NTUIMCB_Eng-Hsueh-Ping Chu, Associate Professor

Hsueh-Ping Chu, Associate Professor

Date：2018-09-12

Associate Professor

Born in 1978

Ph. D., Rutgers University, U.S.A

Postdoctoral researcher, Harvard Medical School, U.S.A

Specialty: Non-coding RNA and Epigenetics

Email : cchu2017@ntu.edu.tw

Laboratory: Life Science Building R807

TEL 886-2- 33662487

Website: https://lncrnatelomerechu.org/

Recent Research Topics

1.     Interactome of Non-coding RNAs

2.     TERRA in human aging and Alzheimer’s disease

3.     TERRA RNA in telomere maintenance and epigenetic regulation

4.     ALT cancer therapy
Laboratory

More than 90% of the genome is transcribed into non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). LncRNAs play important roles in regulating a wide range of cellular functions and developmental processes via function critically in the cis- and trans-regulation of gene expression, epigenetic modulation in the nucleus and post-transcriptional control in the cytoplasm. The dysregulation of lncRNAs has been linked to numerous human diseases. Our laboratory uses an RNA-centric approach to reveal the network of ncRNA-protein-genome. The long-term goal is to develop a therapeutic technology for human diseases by targeting ncRNAs.
Identify RNA-protein-DNA network by RNA-capture methods.
Tracking TERRA: Telomeric-Repeat Containing RNA That Rises with Age and Brain Disorders

Telomeres, the protective caps at the ends of our chromosomes, are well-known for their role in aging and disease. But there's more to the story—embedded in these regions is a mysterious RNA molecule called TERRA (telomeric repeat-containing RNA), which doesn't code for proteins but may play a critical regulatory role. Understanding TERRA has been a challenge due to its repetitive sequences and the complexity of where and how it's made in the genome. We used cutting-edge Oxford Nanopore direct RNA sequencing to chart where TERRA is transcribed across all human chromosome ends. This high-resolution map allowed us to annotate TERRA transcription regions. We develop a bioinformatic tool (TERRA-QUANT) to measure TERRA expression across a wide range of tissues. This tool allows scientists to quantify TERRA levels from any RNA-sequencing dataset—including bulk tissue and even single-cell data.

What we found was striking: TERRA levels rise with age, especially in human blood and brain tissues. We also observed increased TERRA in fibroblasts from elderly individuals and abnormal TERRA patterns in cells from Hutchinson-Gilford Progeria patients, who exhibit signs of accelerated aging. Further analysis revealed that neurons derived from human stem cells express higher levels of TERRA, and that TERRA is notably upregulated during the early stages of Alzheimer’s disease.

By offering new tools and insights, our study lays the groundwork for exploring TERRA as a potential biomarker for age-related diseases and brain health, opening exciting avenues for future research in genomics, neuroscience, and personalized medicine.
A Novel Mechanism of TERRA in Epigenetic Regulation

Epigenetic regulation is crucial for governing gene activity. This intricate process encompasses alterations in DNA modification, SNA structures, histone modification, and the involvement of non-coding RNAs. Within the genome, distinct DNA structures exist beyond the B-form, including G-quadruplexes (G4), which are stacked quinine tetrads and are involved in regulation of transcription.

TERRA, a long non-coding RNA with telomeric repeat sequences, can fold into an RNA G-quadruplex and interact with chromatin remodeler ATRX. ATRX, a chromatin modifier with DNA G4 binding ability, has emerged as one of prevalent genes linked to human intellectual disability. Mutations in ATRX gene give rise to ATRX syndrome, characterized by cognitive impairment, facial and skeletal anomalies, and thalassemia traits. Our findings unveil that TERRA plays a role in inhibiting ATRX binding to chromatin, thereby upholding DNA G4 structures. The G-rich property of TERRA RNA appear to sequester G4 binding proteins, preventing the unwinding of DNA G4. These discoveries shed light on prospective applications of RNA therapy for modulating gene expression and addressing various human diseases.
Illustration of telomeric-repeat containing RNA (TERRA)

The oval image shows strand-specific staining for telomere using chromosome orientation fluorescence in situ hybridization (CO-FISH) followed by TERRA depletion. Overlapping of red and green signals indicates an event of telomere recombination.

Alternative Lengthening of Telomeres in Cancer

Telomere maintenance significantly impacts aging and cancer pathways. While telomerase is recognized for its role in lengthening telomeres, certain cancers exhibited an unconventional strategy. Termed “Alternative Lengthening of Telomeres (ALT)”, this mechanism involves break-induced replication, extending telomeres—a process observed across various eukaryotes. Notably, patients with ALT-associated cancer face higher mortality rate compared to non-ALT cases.

Our investigations reveal that TERRA involves in generating DNA:RNA hybrids at telomeres, which alongside displaced single-stranded DNA, forming R-loop structures. TERRA R-loops are enriched in cancer cells utilizing the ALT mechanism. Our research team uncovers that TERRA R-loops initiate telomere clustering and activate DNA damage response through XPF recruitment. This DNA damage response at telomeres becomes pivotal for instigating homologous recombination and facilitating telomere synthesis in ALT cancers.
Selected Publications
1.             Yu-Hung Hsieh^1,#, Chin-Hua Tai,^1,#, Meng-Ting Yeh^1,#, Yu-Chen Chen¹, Po-Cheng Yang¹, Chien-Ping Yen¹, Hong-Jhih Shen¹, Chan-Hsien Yeh^2,3, Hung-Chih Kuo^2,3, Der-Sheng Han^4,5,* and Hsueh-Ping Catherine Chu^1,*. Telomeric Repeat-Containing RNA Increases in Aged Human Cells. Nucleic Acids Research, 2025 Jul 8;53(13):gkaf597. *Corresponding author. doi: 10.1093/nar/gkaf597.

2.             Hsiao YT, Liao IH, Wu BK, Chu HC, Hsieh CL*. Probing chromatin condensation dynamics in live cells using interferometric scattering correlation spectroscopy. Commun Biol. 2024 Jun 24;7(1):763. doi: 10.1038/s42003-024-06457-2. *Corresponding author.

3.             Bing-Ze Yang, Me-Yin Liu, Kuan-Lin Chiu, Yuh-Ling Chien, Ching-An Cheng, Yu-Lin Chen, Li-Yu Tsui, Keng-Ru Lin, Hsueh-Ping Catherine Chu, Ching-Shyi Peter Wu*. DHX9 sumoylation is required for the suppression of R-loop-associated genome instability. Nature Communications, 2024 July 17; 15 (1):6009. *Corresponding author.

4.            Mei-Yin Liu, Keng-Ru Lin, Yuh-Ling Chien, Bing-Ze Yang, Li-Yu Tsui, Hsueh-Ping Catherine Chu, Ching-Shyi Peter Wu*. ATR phosphorylates DHX9 at serine 321 to suppress R-loop accumulation upon genotoxic stress. Nucleic Acids Research, 2024 Jan 11;52(1):204-222. *Corresponding author.

5.            Ru-Xuan Tsai^{1, #}, Kuo-Chen Fang^{1, #}, Po-Cheng Yang^{1, #}, Yu-Hung Hsieh¹, I-Tien Chiang¹, Yunfei Chen¹, Hun-Goo Lee², Jeannie T Lee², Hsueh-Ping Catherine Chu¹^,*. TERRA regulates DNA G-quadruplex formation and ATRX recruitment to chromatin. Nucleic Acids Research, Nov 28; 50(21):12217-12234 *Corresponding author. https://academic.oup.com/nar/article/50/21/12217/6849496

6.             Chia-Yu Guh^{1, #}, Hong-Jhih Shen^{1, #}, Liv WeiChien Chen^1,#,Pei-Chen Chiu^{1, #}, I-Hsin Liao¹, Chen-Chia Lo¹, Yunfei Chen¹, Yu-Hung Hsieh¹, Ting-Chia Chang¹, Chien-Ping Yen¹, Yi-Yun Chen², Tom Wei-Wu Chen³, Liuh-Yow Chen⁴, Ching-Shyi Wu⁵, Jean-Marc Egly^6,7 and Hsueh-Ping Catherine Chu^1,*. XPF activates break-induced telomere synthesis. Nature Communications (SCI), 2022 Oct 2;13(1):5781. *Corresponding author. https://www.nature.com/articles/s41467-022-33428-0

7.             Hyun Jung Oh, Rodrigo Aguilar, Barry Kesner, Hun-Goo Lee, Andrea J. Kriz, Hsueh-Ping Chu, and Jeannie T. Lee. Jpx RNA regulates CTCF anchor site selection and formation of chromosome loops. Cell, 2021 Nov 25; S0092-8674(21)01327-1. https://pubmed.ncbi.nlm.nih.gov/34856126/

8.            Hsueh-Ping Chu*, Anand Minajigi, Yunfei Chen, Robert Morris, Chia-Yu Guh, Yu-Hung Hsieh, Myriam Boukhali, Wilhelem Haas, Jeannie T Lee. iDRiP for the systematic discovery of proteins bound directly to noncoding RNA. Nature Protocols, 2021 Jul;16(7):3672-3694. *Co-corresponding author and first author. https://www.nature.com/articles/s41596-021-00555-9

9.            Ke-Vin Chang , Yu-Chen Chen , Wei-Ting Wu , Hong-Jhin Shen , Kuo-Chin Huang , Hsueh-Ping Chu * and Der-Sheng Han* (2020, Dec). Expression of Telomeric Repeat–Containing RNA Decreases in Sarcopenia and Increases after Exercise and Nutrition Intervention. Nutrients, 8;12(12):E3766. *Co-corresponding author.

10.       Chia-Yu Guh, Yu-Hung Hsieh, Hsueh-Ping Chu*. *Corresponding author. Functions and Properties of Nuclear lncRNAs-from Systematically Mapping the Interactomes of lncRNAs. J Biomed Sci, 27 (1), 44. 2020 Mar 17. ---Review article

11.       Xiaolei Pan, Yun Chen, Beena Bijiu, Naveed Ahmed, Joyce Kong, Marti Goldenberg, Judy Huang, Nandakumar Mohan, Stephanie Klosek, Kian Parsa, Chia-Yu Guh, Robert Lu, Hilda A Pickett, Hsueh-Ping Chu*, and Dong Zhang. FANCM suppresses DNA replication stress at ALT telomeres by disrupting TERRA R-loops. Sci Rep. 2019 Dec 13;9(1):19110. *Co-corresponding author.

12.       Chen-Yu Wang, Teddy Jegu, Hsueh-Ping Chu, Hyun Jung Oh, Jeannie T. Lee. SMCHD1 Merges Chromosome Compartments and Assists Formation of Super-Structures on the Inactive X. Cell. 174, 1–16. July 12, 2018

13.       Hsueh-Ping Chu, Catherine Cifuentes-Rojas, Barry Kesner, Eric Abey, Hyun Jung Oh, Myriam Boukhali, Wilhelm Hass, and Jeannie T. Lee. TERRA RNA Antagonizes ATRX and Protects Telomeres. Cell. 2017 June 29 Volume 170, p86-101. --First author.

I.               [This paper was the subject of a perspective by Roake CM, Artandi SE. Approaching TERRA Firma: Genomic Functions of Telomeric Noncoding RNA. Cell. 2017 Jun 29;170(1):8-9.]

II.        [This paper was the subject of a perspective by Koch L. Nat Rev Genet. 2017 Jul 17;18(8):453. Non-coding RNA: A protective role for TERRA at telomeres.

14.       Hsueh-Ping Chu, Barry Kesner, John E. Froberg, Hyun Jung Oh, Stefan F. Pinter, and Jeannie T. Lee. PAR-TERRA directs homologous sex chromosome pairing. Nature Structural & Molecular Biology. 2017 July 10, 24, p620-631, doi:10.1038/nsmb.3432. --First author.

15.       Athanasios Zovoilis, Catherine Cifuentes-Rojas, Hsueh-Ping Chu, Alfredo J. Hernandez, and Jeannie T. Lee. Destabilization of B2 RNA by EZH2 activates the stress response. Cell. 2016 Dec 15 Volume 167, Issue 7, p1788–1802.e13

16.       Yi Liao, Hsueh-Ping Chu*, Zhixain Hu, Jason J. Merkin, Jianmin Chen, Zuguo Liu, Kurt Degenhardt, Eileen White and Alexey G. Ryazanov. Paradoxical roles of elongation factor-2 kinase in stem cell survival. * CO-FIRST AUTHOR. J Biol. Chem. 2016 July 27 (jbc.M116.724856)

17.       Hsueh-Ping Chu, Yi Liao, James S. Novak, Zhixian Hu, Jason J. Merkin, Yuriy Shymkiv, Bart P. Braeckman, Maxim V. Dorovkov, Alexandra Nguyen, Peter M, Clifford, Robert G. Nagele, David E. Harrison, Ronald E. Ellis, Alexey G. Ryazanov. Germline quality control: eEF2K stands guard to eliminate defective oocytes. Developmental Cell. 2014 Mar 10;28(5):561-72. --First author.
Courses information

MCB5036	Seminar in Non-coding RNAs
MCB7002	Research Training
MCB5037	Applications of NGS sequencing in Molecular Biology
MCB8001	Seminar (Ph.D)
MCB5007	Molecular Cell Biology