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

Abstract

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.

NSD2 Promotes Tumor Angiogenesis Through Methylating and Activating STAT3 Signaling

“…Mounting evidence suggests that NSD2 plays a key role in tumorigenesis and tumor progression [38][39][40][41][42][43][44].…”

Epigenetic regulation in human cancer: the potential role of epi-drug in cancer therapy

“…Even one type of histone alteration can affect other histone marks. For example, H3K36me2 expansion caused by NSD2 overexpression in multiple myeloma favored the enrichment of H3K27ac and interactions with other regulatory elements, thus activating oncogenic pathways [59]. Increasing evidence supported that abnormal epigenetic changes may either arise stochastically or be driven by transcriptional program, indicating that the mutations in key elements of epigenetic regulation (e.g.…”

Chromosome structural variation in tumorigenesis: mechanisms of formation and carcinogenesis

“…Second, the disruption or overexpression of genes involved in methylation (e.g., DNMTs, and NSD2 ) is involved in DNA methylation alterations in structural variation. The overexpression of epigenetic factors resulting from structural variants is also associated with changes in the 3D chromosome structure [ 114 , 115 ]. For example, overexpression of histone methyltransferase, NSD2, is induced in multiple myeloma (MM) with t(4;14), leading to changes in the 3D organization (including A/B compartmentalization and TADs) involving chromatin modifications such as the expansion of H3K36me2 [ 115 ].…”

“…The overexpression of epigenetic factors resulting from structural variants is also associated with changes in the 3D chromosome structure [ 114 , 115 ]. For example, overexpression of histone methyltransferase, NSD2, is induced in multiple myeloma (MM) with t(4;14), leading to changes in the 3D organization (including A/B compartmentalization and TADs) involving chromatin modifications such as the expansion of H3K36me2 [ 115 ]. Subsequently, expansion of H3K36me2 outside of active gene bodies increases chromatin accessibility to favor transcription factors and CTCF binding, thereby altering gene expression [ 115 ].…”