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 I. Cornwell, Sourya Bhattacharyya, Ferhat Ay, Richard Bonneau, Aristotelis Tsirigos, Jane A. Skok

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number4843
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Lhoumaud, P., Badri, S., Rodriguez-Hernaez, J., Sakellaropoulos, T., Sethia, G., Kloetgen, A., Cornwell, M. I., Bhattacharyya, S., Ay, F., Bonneau, R., Tsirigos, A., & Skok, J. A. (2019). NSD2 overexpression drives clustered chromatin and transcriptional changes in a subset of insulated domains. Nature communications, 10(1), [4843]. https://doi.org/10.1038/s41467-019-12811-4