Biology subjects

Mobley, R. J.

Publications and source records attributed to Mobley, R. J..

3 recordsLinked to original sources

bioRxiv2023

Epigenomic mapping in B-cell acute lymphoblastic leukemia identifies transcriptional regulators and noncoding variants promoting distinct chromatin architectures

B-cell lineage acute lymphoblastic leukemia (B-ALL) is comprised of diverse molecular subtypes and while transcriptional and DNA methylation profiling of B-ALL subtypes has been extensively examined, the accompanying chromatin landscape is not well characterized for many subtypes. We therefore mapped chromatin accessibility using ATAC-seq for 10 B-ALL molecular subtypes in primary ALL cells from 154 patients. Comparisons with B-cell progenitors identified candidate B-ALL cell-of-origin and AP-1-associated cis-regulatory rewiring in B-ALL. Cis-regulatory rewiring promoted B-ALL-specific gene regulatory networks impacting oncogenic signaling pathways that perturb normal B-cell development. We also identified that over 20% of B-ALL accessible chromatin sites exhibit strong subtype enrichment, with transcription factor (TF) footprint profiling identifying candidate TFs that maintain subtype-specific chromatin architectures. Over 9000 inherited genetic variants were further uncovered that contribute to variability in chromatin accessibility among individual patient samples. Overall, our data suggest that distinct chromatin architectures are driven by diverse TFs and inherited genetic variants which promote unique gene regulatory networks that contribute to transcriptional differences among B-ALL subtypes. HIGHLIGHTSO_LIPro-B progenitor cells as the most common cell-of-origin for B-ALL C_LIO_LIAP-1 TF-associated cis-regulatory rewiring in B-ALL C_LIO_LISubtype-specific accessible chromatin signatures representing 20% of all B-ALL sites C_LIO_LIRole for distinct TFs in promoting subtype-specific chromatin architectures C_LIO_LIThousands of inherited genetic variants identified impacting chromatin state C_LI

cancer biology↗

bioRxiv2023

Mutual antagonism between glucocorticoid and canonical Wnt signaling pathways in B-cell acute lymphoblastic leukemia

Glucocorticoids (GCs; i.e., steroids) are important chemotherapeutic agents in the treatment of B-cell precursor acute lymphoblastic leukemia (B-ALL) and de novo GC resistance predicts relapse and poor clinical outcome in patients. Glucocorticoids induce B-ALL cell apoptosis through activation of glucocorticoid receptor (GR), a ligand-induced nuclear receptor transcription factor (TF). We previously identified disruptions to glucocorticoid receptor (GR)-bound cis-regulatory elements controlling TLE1 expression in GC-resistant primary B-ALL cells from patients. TLE1 is a GC-response gene up-regulated by steroids and functions as a canonical Wnt signaling repressor. To better understand the mechanistic relationship between GC signaling and canonical Wnt signaling, we performed diverse functional analyses that identified extensive crosstalk and mutual antagonism between these two signaling pathways in B-ALL. We determined that crosstalk and antagonism was driven by the binding of GR and the canonical Wnt signaling TFs LEF1 and TCF7L2 to overlapping sets of cis-regulatory elements associated with genes impacting cell death and cell proliferation, and was further accompanied by overlapping and opposing transcriptional programs. Our data additionally suggest that cis-regulatory disruptions at TLE1 are linked to GC resistance through a dampening of the GC response and GC-mediated apoptosis via enhanced canonical Wnt signaling. As a result of the extensive genomic and gene regulatory connectivity between these two signaling pathways, our data supports the importance of canonical Wnt signaling in mediating GC resistance in B-ALL.

cancer biology↗

bioRxiv2022

Functional interplay between SWI/SNF complexes underlies BRD9 dependency in SMARCB1-mutant cancers

Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are mutated in >20% of cancers. SWI/SNF complexes exist in three distinct families that each contribute to regulation of transcription, although the functional interactions between the families are not well understood. Rhabdoid tumors constitute an informative model system as these highly aggressive cancers are driven by inactivation of a single SWI/SNF subunit, SMARCB1, which is present in two SWI/SNF families (cBAF and PBAF) but not in the third (GBAF/ncBAF). We and others have shown that BRD9, a therapeutically targetable member of ncBAF, is essential specifically in SMARCB1-deficient cancers, suggesting key functional relationships between SMARCB1-containing complexes and BRD9/ncBAF. However, the mechanistic underpinnings of these relationships are poorly understood. Here, we demonstrate that genomic binding of BRD9 is largely dependent upon SMARCB1 such that the absence of SMARCB1 results in significantly reduced BRD9 binding. At select sites, however, we show that SMARCB1-loss results in gain of BRD9 binding and BRD9-dependent accessibility. We find that this gain is associated with expression of genes promoting cell migration. Our results define relationships between SWI/SNF complex families, elucidate mechanisms by which SMARCB1 loss drives oncogenesis, and provide mechanistic insight into the synthetic-lethal relationship between SMARCB1 and BRD9.

cancer biology↗