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

Priscillia Lhoumaud | Sana Badri | Javier Rodriguez-Hernaez | Theodore Sakellaropoulos | Gunjan Sethia | Andreas Kloetgen | MacIntosh Cornwell | Sourya Bhattacharyya | Ferhat Ay | Richard Bonneau | Aristotelis Tsirigos | Jane A Skok
Nature communications | 2019

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.

Pubmed ID: 31649247

Research resources used in this publication

None found

Antibodies used in this publication

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Associated grants

  • Agency: NIGMS NIH HHS, United States
    Id: R35 GM122515
  • Agency: NIGMS NIH HHS, United States
    Id: R35 GM128938

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