive defense system. This mechanism is conserved across vertebrates, indicating its evolutionary importance.

This work reveals a direct connection between piRNA production and translation. It suggests that ribosomes can act as regulators of RNA fate, not only as machines for protein synthesis. It also provides a new framework for understanding how the germline identifies and responds to transposons, viruses, and other genomic threats.

In chickens, we showed that host genomes can convert viral sequences into piRNA-producing loci. Conceptually, this resembles the bacterial CRISPR system: life can turn foreign threats into molecular defense information. Unlike CRISPR, however, the piRNA system is centered on RNA and operates in the germline to defend against evolving internal genomic threats.

We also use chickens, quail, and other non-mammalian models to study RNA regulation in reproduction, including avian ZW/ZZ sex chromosome dosage compensation, RNA stability differences, meiosis, and germ cell RNA fate. These systems help us understand how different species use RNA mechanisms to adapt to reproductive, genetic, and environmental pressures.

Adaptation Principle

RNA systems provide the germline with a fast and flexible defense mechanism against evolving internal genomic threats.

2. Sperm RNA and Environmental Reproductive Toxicology: RNA as an Intergenerational Information Carrier

Adaptive Challenge

Parental environments can influence offspring health even when DNA sequence remains unchanged. Toxic exposure, diet, metabolic disease, microbiome, and lifestyle can alter germ cell states and affect offspring phenotypes.

Understanding how environment acts on germ cells and how this information influences the next generation is a central problem in environmental health, reproductive medicine, and developmental biology.

Our View

We propose that sperm RNA is an important information carrier linking parental environmental experience to offspring health.

We discovered that mammalian sperm retain a conserved profile of intact long RNAs. Many of these RNAs are associated with ribosomes, translation, and early developmental regulation. This suggests that sperm RNAs are not merely passive remnants of spermatogenesis, but may represent selectively retained, stabilized, and functionally licensed paternal information.

We Study

- How environmental factors reshape sperm RNA profiles;

- Which RNAs are selectively retained in sperm;

- Whether mRNAs and miRNAs are co-selected during sperm RNA formation;

- Whether sperm RNAs function after fertilization to influence early embryonic development;

- How metabolic disease changes the absorption, clearance, and intergenerational transmission of environmental toxicants;

- Why some paternal environmental effects persist across generations while others fade;

- How germ cells preserve genome integrity while carrying selected information about parental environmental states.

Disease States Reshape Environmental Risk

Our environmental health research does not only ask how the environment causes disease. We also ask the reverse question:

How does disease change the way organisms handle environmental factors?

Using type 2 diabetes and lead exposure as a model, we found that diabetes can alter lead absorption, retention, and clearance. As a result, low or moderate environmental lead exposure can be amplified under a diabetic metabolic state, leading to greater kidney injury, reproductive damage, and offspring health risk.

This finding suggests that environmental health risk should not be evaluated only in an “average” population. Internal states such as metabolic disease, inflammation, aging, and endocrine dysregulation may reshape sensitivity to environmental exposures. Future precision medicine and environmental regulation should consider this two-way relationship between disease and environment.

Adaptation Principle

RNA may allow organisms to convert environmental experience into biological information that affects offspring health without altering DNA sequence.

3. RNA Medicine: From Natural Adaptation to Artificial Functional Restoration

Adaptive Challenge

Many diseases can be understood as failed, insufficient, or mistimed adaptation. Traditional therapies often target damaged organs or downstream symptoms. Yet if external or internal disease drivers persist, durable recovery may be difficult.

Genetic disease, reproductive dysfunction, metabolic disease, infectious disease, and public health emergencies all require interventions that are faster, more precise, and more controllable.

Our View

We view RNA medicine as an artificial intervention strategy inspired by natural adaptive mechanisms. RNA therapeutics can transiently and controllably supplement, silence, or reshape functional molecules without permanently rewriting the genome.

mRNA can temporarily supply missing function. siRNA can precisely silence harmful transcripts. UTR and RNA structure design can tune RNA stability and translation efficiency. Together, these strategies define a new medical paradigm:

Do not rewrite the genome. Regulate RNA fate.

We Develop

- mRNA therapies for functional restoration in hereditary male infertility;

- siRNA strategies for dominant-negative mutations;

- UTR design platforms to tune RNA stability and translation efficiency;

- mRNA-based vaccines, antivenom strategies, and public health emergency technologies;

- Ethical, safety, and clinical translation frameworks for RNA intervention.

Compared with gene therapy, RNA medicine offers several unique advantages:

- It does not permanently modify DNA;

- Its molecular expression can be transient and controllable;

- It can be regulated in time, space, and cell type;

- It closely resembles naturally evolved RNA regulatory mechanisms;

- It may be used for functional restoration, disease intervention, and correction of maladaptive environmental responses.

Adaptation Principle

RNA therapeutics are effective because evolution has long used RNA as a central tool for biological adaptation.

Ongoing Questions

Under the theme of RNA biology of life adaptation, we are pursuing the following questions:

- How does the environment directly affect RNA stability, translation, modification, processing, and degradation?

- How do disease states alter the absorption, distribution, metabolism, excretion, and transmission of environmental toxicants?

- How do metabolic disease and heavy metal exposure jointly affect reproduction and offspring health?

- How are sperm RNAs selectively retained, and how do they influence early embryos and offspring phenotypes?

- How do piRNAs defend the germline against transposons, viruses, and internal genomic threats?

- How do ribosomes transition from protein synthesis machines to participants in RNA fate selection and piRNA biogenesis?

- Does avian ZW/ZZ sex chromosome dosage compensation depend on RNA stability and RNA fate regulation?

- Can poultry, quail, and other non-model organisms reveal RNA strategies for adapting to environmental pressure?

- Can mRNA and siRNA restore reproductive function without rewriting DNA?

- Can RNA therapeutics correct failed adaptation caused by environmental, metabolic, or genetic factors?

Unifying Concept

Across all directions, our work converges on one question:

How does RNA help life adapt to environmental change?

Environmental change can come from outside the organism, such as toxins, pathogens, diet, climate, and the microbiome. It can also come from within, such as transposon activity, metabolic disease, inflammation, aging, and endocrine disruption.

RNA lies between these changes and biological function. It determines how cells respond, how organs become diseased, how reproductive systems transmit information, and how medicine can intervene.

By studying RNA-mediated adaptation, we aim to build a new biological framework that connects RNA fate regulation, germline defense, environmental health, intergenerational effects, and RNA therapeutics. We seek to understand how life maintains stability in a changing world and how medicine can intervene when adaptation fails.

Our long-term goals are to:

- Build a new framework for life science in which RNA fate regulation, germline defense, intergenerational effects, and adaptive functions of core cellular machines are integrated into our understanding of heredity and evolution;

- Redefine environmental health and reproductive toxicology by expanding from “environment causes disease” to a two-way model in which disease states reshape environmental risk;

- Expand breeding and trait selection beyond DNA-only models to include environmentally responsive and heritable RNA states, especially for poultry and agricultural animals;

- Develop RNA-based therapeutic strategies for major unmet medical needs by using nature’s own adaptive mechanisms rather than permanently rewriting the genome.