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bioRxiv · 10.1101/2024.10.04.616681

SATB2 and circ3915 RNA chromatin dysregulation drive KRAS-like oncogenic transformation

Eleazer, R.·George, S.·Shoemaker, L.·Saintilnord, W.·Lau, K.·Chandler, D.·Fondufe-Mittendorf, Y.
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Abstract

Even though epigenetic factors contribute to oncogenesis, most human cancer models still assume that disease originates from driver DNA mutations. Thus, it is still unclear if non-genetic mechanisms are sufficient to trigger malignant transformation. Special AT-rich binding protein 2 (SATB2) is a chromatin organizer that brings distal DNA elements into close proximity, thus remodeling chromatin structures to reprogram cell-specific and/or developmentally-sensitive gene networks. Here, we discover that SATB2 generates a co-expressed circ3915 RNA that is translated into a peptide and co-locates with SATB2 in the cell nucleus. Ectopic SATB2 or circ3915 over- expression rearranges global chromatin accessibility, generates KRAS- and NFE2L2-like oncogenic gene expression patterns, and transforms lung epithelial cells independent of driver mutations. Thus, oncogenic pathways can be activated in mammalian cells without pre-disposing mutations in oncogenes or epigenetic regulators. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC="FIGDIR/small/616681v1_ufig1.gif" ALT="Figure 1000"> View larger version (32K): org.highwire.dtl.DTLVardef@1314b69org.highwire.dtl.DTLVardef@14df9e1org.highwire.dtl.DTLVardef@505bddorg.highwire.dtl.DTLVardef@1bf3fab_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Eleazer, R., George, S., Shoemaker, L., Saintilnord, W., Lau, K., Chandler, D., Fondufe-Mittendorf, Y.. 2024-10-04. SATB2 and circ3915 RNA chromatin dysregulation drive KRAS-like oncogenic transformation. https://doi.org/10.1101/2024.10.04.616681

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