NSD2 overexpression drives clustered chromatin and transcriptional changes in a subset of insulated domains
| Autor: | Sourya Bhattacharyya, MacIntosh Cornwell, Theodore Sakellaropoulos, Aristotelis Tsirigos, Andreas Kloetgen, Sana Badri, Ferhat Ay, Priscillia Lhoumaud, Javier Rodriguez Hernaez, Jane A. Skok, Gunjan Sethia, Richard Bonneau |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
CCCTC-Binding Factor Chromosomal Proteins Non-Histone Science Gene Expression General Physics and Astronomy Myeloma Cell Cycle Proteins Chromosomal translocation Biology Chromatin structure Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Histone post-translational modifications Humans lcsh:Science Gene 030304 developmental biology Genomic organization Regulation of gene expression 0303 health sciences Binding Sites Multidisciplinary Cohesin Histone-Lysine N-Methyltransferase General Chemistry Chromatin Assembly and Disassembly Isogenic human disease models Gene regulation Chromatin Cell biology Gene Expression Regulation Neoplastic Repressor Proteins Logistic Models 030104 developmental biology CTCF 030220 oncology & carcinogenesis Histone methyltransferase lcsh:Q Multiple Myeloma |
| Zdroj: | Nature Communications Nature Communications, Vol 10, Iss 1, Pp 1-18 (2019) |
| ISSN: | 2041-1723 |
| Popis: | 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. In multiple myeloma, a 4;14 translocation induces overexpression of histone methyltransferase NSD2, resulting in expansion of H3K36me2 and shrinkage of H3K27me3 domains. Here the authors find that CTCF, H3K27ac and gene expression changes cluster within a subset of insulated domains implicating 3D chromosome organization as a key factor in the NSD2-mediated phenotype. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|