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NSD2 overexpression drives clustered chromatin and transcriptional changes in a subset of insulated domains

Author

Listed:
  • Priscillia Lhoumaud

    (New York University Langone Health)

  • Sana Badri

    (New York University Langone Health)

  • Javier Rodriguez-Hernaez

    (New York University Langone Health)

  • Theodore Sakellaropoulos

    (New York University Langone Health
    NYU School of Medicine)

  • Gunjan Sethia

    (New York University Langone Health)

  • Andreas Kloetgen

    (New York University Langone Health)

  • MacIntosh Cornwell

    (New York University Langone Health)

  • Sourya Bhattacharyya

    (La Jolla Institute for Immunology
    University of California, San Diego)

  • Ferhat Ay

    (La Jolla Institute for Immunology
    University of California, San Diego)

  • Richard Bonneau

    (Center for Genomics and Systems Biology, NYU)

  • Aristotelis Tsirigos

    (New York University Langone Health
    NYU School of Medicine)

  • Jane A. Skok

    (New York University Langone Health
    NYU School of Medicine)

Abstract

CTCF and cohesin play a key role in organizing chromatin into topologically associating domain (TAD) structures. Disruption of a single CTCF binding site is sufficient to change chromosomal interactions leading to alterations in chromatin modifications and gene regulation. However, the extent to which alterations in chromatin modifications can disrupt 3D chromosome organization leading to transcriptional changes is unknown. In multiple myeloma, a 4;14 translocation induces overexpression of the histone methyltransferase, NSD2, resulting in expansion of H3K36me2 and shrinkage of antagonistic H3K27me3 domains. Using isogenic cell lines producing high and low levels of NSD2, here we find oncogene activation is linked to alterations in H3K27ac and CTCF within H3K36me2 enriched chromatin. A logistic regression model reveals that differentially expressed genes are significantly enriched within the same insulated domain as altered H3K27ac and CTCF peaks. These results identify a bidirectional relationship between 2D chromatin and 3D genome organization in gene regulation.

Suggested Citation

  • Priscillia Lhoumaud & Sana Badri & Javier Rodriguez-Hernaez & Theodore Sakellaropoulos & Gunjan Sethia & Andreas Kloetgen & MacIntosh Cornwell & Sourya Bhattacharyya & Ferhat Ay & Richard Bonneau & Ar, 2019. "NSD2 overexpression drives clustered chromatin and transcriptional changes in a subset of insulated domains," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12811-4
    DOI: 10.1038/s41467-019-12811-4
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    Cited by:

    1. Yael Aylon & Noa Furth & Giuseppe Mallel & Gilgi Friedlander & Nishanth Belugali Nataraj & Meng Dong & Ori Hassin & Rawan Zoabi & Benjamin Cohen & Vanessa Drendel & Tomer Meir Salame & Saptaparna Mukh, 2022. "Breast cancer plasticity is restricted by a LATS1-NCOR1 repressive axis," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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