IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-49926-2.html
   My bibliography  Save this article

Transposable elements-mediated recruitment of KDM1A epigenetically silences HNF4A expression to promote hepatocellular carcinoma

Author

Listed:
  • Tiantian Jing

    (Shanghai Jiao Tong University School of Medicine)

  • Dianhui Wei

    (Shanghai Jiao Tong University School of Medicine)

  • Xiaoli Xu

    (Shanghai Jiao Tong University School of Medicine)

  • Chengsi Wu

    (Shanghai Jiao Tong University School of Medicine)

  • Lili Yuan

    (Shanghai Jiao Tong University School of Medicine)

  • Yiwen Huang

    (Shanghai Jiao Tong University School of Medicine)

  • Yizhen Liu

    (Fudan University)

  • Yanyi Jiang

    (Chinese Academy of Sciences
    University of Science and Technology of China)

  • Boshi Wang

    (Shanghai Jiao Tong University School of Medicine)

Abstract

Transposable elements (TEs) contribute to gene expression regulation by acting as cis-regulatory elements that attract transcription factors and epigenetic regulators. This research aims to explore the functional and clinical implications of transposable element-related molecular events in hepatocellular carcinoma, focusing on the mechanism through which liver-specific accessible TEs (liver-TEs) regulate adjacent gene expression. Our findings reveal that the expression of HNF4A is inversely regulated by proximate liver-TEs, which facilitates liver cancer cell proliferation. Mechanistically, liver-TEs are predominantly occupied by the histone demethylase, KDM1A. KDM1A negatively influences the methylation of histone H3 Lys4 (H3K4) of liver-TEs, resulting in the epigenetic silencing of HNF4A expression. The suppression of HNF4A mediated by KDM1A promotes liver cancer cell proliferation. In conclusion, this study uncovers a liver-TE/KDM1A/HNF4A regulatory axis that promotes liver cancer growth and highlights KDM1A as a promising therapeutic target. Our findings provide insight into the transposable element-related molecular mechanisms underlying liver cancer progression.

Suggested Citation

  • Tiantian Jing & Dianhui Wei & Xiaoli Xu & Chengsi Wu & Lili Yuan & Yiwen Huang & Yizhen Liu & Yanyi Jiang & Boshi Wang, 2024. "Transposable elements-mediated recruitment of KDM1A epigenetically silences HNF4A expression to promote hepatocellular carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49926-2
    DOI: 10.1038/s41467-024-49926-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-49926-2
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-49926-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Alessandra Chesi & Yadav Wagley & Matthew E. Johnson & Elisabetta Manduchi & Chun Su & Sumei Lu & Michelle E. Leonard & Kenyaita M. Hodge & James A. Pippin & Kurt D. Hankenson & Andrew D. Wells & Stru, 2019. "Genome-scale Capture C promoter interactions implicate effector genes at GWAS loci for bone mineral density," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    2. Silvana Konermann & Mark D. Brigham & Alexandro E. Trevino & Julia Joung & Omar O. Abudayyeh & Clea Barcena & Patrick D. Hsu & Naomi Habib & Jonathan S. Gootenberg & Hiroshi Nishimasu & Osamu Nureki &, 2015. "Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex," Nature, Nature, vol. 517(7536), pages 583-588, January.
    3. Parinaz Mehdipour & Sajid A. Marhon & Ilias Ettayebi & Ankur Chakravarthy & Amir Hosseini & Yadong Wang & Fabíola Attié Castro & Helen Loo Yau & Charles Ishak & Sagi Abelson & Catherine A. O’Brien & D, 2020. "Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency," Nature, Nature, vol. 588(7836), pages 169-173, December.
    4. Jianxun Wang & Kathleen Scully & Xiaoyan Zhu & Ling Cai & Jie Zhang & Gratien G. Prefontaine & Anna Krones & Kenneth A. Ohgi & Ping Zhu & Ivan Garcia-Bassets & Forrest Liu & Havilah Taylor & Jean Loza, 2007. "Opposing LSD1 complexes function in developmental gene activation and repression programmes," Nature, Nature, vol. 446(7138), pages 882-887, April.
    5. Warren A. Whyte & Steve Bilodeau & David A. Orlando & Heather A. Hoke & Garrett M. Frampton & Charles T. Foster & Shaun M. Cowley & Richard A. Young, 2012. "Enhancer decommissioning by LSD1 during embryonic stem cell differentiation," Nature, Nature, vol. 482(7384), pages 221-225, February.
    6. Min Gyu Lee & Christopher Wynder & Neil Cooch & Ramin Shiekhattar, 2005. "An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation," Nature, Nature, vol. 437(7057), pages 432-435, September.
    7. Eric Metzger & Melanie Wissmann & Na Yin & Judith M. Müller & Robert Schneider & Antoine H. F. M. Peters & Thomas Günther & Reinhard Buettner & Roland Schüle, 2005. "LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription," Nature, Nature, vol. 437(7057), pages 436-439, September.
    8. E. Christopher Partridge & Surya B. Chhetri & Jeremy W. Prokop & Ryne C. Ramaker & Camden S. Jansen & Say-Tar Goh & Mark Mackiewicz & Kimberly M. Newberry & Laurel A. Brandsmeier & Sarah K. Meadows & , 2020. "Occupancy maps of 208 chromatin-associated proteins in one human cell type," Nature, Nature, vol. 583(7818), pages 720-728, July.
    9. Hale Tunbak & Rocio Enriquez-Gasca & Christopher H. C. Tie & Poppy A. Gould & Petra Mlcochova & Ravindra K. Gupta & Liane Fernandes & James Holt & Annemarthe G. Veen & Evangelos Giampazolias & Kathlee, 2020. "The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    10. Shang-Min Zhang & Wesley L. Cai & Xiaoni Liu & Durga Thakral & Jiesi Luo & Lok Hei Chan & Meaghan K. McGeary & Eric Song & Kim R. M. Blenman & Goran Micevic & Shlomit Jessel & Yangyi Zhang & Mingzhu Y, 2021. "KDM5B promotes immune evasion by recruiting SETDB1 to silence retroelements," Nature, Nature, vol. 598(7882), pages 682-687, October.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Cheng Zeng & Jiwei Chen & Emmalee W. Cooke & Arijita Subuddhi & Eliana T. Roodman & Fei Xavier Chen & Kaixiang Cao, 2023. "Demethylase-independent roles of LSD1 in regulating enhancers and cell fate transition," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Beatriz del Blanco & Sergio Niñerola & Ana M. Martín-González & Juan Paraíso-Luna & Minji Kim & Rafael Muñoz-Viana & Carina Racovac & Jose V. Sanchez-Mut & Yijun Ruan & Ángel Barco, 2024. "Kdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Xue Zhong & Nagesh Peddada & Jianhui Wang & James J. Moresco & Xiaowei Zhan & John M. Shelton & Jeffrey A. SoRelle & Katie Keller & Danielle Renee Lazaro & Eva Marie Y. Moresco & Jin Huk Choi & Bruce , 2023. "OVOL2 sustains postnatal thymic epithelial cell identity," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    4. Hanhan Ning & Shan Huang & Yang Lei & Renyong Zhi & Han Yan & Jiaxing Jin & Zhenyu Hu & Kaimin Guo & Jinhua Liu & Jie Yang & Zhe Liu & Yi Ba & Xin Gao & Deqing Hu, 2022. "Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    5. Lei Tao & Yue Zhou & Xiangyu Pan & Yuan Luo & Jiahao Qiu & Xia Zhou & Zhiqian Chen & Yan Li & Lian Xu & Yang Zhou & Zeping Zuo & Chunqi Liu & Liang Wang & Xiaocong Liu & Xinyu Tian & Na Su & Zhengnan , 2023. "Repression of LSD1 potentiates homologous recombination-proficient ovarian cancer to PARP inhibitors through down-regulation of BRCA1/2 and RAD51," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    6. Qin Yu & Alba Herrero del Valle & Rahul Singh & Yorgo Modis, 2021. "MDA5 disease variant M854K prevents ATP-dependent structural discrimination of viral and cellular RNA," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    7. Heathcliff Dorado García & Fabian Pusch & Yi Bei & Jennifer Stebut & Glorymar Ibáñez & Kristina Guillan & Koshi Imami & Dennis Gürgen & Jana Rolff & Konstantin Helmsauer & Stephanie Meyer-Liesener & N, 2022. "Therapeutic targeting of ATR in alveolar rhabdomyosarcoma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    8. Ramachandran Prakasam & Angela Bonadiman & Roberta Andreotti & Emanuela Zuccaro & Davide Dalfovo & Caterina Marchioretti & Debasmita Tripathy & Gianluca Petris & Eric N. Anderson & Alice Migazzi & Lau, 2023. "LSD1/PRMT6-targeting gene therapy to attenuate androgen receptor toxic gain-of-function ameliorates spinobulbar muscular atrophy phenotypes in flies and mice," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    9. Xiangfeng Kong & Hainan Zhang & Guoling Li & Zikang Wang & Xuqiang Kong & Lecong Wang & Mingxing Xue & Weihong Zhang & Yao Wang & Jiajia Lin & Jingxing Zhou & Xiaowen Shen & Yinghui Wei & Na Zhong & W, 2023. "Engineered CRISPR-OsCas12f1 and RhCas12f1 with robust activities and expanded target range for genome editing," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    10. Jian Wang & Yuxi Teng & Ruihua Zhang & Yifei Wu & Lei Lou & Yusong Zou & Michelle Li & Zhong-Ru Xie & Yajun Yan, 2021. "Engineering a PAM-flexible SpdCas9 variant as a universal gene repressor," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    11. Chirag Nepal & Jesper B. Andersen, 2023. "Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    12. Yong Yean Kim & Berkley E. Gryder & Ranuka Sinniah & Megan L. Peach & Jack F. Shern & Abdalla Abdelmaksoud & Silvia Pomella & Girma M. Woldemichael & Benjamin Z. Stanton & David Milewski & Joseph J. B, 2024. "KDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    13. Wenfeng Ren & Zilong Xu & Yating Chang & Fei Ju & Hongning Wu & Zhiqi Liang & Min Zhao & Naizhen Wang & Yanhua Lin & Chenhang Xu & Shengming Chen & Yipeng Rao & Chaolong Lin & Jianxin Yang & Pingguo L, 2024. "Pharmaceutical targeting of OTUB2 sensitizes tumors to cytotoxic T cells via degradation of PD-L1," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    14. Pengfei Guo & Nam Hoang & Joseph Sanchez & Elaine H. Zhang & Keshari Rajawasam & Kristiana Trinidad & Hong Sun & Hui Zhang, 2022. "The assembly of mammalian SWI/SNF chromatin remodeling complexes is regulated by lysine-methylation dependent proteolysis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    15. Jasmin Bartl & Marco Zanini & Flavia Bernardi & Antoine Forget & Lena Blümel & Julie Talbot & Daniel Picard & Nan Qin & Gabriele Cancila & Qingsong Gao & Soumav Nath & Idriss Mahoungou Koumba & Mariet, 2022. "The HHIP-AS1 lncRNA promotes tumorigenicity through stabilization of dynein complex 1 in human SHH-driven tumors," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    16. Yi Liu & Brian Debo & Mingfeng Li & Zhennan Shi & Wanqiang Sheng & Yang Shi, 2021. "LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    17. Ahmad Luqman-Fatah & Yuzo Watanabe & Kazuko Uno & Fuyuki Ishikawa & John V. Moran & Tomoichiro Miyoshi, 2023. "The interferon stimulated gene-encoded protein HELZ2 inhibits human LINE-1 retrotransposition and LINE-1 RNA-mediated type I interferon induction," Nature Communications, Nature, vol. 14(1), pages 1-26, December.
    18. Hsiao-Yun Chen & Yavuz T. Durmaz & Yixiang Li & Amin H. Sabet & Amir Vajdi & Thomas Denize & Emily Walton & Yasmin Nabil Laimon & John G. Doench & Navin R. Mahadevan & Julie-Aurore Losman & David A. B, 2022. "Regulation of neuroendocrine plasticity by the RNA-binding protein ZFP36L1," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    19. Arpiar Saunders & Kee Wui Huang & Cassandra Vondrak & Christina Hughes & Karina Smolyar & Harsha Sen & Adrienne C. Philson & James Nemesh & Alec Wysoker & Seva Kashin & Bernardo L. Sabatini & Steven A, 2022. "Ascertaining cells’ synaptic connections and RNA expression simultaneously with barcoded rabies virus libraries," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    20. Wen Hao Neo & Yiran Meng & Alba Rodriguez-Meira & Muhammad Z. H. Fadlullah & Christopher A. G. Booth & Emanuele Azzoni & Supat Thongjuea & Marella F. T. R. Bruijn & Sten Eirik W. Jacobsen & Adam J. Me, 2021. "Ezh2 is essential for the generation of functional yolk sac derived erythro-myeloid progenitors," Nature Communications, Nature, vol. 12(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49926-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.