IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-45773-3.html
   My bibliography  Save this article

Kdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons

Author

Listed:
  • Beatriz del Blanco

    (Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant)

  • Sergio Niñerola

    (Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant)

  • Ana M. Martín-González

    (Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant)

  • Juan Paraíso-Luna

    (Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant
    Universidad Complutense de Madrid)

  • Minji Kim

    (The Jackson laboratory for Genomic Medicine
    University of Michigan)

  • Rafael Muñoz-Viana

    (Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant
    Bioinformatics Unit, Hospital universitario Puerta de Hierro Majadahonda)

  • Carina Racovac

    (Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant)

  • Jose V. Sanchez-Mut

    (Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant)

  • Yijun Ruan

    (The Jackson laboratory for Genomic Medicine
    Zhejiang University)

  • Ángel Barco

    (Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant)

Abstract

Kdm1a is a histone demethylase linked to intellectual disability with essential roles during gastrulation and the terminal differentiation of specialized cell types, including neurons, that remains highly expressed in the adult brain. To explore Kdm1a’s function in adult neurons, we develop inducible and forebrain-restricted Kdm1a knockouts. By applying multi-omic transcriptome, epigenome and chromatin conformation data, combined with super-resolution microscopy, we find that Kdm1a elimination causes the neuronal activation of nonneuronal genes that are silenced by the polycomb repressor complex and interspersed with active genes. Functional assays demonstrate that the N-terminus of Kdm1a contains an intrinsically disordered region that is essential to segregate Kdm1a-repressed genes from the neighboring active chromatin environment. Finally, we show that the segregation of Kdm1a-target genes is weakened in neurons during natural aging, underscoring the role of Kdm1a safeguarding neuronal genome organization and gene silencing throughout life.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45773-3
    DOI: 10.1038/s41467-024-45773-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-45773-3
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-45773-3?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. Feng Zhang & Dan Xu & Ling Yuan & Yiming Sun & Zhiheng Xu, 2014. "Epigenetic regulation of Atrophin1 by lysine-specific demethylase 1 is required for cortical progenitor maintenance," Nature Communications, Nature, vol. 5(1), pages 1-12, December.
    2. Yichao Cai & Ying Zhang & Yan Ping Loh & Jia Qi Tng & Mei Chee Lim & Zhendong Cao & Anandhkumar Raju & Erez Lieberman Aiden & Shang Li & Lakshmanan Manikandan & Vinay Tergaonkar & Greg Tucker-Kellogg , 2021. "H3K27me3-rich genomic regions can function as silencers to repress gene expression via chromatin interactions," Nature Communications, Nature, vol. 12(1), pages 1-22, December.
    3. Melissa J. Fullwood & Mei Hui Liu & You Fu Pan & Jun Liu & Han Xu & Yusoff Bin Mohamed & Yuriy L. Orlov & Stoyan Velkov & Andrea Ho & Poh Huay Mei & Elaine G. Y. Chew & Phillips Yao Hui Huang & Willem, 2009. "An oestrogen-receptor-α-bound human chromatin interactome," Nature, Nature, vol. 462(7269), pages 58-64, November.
    4. Sandhya Chandrasekaran & Sergio Espeso-Gil & Yong-Hwee Eddie Loh & Behnam Javidfar & Bibi Kassim & Yueyan Zhu & Yuan Zhang & Yuhao Dong & Lucy K. Bicks & Haixin Li & Prashanth Rajarajan & Cyril J. Pet, 2021. "Neuron-specific chromosomal megadomain organization is adaptive to recent retrotransposon expansions," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    5. Yin Shen & Feng Yue & David F. McCleary & Zhen Ye & Lee Edsall & Samantha Kuan & Ulrich Wagner & Jesse Dixon & Leonard Lee & Victor V. Lobanenkov & Bing Ren, 2012. "A map of the cis-regulatory sequences in the mouse genome," Nature, Nature, vol. 488(7409), pages 116-120, August.
    6. Pan Jia & Xiang Li & Xuelei Wang & Liangjiao Yao & Yingying Xu & Yu Hu & Wenwen Xu & Zhe He & Qifan Zhao & Yicong Deng & Yi Zang & Meiyu Zhang & Yan Zhang & Jun Qin & Wei Lu, 2021. "ZMYND8 mediated liquid condensates spatiotemporally decommission the latent super-enhancers during macrophage polarization," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    7. 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.
    8. 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.
    9. Satomi Ito & Adriana Magalska & Manuel Alcaraz-Iborra & Jose P. Lopez-Atalaya & Victor Rovira & Bruno Contreras-Moreira & Michal Lipinski & Roman Olivares & Jose Martinez-Hernandez & Blazej Ruszczycki, 2014. "Loss of neuronal 3D chromatin organization causes transcriptional and behavioural deficits related to serotonergic dysfunction," Nature Communications, Nature, vol. 5(1), pages 1-14, December.
    10. Caryn S. Ross-Innes & Rory Stark & Andrew E. Teschendorff & Kelly A. Holmes & H. Raza Ali & Mark J. Dunning & Gordon D. Brown & Ondrej Gojis & Ian O. Ellis & Andrew R. Green & Simak Ali & Suet-Feung C, 2012. "Differential oestrogen receptor binding is associated with clinical outcome in breast cancer," Nature, Nature, vol. 481(7381), pages 389-393, January.
    11. Jesse R. Dixon & Siddarth Selvaraj & Feng Yue & Audrey Kim & Yan Li & Yin Shen & Ming Hu & Jun S. Liu & Bing Ren, 2012. "Topological domains in mammalian genomes identified by analysis of chromatin interactions," Nature, Nature, vol. 485(7398), pages 376-380, May.
    12. Zhonghua Gao & Pedro Lee & James M. Stafford & Melanie von Schimmelmann & Anne Schaefer & Danny Reinberg, 2014. "An AUTS2–Polycomb complex activates gene expression in the CNS," Nature, Nature, vol. 516(7531), pages 349-354, December.
    13. Jincheng Wang & Jiajia Wang & Lijun Yang & Chuntao Zhao & Laiman Natalie Wu & Lingli Xu & Feng Zhang & Qinjie Weng & Michael Wegner & Q. Richard Lu, 2020. "CTCF-mediated chromatin looping in EGR2 regulation and SUZ12 recruitment critical for peripheral myelination and repair," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    14. 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.
    15. Michael A. Christopher & Dexter A. Myrick & Benjamin G. Barwick & Amanda K. Engstrom & Kirsten A. Porter-Stransky & Jeremy M. Boss & David Weinshenker & Allan I. Levey & David J. Katz, 2017. "LSD1 protects against hippocampal and cortical neurodegeneration," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    16. Martin Franke & Daniel M. Ibrahim & Guillaume Andrey & Wibke Schwarzer & Verena Heinrich & Robert Schöpflin & Katerina Kraft & Rieke Kempfer & Ivana Jerković & Wing-Lee Chan & Malte Spielmann & Bernd , 2016. "Formation of new chromatin domains determines pathogenicity of genomic duplications," Nature, Nature, vol. 538(7624), pages 265-269, October.
    17. S. Sanulli & M. J. Trnka & V. Dharmarajan & R. W. Tibble & B. D. Pascal & A. L. Burlingame & P. R. Griffin & J. D. Gross & G. J. Narlikar, 2019. "HP1 reshapes nucleosome core to promote phase separation of heterochromatin," Nature, Nature, vol. 575(7782), pages 390-394, November.
    18. Stefan Schoenfelder & Borbala Mifsud & Claire E. Senner & Christopher D. Todd & Stephanie Chrysanthou & Elodie Darbo & Myriam Hemberger & Miguel R. Branco, 2018. "Divergent wiring of repressive and active chromatin interactions between mouse embryonic and trophoblast lineages," Nature Communications, Nature, vol. 9(1), pages 1-10, 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. 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. 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.
    3. Jia-Yong Zhong & Longjian Niu & Zhuo-Bin Lin & Xin Bai & Ying Chen & Feng Luo & Chunhui Hou & Chuan-Le Xiao, 2023. "High-throughput Pore-C reveals the single-allele topology and cell type-specificity of 3D genome folding," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. Vinícius G. Contessoto & Olga Dudchenko & Erez Lieberman Aiden & Peter G. Wolynes & José N. Onuchic & Michele Pierro, 2023. "Interphase chromosomes of the Aedes aegypti mosquito are liquid crystalline and can sense mechanical cues," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    5. Andrea Wilderman & Eva D’haene & Machteld Baetens & Tara N. Yankee & Emma Wentworth Winchester & Nicole Glidden & Ellen Roets & Jo Dorpe & Sandra Janssens & Danny E. Miller & Miranda Galey & Kari M. B, 2024. "A distant global control region is essential for normal expression of anterior HOXA genes during mouse and human craniofacial development," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    6. 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.
    7. Haoxi Chai & Harianto Tjong & Peng Li & Wei Liao & Ping Wang & Chee Hong Wong & Chew Yee Ngan & Warren J. Leonard & Chia-Lin Wei & Yijun Ruan, 2023. "ChIATAC is an efficient strategy for multi-omics mapping of 3D epigenomes from low-cell inputs," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    8. 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.
    9. Mingsen Li & Huaxing Huang & Bofeng Wang & Shaoshuai Jiang & Huizhen Guo & Liqiong Zhu & Siqi Wu & Jiafeng Liu & Li Wang & Xihong Lan & Wang Zhang & Jin Zhu & Fuxi Li & Jieying Tan & Zhen Mao & Chunqi, 2022. "Comprehensive 3D epigenomic maps define limbal stem/progenitor cell function and identity," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    10. Konstantin Okonechnikov & Aylin Camgöz & Owen Chapman & Sameena Wani & Donglim Esther Park & Jens-Martin Hübner & Abhijit Chakraborty & Meghana Pagadala & Rosalind Bump & Sahaana Chandran & Katerina K, 2023. "3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    11. Dohoon Lee & Jeewon Yang & Sun Kim, 2022. "Learning the histone codes with large genomic windows and three-dimensional chromatin interactions using transformer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    12. Tomas Zelenka & Antonios Klonizakis & Despina Tsoukatou & Dionysios-Alexandros Papamatheakis & Sören Franzenburg & Petros Tzerpos & Ioannis-Rafail Tzonevrakis & George Papadogkonas & Manouela Kapsetak, 2022. "The 3D enhancer network of the developing T cell genome is shaped by SATB1," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    13. Ziad Ibrahim & Tao Wang & Olivier Destaing & Nicola Salvi & Naghmeh Hoghoughi & Clovis Chabert & Alexandra Rusu & Jinjun Gao & Leonardo Feletto & Nicolas Reynoird & Thomas Schalch & Yingming Zhao & Ma, 2022. "Structural insights into p300 regulation and acetylation-dependent genome organisation," Nature Communications, Nature, vol. 13(1), pages 1-23, December.
    14. Markus Götz & Olivier Messina & Sergio Espinola & Jean-Bernard Fiche & Marcelo Nollmann, 2022. "Multiple parameters shape the 3D chromatin structure of single nuclei at the doc locus in Drosophila," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    15. Sonali Narang & Yohana Ghebrechristos & Nikki A. Evensen & Nina Murrell & Sylwia Jasinski & Talia H. Ostrow & David T. Teachey & Elizabeth A. Raetz & Timothee Lionnet & Matthew Witkowski & Iannis Aifa, 2024. "Clonal evolution of the 3D chromatin landscape in patients with relapsed pediatric B-cell acute lymphoblastic leukemia," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    16. Sandhya Malla & Kanchan Kumari & Carlos A. García-Prieto & Jonatan Caroli & Anna Nordin & Trinh T. T. Phan & Devi Prasad Bhattarai & Carlos Martinez-Gamero & Eshagh Dorafshan & Stephanie Stransky & Da, 2024. "The scaffolding function of LSD1 controls DNA methylation in mouse ESCs," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    17. Shuai Liu & Yaqiang Cao & Kairong Cui & Qingsong Tang & Keji Zhao, 2022. "Hi-TrAC reveals division of labor of transcription factors in organizing chromatin loops," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    18. Abrar Aljahani & Peng Hua & Magdalena A. Karpinska & Kimberly Quililan & James O. J. Davies & A. Marieke Oudelaar, 2022. "Analysis of sub-kilobase chromatin topology reveals nano-scale regulatory interactions with variable dependence on cohesin and CTCF," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    19. Surya K Ghosh & Daniel Jost, 2018. "How epigenome drives chromatin folding and dynamics, insights from efficient coarse-grained models of chromosomes," PLOS Computational Biology, Public Library of Science, vol. 14(5), pages 1-26, May.
    20. Takeshi Katsuda & Jonathan H. Sussman & Kenji Ito & Andrew Katznelson & Salina Yuan & Naomi Takenaka & Jinyang Li & Allyson J. Merrell & Hector Cure & Qinglan Li & Reyaz Ur Rasool & Irfan A. Asangani , 2024. "Cellular reprogramming in vivo initiated by SOX4 pioneer factor activity," Nature Communications, Nature, vol. 15(1), pages 1-20, 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_s41467-024-45773-3. 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.