Saturday, May 4, 2024
5/4/2024
ABSTRACT Inorganic arsenic (iAs) is an environmentally ubiquitous toxin that affects >100 million people worldwide, with health consequences ranging from acute toxicity to cancer. While iAs exposure can generate reactive oxygen species that damage DNA, a significant fraction of iAs-induced disease cannot be attributed to DNA lesions. We previously showed that iAs exposure remodels DNA and histone epigenetic marks in iAs-induced oncogenesis, and now know that iAs exposure also alters higher-order (3-dimensional, or 3D) chromatin structure. One of those structures involves a dynamic link between chromatin and the inner nuclear matrix, which brings distal genes into proximity with one another. This link is maintained by the SATB proteins; is necessary for proper gene regulation during cellular differentiation; and is disrupted by iAs exposure. SATB1 is a known oncogene, whereas SATB2 can either act as an oncogene or tumor suppressor depending on the cell type and gene environment. We recently discovered that during iAs-induced oncogenesis, SATB2 is upregulated and produces a novel, circular RNA (circSATB2) that “protects” linear SATB2 mRNA from degradation, possibly by interfering with a microRNA (miR31). The circSATB2 RNA is translated into a peptide (circSATB2p), and this peptide alters the native SATB2 interactome and gene expression profile. These data support the idea that transcriptional and post-translational, temporal control over SATB2 and chromatin higher-order structures are critical for coordinating normal cellular differentiation. They suggest that SATB2 is regulated by a novel circRNA-miRNA- mRNA regulatory axis. The objective of this project is therefore to determine exactly how iAs exposure regulates SATB2 expression and activity to promote oncogenesis. In Aim 1, we will test how SATB2 is regulated transcriptionally (via the circRNA-miR-mRNA pathway) and post-transcrionally (via regulation of the protein). In Aim 2, we will test how circSATB2p and SATB2 differentially regulate the 3D genome organization and nuclear integrity, and in Aim 3, we will test the role of circSATB2 in metastasis and tumorigenesis. These studies will identify the circSATB2-mirRNA-SATB2 gene regulatory axis, and establish that a novel SATB2 isoform switch drives iAs-induced oncogenesis. The mechanistic understanding of how iAs affects 3D chromatin structure and nuclear integrity will elucidate key (and novel) processes in chromatin biology, and contribute to a framework for developing diagnostics and targeted therapeutics for iAs-induced disease.
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