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

May 28, 2019
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Received Date: 14th May 19

CTCF and cohesin play a key role in organizing chromatin into 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, we find oncogene activation is linked to alterations in H3K27ac and CTCF within H3K36me2 enriched chromatin. A linear regression model reveals that changes in both CTCF and/or H3K27ac significantly increase the probability that a gene sharing the same insulated domain will be differentially expressed. These results identify a bidirectional relationship between 2D chromatin and 3D genome organization in gene regulation.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

Nature Communications

Nature Research, Springer Nature