Speaker

AFFILIATION:

Institute of Molecular and Cellular Biology National Taiwan University

POSITION TITLE:

Assistant Professor

EDUCATION/TRAINING:

Harvard Medical School/Mass General Hospital, Boston, MA, USA

Postdoctoral fellow, Jan.2010—Mar.2017

Advisor: Jeannie T. Lee

Projects: 

1. Using CHIRT-seq and iDRiP to study the genomic and proteomic networking of non-coding RNA ---TERRA (telomeric-repeat containing RNA). 

2. The functions of TERRA in gene regulation, chromatin organization, and telomere maintenance.

HONORS:

 

RESEARCH INTERESTS:

Our lab is interested in the functions of non-coding RNAs. More than 90% of the human 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. We use an RNA-centric approach to reveal the network of ncRNA-protein-genome. We developed the methods to study the interactomes of non-coding RNAs using iDRiP-MS (Nature Protocols, 2021). The long-term goal is to develop a therapeutic technology for human diseases by targeting ncRNAs. 

    We study the roles of TERRA (TElomeric Repeat containing RNA) in epigenetic regulation, telomere maintenance, ageing and human diseases. TERRA is a long non-coding RNA, which is transcribed from the subtelomeric regions toward telomeres in most eukaryotic cells. We demonstrated that TERRA regulates the genomic occupancy of histone modifier ATRX and DNA G-quadruplex structures (Nucleic Acids Research, 2022). ATRX is a chromatin remodeler that is required for silencing retrotransposons and telomere maintenance. The mutations in the ATRX gene cause ATRX syndrome displaying severe defects in neuronal development. Given that TERRA antagonizes ATRX for gene expression, we are working on how modulating TERRA could attenuate the defects in patients carrying ATRX mutations.      

     TERRA is also highly expressed in ALT (Alternative Lengthening of Telomeres) cancer cells, which do not rely on telomerases activity to extend telomeres. The factors driving ALT remain elusive. We recently reported that TERRA invades double-stranded telomeric DNA to form R-loop structures and contributes the telomere clustering to promote homologous recombination between telomeres in ALT cells. One of TERRA interacting proteins, XPF, is recruited by R-loops and is required for DNA breaks at telomeres to drive telomere synthesis in ALT cancer cells. Our work uncovers the mechanism in which TERRA cooperates with DNA damage proteins to lengthen telomeres in ALT cancer cells (Nature Communications, 2022). We are interested in therapeutic approaches that can overcome the drug resistance in ALT cancers. We would like to develop a friendly method for the medical diagnosis of ALT cancers in clinics.   

     In addition, we are interested in the functions of TERRA during human ageing and cellular senescence. We found that TERRA is upregulated in monocytes during human ageing (unpublished). The telomere damage is usually associated with increased TERRA levels. We hypothesize that TERRA forms R-loops at telomeres and triggers DNA damage response to induce cellular senescence. We are going to test if modulating TERRA levels or TERRA R-loops can suppress replicative senescence and delay ageing. 

PUBLICATIONS:

1. Ru-Xuan Tsai1, #, Kuo-Chen Fang1, #, Po-Cheng Yang1, #, 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.

2. Chia-Yu Guh1, #, Hong-Jhih Shen1, #, Liv WeiChien Chen1,#, Pei-Chen Chiu1, #, 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 Egly6,7 and Hsueh-Ping Catherine Chu 1,*.  XPF activates break-induced telomere synthesis. Nature Communications (SCI), 2022 Oct 2;13(1):5781. *Corresponding author.

3. 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. 

4. 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.

5. Meng-Chun Monica Shih, Chen-Che Jeff Huang, Hsueh-Ping Chu, Nai-Chi Hsu, Bon-Chu Chung. Embryonic steroid control developmental programming of energy balance. Endocrinology. 2021 Dec 1; 162(12):bqab196.

6. 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.

7. 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

8. 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.

9. 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 

10. 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.

[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.] 

[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.

11. 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.

12. 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

13. 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)

14. 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.

15. Martin A. Bewley, Trong K. Pham, Helen M. Marriott, Josselin Noirel, Hsueh-Ping Chu, Saw Y. Ow, Alexey, G. Ryazanov, Robert C.Read, Moira K. B. Whyte, Benny Chain, Phillip C. Wright and David H. Dockrell. Proteomic evaluation and validation of cathepsin D regulated proteins in macrophages exposed to Streptococus pneumonia. Molecular & Cellular Proteomics. 2011 Jun;10 (6)M111.008193

16. Grace S. Shieh, Tsai-Hung Fan, Hsueh-Ping Chu (2008). A Bayesian approach to assessing differential expression of microarray data. Journal of Statistical Computation and Simulation, Volume 78, Issue 2 February 2008, p.179 – 191

17. Hsu-Shui Wu, Hui-Ting Lin, Chi-Kuang Leo Wang, Yen-Feng Chiang, Hsueh-Ping Chu, Meng-Chun Hu (2007). Human CYP11A1 promoter drives Cre recombinase expression in the brain in addition to adrenals and gonads. Genesis. 2007 Feb;45(2):59-65.

18. Noomen Ben El Hadj, Meng-Chun Hu, Hsueh-Ping Chu, Leo Chi-Kuang Wang, and Bon-chu Chung (2006)- Phenotypic Analysis of Mice with Steroid Deficiency. Genetically Engineered Mice Handbook, Taylor&Francis. Edited by John P. Sundberg and Tsutomu Ichiki.  Chapter 19, p253- 262, 2006. 

19. Martin Heine, Catharina I. Cramm-Behrens, Athar Ansari, Hsueh-Ping Chu, Alexey G Ryazanov, Hassan Y Naim, and Ralf Jacob. Alpha-kinase 1, a new component in apical protein transport. J Biol. Chem. 2005 Jul 8;280(27):25637-43

20. Meng-Chun Hu, Nai-Chi Hsu, Noomen en El Hadj, Chin-I Pai, Hsueh-Ping Chu, Chi-Kuang Leo Wang, and Bon-Chu Chung, Steriod Deficiency Syndromes in Mice with Targeted Disruption of Cyp11A1.  Mol Endocrinol, 2002.16(8)p.1943-1950.