Biology subjects

Tav, C.

Publications and source records attributed to Tav, C..

3 recordsLinked to original sources

bioRxiv2026

Interplay of NuA4/TIP60 and PRC2 Complex Activities in Fusion Driven Endometrial Stromal Sarcoma

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.

cancer biology↗

bioRxiv2026

ZNF768 regulates expression of E2F1 protein to drive G0/G1 transition and cell cycle progression.

Accurate and tightly coordinated cell cycle progression and cell proliferation are critical for development, growth and homeostasis of an organism. Recently, Zinc finger protein 768 (ZNF768) was identified as a transcription factor driving cellular proliferation, in both a p53-dependent and independent manner. ZNF768 interacts with and represses p53 functions to limit cell cycle delay. Independently, ZNF768 promotes the transcription of key regulators of the cell cycle machinery, although the mechanisms through which this occurs remain unknown. Here, we report that ZNF768 protein levels are tightly regulated during the cell cycle, and its depletion leads to cell cycle exit and induction of quiescence. We found that ZNF768 modulates the cell cycle, at least in part, by controlling expression of the major pro-proliferative transcription factor E2F1 independently of p53 activation. Consequently, depletion of ZNF768, which also represses expression of the key mitotic transcription factor and E2F1 target FOXM1, leads to numerous mitotic errors. Supporting these findings, cancer genomics analyses reveal that ZNF768 expression levels are positively associated with E2F1 and FOXM1 expression levels in human tumors, suggesting that cancer cells might use ZNF768 to override cell cycle arrest, sustain proliferation, and promote cancer progression. Altogether, our results reveal that ZNF768 modulates cell cycle entry and proliferation, at least in part by regulating E2F1 expression.

cell biology↗

bioRxiv2024

TTF1 control of LncRNA synthesis and cell growth delineates a tumour suppressor pathway acting directly on the ribosomal RNA Genes

The tumour suppressor p14/19ARF regulates ribosomal RNA (rRNA) synthesis by controlling the nucleolar localization of Transcription Termination Factor 1 (TTF1). However, the role played by TTF1 in regulating the rRNA genes and in potentially controlling growth has remained unclear. We now show that TTF1 expression regulates cell growth by determining the cellular complement of ribosomes. Unexpectedly, it achieves this by acting as a "roadblock" to synthesis of the non-coding LncRNA and pRNA that we show are generated from the "Spacer Promoter" duplications present upstream of the 47S pre-rRNA promoter on the mouse and human ribosomal RNA genes. Unexpectedly, the endogenous generation of these non-coding RNAs does not induce CpG methylation or gene silencing. Rather, it acts in cis to suppress 47S preinitiation complex formation and hence de novo pre-rRNA synthesis by a mechanism reminiscent of promoter interference or occlusion. Taken together, our data delineate a pathway from p19ARF to cell growth suppression via the regulation of ribosome biogenesis by non-coding RNAs and validate a key cellular growth law in mammalian cells.

molecular biology↗