IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-54824-8.html
   My bibliography  Save this article

SAM-DNMT3A, a strategy for induction of genome-wide DNA methylation, identifies DNA methylation as a vulnerability in ER-positive breast cancers

Author

Listed:
  • Mahnaz Hosseinpour

    (Monash University
    Monash University
    The University of Melbourne)

  • Xinqi Xi

    (Monash University)

  • Ling Liu

    (Monash University)

  • Luis Malaver-Ortega

    (Monash University)

  • Laura Perlaza-Jimenez

    (Monash University)

  • Jihoon E. Joo

    (The University of Melbourne)

  • Harrison M. York

    (Monash University)

  • Jonathan Beesley

    (QIMR Berghofer Medical Research Institute)

  • C. Elizabeth Caldon

    (Garvan Institute of Medical Research)

  • Pierre-Antoine Dugué

    (Monash University
    Cancer Council Victoria
    The University of Melbourne)

  • James G. Dowty

    (The University of Melbourne)

  • Senthil Arumugam

    (Monash University
    Monash University)

  • Melissa C. Southey

    (Monash University
    The University of Melbourne
    Cancer Council Victoria)

  • Joseph Rosenbluh

    (Monash University
    Monash University)

Abstract

DNA methylation is an epigenetic mark that plays a critical role in regulating gene expression. DNA methyltransferase (DNMT) inhibitors, inhibit global DNA methylation and have been a key tool in studies of DNA methylation. A major bottleneck is the lack of tools to induce global DNA methylation. Here, we engineered a CRISPR based approach, that we initially designed, to enable site-specific DNA methylation. Using the synergistic activation mediator (SAM) system, we unexpectedly find that regardless of the targeted sequence any sgRNA induces global genome-wide DNA methylation. We term this method SAM-DNMT3A and show that induction of global DNA methylation is a unique vulnerability in ER-positive breast cancer suggesting a therapeutic approach. Our findings highlight the need of caution when using CRISPR based approaches for inducing DNA methylation and demonstrate a method for global induction of DNA methylation.

Suggested Citation

  • Mahnaz Hosseinpour & Xinqi Xi & Ling Liu & Luis Malaver-Ortega & Laura Perlaza-Jimenez & Jihoon E. Joo & Harrison M. York & Jonathan Beesley & C. Elizabeth Caldon & Pierre-Antoine Dugué & James G. Dow, 2024. "SAM-DNMT3A, a strategy for induction of genome-wide DNA methylation, identifies DNA methylation as a vulnerability in ER-positive breast cancers," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54824-8
    DOI: 10.1038/s41467-024-54824-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-54824-8
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-54824-8?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. Ryan Lister & Mattia Pelizzola & Robert H. Dowen & R. David Hawkins & Gary Hon & Julian Tonti-Filippini & Joseph R. Nery & Leonard Lee & Zhen Ye & Que-Minh Ngo & Lee Edsall & Jessica Antosiewicz-Bourg, 2009. "Human DNA methylomes at base resolution show widespread epigenomic differences," Nature, Nature, vol. 462(7271), pages 315-322, November.
    2. Harrison M. York & Kunaal Joshi & Charles S. Wright & Laura Z. Kreplin & Samuel J. Rodgers & Ullhas K. Moorthi & Hetvi Gandhi & Abhishek Patil & Christina A. Mitchell & Srividya Iyer-Biswas & Senthil , 2023. "Deterministic early endosomal maturations emerge from a stochastic trigger-and-convert mechanism," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Sam Buckberry & Xiaodong Liu & Daniel Poppe & Jia Ping Tan & Guizhi Sun & Joseph Chen & Trung Viet Nguyen & Alex de Mendoza & Jahnvi Pflueger & Thomas Frazer & Dulce B. Vargas-Landín & Jacob M. Paynte, 2023. "Transient naive reprogramming corrects hiPS cells functionally and epigenetically," Nature, Nature, vol. 620(7975), pages 863-872, August.
    4. 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.
    5. Kendall R. Sanson & Ruth E. Hanna & Mudra Hegde & Katherine F. Donovan & Christine Strand & Meagan E. Sullender & Emma W. Vaimberg & Amy Goodale & David E. Root & Federica Piccioni & John G. Doench, 2018. "Optimized libraries for CRISPR-Cas9 genetic screens with multiple modalities," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    6. Andrew Stone & Elena Zotenko & Warwick J. Locke & Darren Korbie & Ewan K. A. Millar & Ruth Pidsley & Clare Stirzaker & Peter Graham & Matt Trau & Elizabeth A. Musgrove & Robert I. Nicholson & Julia M., 2015. "DNA methylation of oestrogen-regulated enhancers defines endocrine sensitivity in breast cancer," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
    7. Jihoon E. Joo & James G. Dowty & Roger L. Milne & Ee Ming Wong & Pierre-Antoine Dugué & Dallas English & John L. Hopper & David E. Goldgar & Graham G. Giles & Melissa C. Southey, 2018. "Heritable DNA methylation marks associated with susceptibility to breast cancer," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    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. Amy J. Heidersbach & Kristel M. Dorighi & Javier A. Gomez & Ashley M. Jacobi & Benjamin Haley, 2023. "A versatile, high-efficiency platform for CRISPR-based gene activation," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    2. Yiqian Wu & Ziliang Huang & Yahan Liu & Peixiang He & Yuxuan Wang & Liyanran Yan & Xinhui Wang & Shanzi Gao & Xintao Zhou & Chi Woo Yoon & Kun Sun & Yinglin Situ & Phuong Ho & Yushun Zeng & Zhou Yuan , 2024. "Ultrasound Control of Genomic Regulatory Toolboxes for Cancer Immunotherapy," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Yexuan Deng & Sarah T. Diepstraten & Margaret A. Potts & Göknur Giner & Stephanie Trezise & Ashley P. Ng & Gerry Healey & Serena R. Kane & Amali Cooray & Kira Behrens & Amy Heidersbach & Andrew J. Kue, 2022. "Generation of a CRISPR activation mouse that enables modelling of aggressive lymphoma and interrogation of venetoclax resistance," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Sean A. Misek & Aaron Fultineer & Jeremie Kalfon & Javad Noorbakhsh & Isabella Boyle & Priyanka Roy & Joshua Dempster & Lia Petronio & Katherine Huang & Alham Saadat & Thomas Green & Adam Brown & John, 2024. "Germline variation contributes to false negatives in CRISPR-based experiments with varying burden across ancestries," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    5. Chen Dong & Shuhua Fu & Rowan M. Karvas & Brian Chew & Laura A. Fischer & Xiaoyun Xing & Jessica K. Harrison & Pooja Popli & Ramakrishna Kommagani & Ting Wang & Bo Zhang & Thorold W. Theunissen, 2022. "A genome-wide CRISPR-Cas9 knockout screen identifies essential and growth-restricting genes in human trophoblast stem cells," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    6. Zengyu Shao & Jiuwei Lu & Nelli Khudaverdyan & Jikui Song, 2024. "Multi-layered heterochromatin interaction as a switch for DIM2-mediated DNA methylation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    7. Yudong Gao & Daichi Shonai & Matthew Trn & Jieqing Zhao & Erik J. Soderblom & S. Alexandra Garcia-Moreno & Charles A. Gersbach & William C. Wetsel & Geraldine Dawson & Dmitry Velmeshev & Yong-hui Jian, 2024. "Proximity analysis of native proteomes reveals phenotypic modifiers in a mouse model of autism and related neurodevelopmental conditions," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    8. Tian Zhou & Xinyi Zhu & Zhizhong Ye & Yong-Fei Wang & Chao Yao & Ning Xu & Mi Zhou & Jianyang Ma & Yuting Qin & Yiwei Shen & Yuanjia Tang & Zhihua Yin & Hong Xu & Yutong Zhang & Xiaoli Zang & Huihua D, 2022. "Lupus enhancer risk variant causes dysregulation of IRF8 through cooperative lncRNA and DNA methylation machinery," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    9. Shaela Wright & Xujie Zhao & Wojciech Rosikiewicz & Shelby Mryncza & Judith Hyle & Wenjie Qi & Zhenling Liu & Siqi Yi & Yong Cheng & Beisi Xu & Chunliang Li, 2023. "Systematic characterization of the HOXA9 downstream targets in MLL-r leukemia by noncoding CRISPR screens," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    10. Haipeng Fu & Tingyu Wang & Xiaohui Kong & Kun Yan & Yang Yang & Jingyi Cao & Yafei Yuan & Nan Wang & Kehkooi Kee & Zhi John Lu & Qiaoran Xi, 2022. "A Nodal enhanced micropeptide NEMEP regulates glucose uptake during mesendoderm differentiation of embryonic stem cells," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    11. Xuelong Yao & Zongyang Lu & Zhanying Feng & Lei Gao & Xin Zhou & Min Li & Suijuan Zhong & Qian Wu & Zhenbo Liu & Haofeng Zhang & Zeyuan Liu & Lizhi Yi & Tao Zhou & Xudong Zhao & Jun Zhang & Yong Wang , 2022. "Comparison of chromatin accessibility landscapes during early development of prefrontal cortex between rhesus macaque and human," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    12. 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.
    13. Rakesh Chettier & Lesa Nelson & James W Ogilvie & Hans M Albertsen & Kenneth Ward, 2015. "Haplotypes at LBX1 Have Distinct Inheritance Patterns with Opposite Effects in Adolescent Idiopathic Scoliosis," PLOS ONE, Public Library of Science, vol. 10(2), pages 1-11, February.
    14. Yafeng Wang & Guiquan Zhang & Qingzhou Meng & Shisheng Huang & Panpan Guo & Qibin Leng & Lingyun Sun & Geng Liu & Xingxu Huang & Jianghuai Liu, 2022. "Precise tumor immune rewiring via synthetic CRISPRa circuits gated by concurrent gain/loss of transcription factors," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    15. Chih-Hao Wang & Tadataka Tsuji & Li-Hong Wu & Cheng-Ying Yang & Tian Lian Huang & Mari Sato & Farnaz Shamsi & Yu-Hua Tseng, 2024. "Endothelin 3/EDNRB signaling induces thermogenic differentiation of white adipose tissue," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    16. Xue Yue & Zhiyuan Xie & Moran Li & Kai Wang & Xiaojing Li & Xiaoqing Zhang & Jian Yan & Yimeng Yin, 2022. "Simultaneous profiling of histone modifications and DNA methylation via nanopore sequencing," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    17. Anyou Wang & Ying Du & Qianchuan He & Chunxiao Zhou, 2013. "A Quantitative System for Discriminating Induced Pluripotent Stem Cells, Embryonic Stem Cells and Somatic Cells," PLOS ONE, Public Library of Science, vol. 8(2), pages 1-10, February.
    18. 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.
    19. Vicky Chou & Richard V. Pearse & Aimee J. Aylward & Nancy Ashour & Mariko Taga & Gizem Terzioglu & Masashi Fujita & Seeley B. Fancher & Alina Sigalov & Courtney R. Benoit & Hyo Lee & Matti Lam & Nicho, 2023. "INPP5D regulates inflammasome activation in human microglia," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    20. 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.

    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_s41467-024-54824-8. 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.