Interplay of NuA4/TIP60 and PRC2 Complex Activities in Fusion Driven Endometrial Stromal Sarcoma
- 1Laval University
Abstract
Low-grade endometrial stromal sarcoma (LGESS) exhibits frequent chromosomal translocations that fuse various subunits of the NuA4/TIP60 co-activator complex to subunits of the Polycomb Repressive Complex 2 (PRC2) complex. LGESS fusion proteins, such as the commonly occurring JAZF1-SUZ12, have been shown to upregulate genes through mislocalization of NuA4/TIP60 activity to Polycomb target genes. In this study, we characterized an interesting recurrent fusion protein in LGESS that fused a NuA4/TIP60 component, MBTD1, to EZHIP. EZHIP is a recently described vertebrate protein that enzymatically inhibits methyltransferase activity of the PRC2 complex and is a potent oncogene. The MBTD1-EZHIP fusion protein forms a chimeric TIP60-PRC2.1 complex and drastically reduces H3K27me3 levels at Polycomb target genes, similar to EZHIP-overexpressing cancers. However, unlike EZHIP overexpression, MBTD1-EZHIP requires mislocalization of NuA4/TIP60 activity through the MBTD1 protein to upregulate oncogenes. Despite differences in the finer molecular mechanisms, MBTD1-EZHIP and the common JAZF1-SUZ12 fusion protein upregulated similar sets of genes in cell lines, showing a convergence of oncogenic gene expression. Surprisingly, unlike in cellular models, JAZF1-SUZ12 translocated patient samples showed not only upregulation of genes driven by increased H4K8ac and decreased H3K27me3 but also downregulation of specific genes due to accumulated H3K27me3, revealing an additional oncogenic mechanism in LGESS.
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BibTeX
@misc{sudarshan2026interplay,
title = {{Interplay of NuA4/TIP60 and PRC2 Complex Activities in Fusion Driven Endometrial Stromal Sarcoma}},
author = {D. Sudarshan and C. Joly-Beauparlant and S. Bianco and C. Lachance and M. Le Goff and N. Alerasool and E. Gregoire and L. Hermann and C. Tav and J.-P. Lambert and M. Q. Bernardini and A. Droit and M. Taipale and J. Cote},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.04.749526},
url = {https://www.biorxiv.org/content/10.64898/2026.09.04.749526v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Interplay of NuA4/TIP60 and PRC2 Complex Activities in Fusion Driven Endometrial Stromal Sarcoma
AU - D. Sudarshan
AU - C. Joly-Beauparlant
AU - S. Bianco
AU - C. Lachance
AU - M. Le Goff
AU - N. Alerasool
AU - E. Gregoire
AU - L. Hermann
AU - C. Tav
AU - J.-P. Lambert
AU - M. Q. Bernardini
AU - A. Droit
AU - M. Taipale
AU - J. Cote
PY - 2026
DA - 2026/09/04
PB - bioRxiv
DO - 10.64898/2026.09.04.749526
UR - https://www.biorxiv.org/content/10.64898/2026.09.04.749526v1
AB - Low-grade endometrial stromal sarcoma (LGESS) exhibits frequent chromosomal translocations that fuse various subunits of the NuA4/TIP60 co-activator complex to subunits of the Polycomb Repressive Complex 2 (PRC2) complex. LGESS fusion proteins, such as the commonly occurring JAZF1-SUZ12, have been shown to upregulate genes through mislocalization of NuA4/TIP60 activity to Polycomb target genes. In this study, we characterized an interesting recurrent fusion protein in LGESS that fused a NuA4/TIP60 component, MBTD1, to EZHIP. EZHIP is a recently described vertebrate protein that enzymatically inhibits methyltransferase activity of the PRC2 complex and is a potent oncogene. The MBTD1-EZHIP fusion protein forms a chimeric TIP60-PRC2.1 complex and drastically reduces H3K27me3 levels at Polycomb target genes, similar to EZHIP-overexpressing cancers. However, unlike EZHIP overexpression, MBTD1-EZHIP requires mislocalization of NuA4/TIP60 activity through the MBTD1 protein to upregulate oncogenes. Despite differences in the finer molecular mechanisms, MBTD1-EZHIP and the common JAZF1-SUZ12 fusion protein upregulated similar sets of genes in cell lines, showing a convergence of oncogenic gene expression. Surprisingly, unlike in cellular models, JAZF1-SUZ12 translocated patient samples showed not only upregulation of genes driven by increased H4K8ac and decreased H3K27me3 but also downregulation of specific genes due to accumulated H3K27me3, revealing an additional oncogenic mechanism in LGESS.
ER -