In the relentless exploration of the mysteries of life, scientists have discovered a type of non-coding ribonucleic acid (RNA) that plays an important role in genetic material but does not directly participate in encoding proteins. These non-coding RNAs account for the vast majority of all RNAs, with an astonishing ratio of up to 98%. These non-coding RNAs are metaphorically referred to as the “dark matter” of the biological world, playing an invisible yet crucial role in regulating life activities.
Chen Lingling, a researcher at the Molecular and Cell Science Excellence Innovation Center of the Chinese Academy of Sciences, as one of the early scientists involved in non-coding RNA research, returned to China in 2011 and has since dedicated herself to uncovering the potential mysteries of this field. The research team led by Chen Lingling has discovered several long non-coding RNA families for the first time globally, which play extremely important functions in maintaining life activities.
2017 was a year full of accomplishments and honors for Chen Lingling. She not only received the National Science Fund for Distinguished Young Scholars, recognizing her outstanding contributions to biology, but also won the globally prestigious Howard Hughes Medical Institute International Young Scientist Award, becoming a scientist with globally recognized achievements in the field.
On how to stand out among many outstanding scholars, Chen Lingling is well aware that applying for the Distinguished Young Scholars program is highly competitive and challenging. Her secret lies in focusing her research on three key points: “innovation,” “systematic approach,” and “potential for development.”
Since returning to China in 2011, Chen Lingling’s research team has made significant progress in the field of long non-coding RNA, such as the discovery of long non-coding RNA families with special functions. These families include long non-coding RNAs that combine with small nucleolar RNAs, the SPA long non-coding RNA family produced by continuous transcription processing of multistage genes, the intronic circRNA family formed by intron lariat structures, and the exonic circRNA family formed by reverse splicing of exons, among others.
In her application, Chen Lingling systematically reviewed her research work and deeply reflected on the potential application value of her work. She strongly believes that dedicating her research to the health of humanity is the sacred mission of basic science.
Recent research findings reveal that long non-coding RNAs possess important functions that have not been fully recognized. These RNAs are involved in the regulation of key life processes such as cell proliferation, differentiation, metabolism, aging, and apoptosis, and their aberrant expression is closely linked to the occurrence of various diseases. Research on long non-coding RNAs offers new hope for the diagnosis and treatment of diseases.
During her defense, Chen Lingling realized that a successful defense requires attention to both details and the big picture. Researchers need to demonstrate the detailed nature of their experiments and the reliability of their data to the reviewers, while also helping the review panel understand the direction and goals of their research.
Reflecting on her experience of being funded by the Distinguished Young Scholars program, Chen Lingling believes the project’s support has enabled her to bravely explore unknown fields. As early as her doctoral studies, she developed a strong interest in the field of non-coding RNAs, and over the following decades, scientists’ understanding of long non-coding RNAs has increased significantly, deepening the understanding of the central dogma of biology even further.
The number of long non-coding RNAs (lncRNAs) is numerous and varied, with diverse forms, potentially harboring many unknown biological functions. Some lncRNAs are structurally similar to messenger RNAs (mRNAs), possessing methylation “caps” and polyadenylated “tails” that ensure stability and guide protein synthesis. On this premise, Chen Lingling proposed a bold hypothesis: not all lncRNAs have structures known to be similar to those of mRNAs, and there may exist entirely new families of lncRNAs awaiting discovery.
To test her conjecture, her laboratory developed a method to isolate RNAs without “tails,” laying a foundation for exploring novel lncRNAs. In 2012, the team led by Chen Lingling discovered a new class of lncRNAs named sno-lncRNAs, which do not have “caps” and “tails” but possess small nucleolar RNAs capable of forming specific structures. In 2016, they found another new class of SPA lncRNAs, which, unlike sno-lncRNAs, have the same “tail” structure as mRNAs, but their “cap” is replaced by small nucleolar RNA.
These discoveries provide a new perspective for explaining the pathogenic mechanism of Prader-Willi syndrome. Recently, the team has also developed a new method for early diagnosis targeting sno-lncRNAs, providing important technical support for the early detection and intervention of Prader-Willi syndrome. With the help of the National Science Fund for Distinguished Young Scholars program, Chen Lingling continues to commit to exploring the lncRNA field, charting a new blueprint for scientific research.
In the related research field, a team has achieved remarkable results under the leadership of a guide. By studying the link between the subcellular localization and function of lncRNAs, the team revealed that the functions of these RNAs evolve in a manner different from other life molecules. They identified a new member of the sno-lncRNA family, “SLERT,” which is present in the cell nucleolus and acts as a “molecular chaperone” involved in the transcription regulation of RNA polymerase I. This discovery marked the first time in human cells that lncRNAs have been shown to regulate the transcription of RNA polymerase I.
Further studies have shown the profound role of lncRNAs in the assembly and functional regulation of cellular nuclear substructures. In particular, the team detailed the fine three-dimensional structure of the cell nucleolus and discovered a selection mechanism for 5′ end precursor ribosomal RNA (rRNA) regulated by phase separation, as well as a new nucleolar substructure involved in the processing of 3′ end precursor rRNA and early development, named the periphery of the dense fibrillar center (PDFC). These research results significantly enhance our understanding of the structure and function of the cell nucleolus.
In addition, based on the previously discovered circular RNA and its new families, the team systematically revealed the processing, folding, and degradation characteristics of circular RNAs, and pointed out the potential application prospects of circular RNAs in the treatment of autoimmune diseases. They have also developed and applied a series of advanced research tools and technologies that can accelerate the discovery of RNA isoforms specific to cells, tissues, and species, and further dissect the action modes of lncRNAs from multiple angles.
The leading scientist of this research feels very fortunate as she believes that self-driven passion and curiosity are key to driving scientific work forward. She sees her laboratory as a small haven for dreaming about exploring the unknown world, and everyday work is not just a commitment, but more like an enjoyment. She believes that when people are passionate about something, they will invest a lot of energy without feeling tired.
The recently implemented National Science Fund for Distinguished Young Scholars program provides graded evaluations for scientific projects, and awards funding for the second and third five-year cycles to outstanding projects, motivating scientists to continue climbing the peaks of science. As a seasoned recipient of project funding, this scientist envies scholars who can receive rolling support and believes that the new measures, like another side of self-motivation, provide momentum for excellent scientists to produce outstanding research results. This spirit of self-motivation also deeply affects her lab members, who enjoy the freedom to control their own pace in scientific work. “We really enjoy this way of interacting between teacher and student,” the leader summarized.
The intrinsic motivation of the team members coalesces into a powerful synergy that propels the team to delve deeply into the field of long non-coding RNA. They believe that the basis of research in life sciences should not only be committed to solving major scientific problems but also aim to maintain human health and continually inject momentum into the development of new productive forces. Even though the Outstanding Youth Science Fund (Outstanding Youth) project has concluded, they still pursue the functions and mechanisms of unknown RNAs and conduct practical application research based on these findings.
In this exploratory process, they discovered that circular RNAs, in comparison to linear RNAs, possess more unique characteristics such as stability, special spatial structure, and lower immunogenicity. These traits make circular RNA an innovative direction for developing new RNA aptamers and gene expression platforms, offering fresh opportunities for the future development of RNA biomedicine.
Chen Lingling as a female scientific researcher, is acutely aware of the heavy social responsibility and believes that women need to play various roles more wisely and persist without giving up during difficult times. She affirms and appreciates the Outstanding Youth project for raising the age limit to 48 for female researchers’ applications. She regards this as a demonstration of trust and respect for female scientific workers by society and emphasizes the need for more care and support for women at the societal, institutional, and team levels.
Looking to the future, Chen Lingling indicates that the exploration of the long non-coding RNA field is endless. She particularly mentions the continuous advancements in third-generation long-read RNA sequencing technology, ultra-high-resolution microscopic imaging, and gene editing and base editing technologies, as they are bringing new opportunities for unveiling novel RNA mechanisms and their original theoretical applications. In the global competition for technological innovation, she calls on her peers to have the courage to lead the world and strives to seize the commanding heights of technology in this field.