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 and Jane A. Skok ()
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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
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
Ferhat Ay: La Jolla Institute for Immunology
Richard Bonneau: Center for Genomics and Systems Biology, NYU
Aristotelis Tsirigos: New York University Langone Health
Jane A. Skok: New York University Langone Health

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12811-4

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