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Topoisomerases facilitate transcription of long genes linked to autism

Author

Listed:
  • Ian F. King

    (The University of North Carolina at Chapel Hill)

  • Chandri N. Yandava

    (Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill)

  • Angela M. Mabb

    (The University of North Carolina at Chapel Hill)

  • Jack S. Hsiao

    (University of Connecticut Health Center)

  • Hsien-Sung Huang

    (The University of North Carolina at Chapel Hill
    Present address: Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.)

  • Brandon L. Pearson

    (The University of North Carolina at Chapel Hill)

  • J. Mauro Calabrese

    (The University of North Carolina at Chapel Hill)

  • Joshua Starmer

    (The University of North Carolina at Chapel Hill)

  • Joel S. Parker

    (The University of North Carolina at Chapel Hill
    Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill)

  • Terry Magnuson

    (The University of North Carolina at Chapel Hill
    Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill)

  • Stormy J. Chamberlain

    (University of Connecticut Health Center)

  • Benjamin D. Philpot

    (The University of North Carolina at Chapel Hill
    Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill
    UNC Neuroscience Center, The University of North Carolina at Chapel Hill)

  • Mark J. Zylka

    (The University of North Carolina at Chapel Hill
    Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill
    UNC Neuroscience Center, The University of North Carolina at Chapel Hill)

Abstract

Topoisomerases are expressed throughout the developing and adult brain and are mutated in some individuals with autism spectrum disorder (ASD). However, how topoisomerases are mechanistically connected to ASD is unknown. Here we find that topotecan, a topoisomerase 1 (TOP1) inhibitor, dose-dependently reduces the expression of extremely long genes in mouse and human neurons, including nearly all genes that are longer than 200 kilobases. Expression of long genes is also reduced after knockdown of Top1 or Top2b in neurons, highlighting that both enzymes are required for full expression of long genes. By mapping RNA polymerase II density genome-wide in neurons, we found that this length-dependent effect on gene expression was due to impaired transcription elongation. Interestingly, many high-confidence ASD candidate genes are exceptionally long and were reduced in expression after TOP1 inhibition. Our findings suggest that chemicals and genetic mutations that impair topoisomerases could commonly contribute to ASD and other neurodevelopmental disorders.

Suggested Citation

  • Ian F. King & Chandri N. Yandava & Angela M. Mabb & Jack S. Hsiao & Hsien-Sung Huang & Brandon L. Pearson & J. Mauro Calabrese & Joshua Starmer & Joel S. Parker & Terry Magnuson & Stormy J. Chamberlai, 2013. "Topoisomerases facilitate transcription of long genes linked to autism," Nature, Nature, vol. 501(7465), pages 58-62, September.
    • Handle: RePEc:nat:nature:v:501:y:2013:i:7465:d:10.1038_nature12504
    DOI: 10.1038/nature12504
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    Cited by:

    1. Mei Sheng Lau & Zhenhua Hu & Xiaodan Zhao & Yaw Sing Tan & Jinyue Liu & Hua Huang & Clarisse Jingyi Yeo & Hwei Fen Leong & Oleg V. Grinchuk & Justin Kaixuan Chan & Jie Yan & Wee-Wei Tee, 2023. "Transcriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscription," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Sang S. Seo & Susana R. Louros & Natasha Anstey & Miguel A. Gonzalez-Lozano & Callista B. Harper & Nicholas C. Verity & Owen Dando & Sophie R. Thomson & Jennifer C. Darnell & Peter C. Kind & Ka Wan Li, 2022. "Excess ribosomal protein production unbalances translation in a model of Fragile X Syndrome," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    3. Hanna Vihma & Kelin Li & Anna Welton-Arndt & Audrey L. Smith & Kiran R. Bettadapur & Rachel B. Gilmore & Eric Gao & Justin L. Cotney & Hsueh-Cheng Huang & Jon L. Collins & Stormy J. Chamberlain & Hyeo, 2024. "Ube3a unsilencer for the potential treatment of Angelman syndrome," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Junho Kim & August Yue Huang & Shelby L. Johnson & Jenny Lai & Laura Isacco & Ailsa M. Jeffries & Michael B. Miller & Michael A. Lodato & Christopher A. Walsh & Eunjung Alice Lee, 2022. "Prevalence and mechanisms of somatic deletions in single human neurons during normal aging and in DNA repair disorders," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    5. Chen Sun & Kunal Kathuria & Sarah B. Emery & ByungJun Kim & Ian E. Burbulis & Joo Heon Shin & Daniel R. Weinberger & John V. Moran & Jeffrey M. Kidd & Ryan E. Mills & Michael J. McConnell, 2024. "Mapping recurrent mosaic copy number variation in human neurons," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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