Biology subjects

Stockley, J.

Publications and source records attributed to Stockley, J..

2 recordsLinked to original sources

bioRxiv2022

HNRNPA2B1 controls an unfolded protein response-related prognostic gene signature in prostate cancer

HNRNPA2B1 is associated with prostate cancer (PC) disease aggressiveness and underlies pro-tumourigenic cellular stress responses. By analysing >500 PC transcriptomes, we reveal that HNRNPA2B1 over-expression is associated with poor patient prognosis and stress response pathways. These include the "protein processing in the endoplasmic reticulum" (ER) pathway, which incorporates the unfolded protein response (UPR). By RNA-sequencing of HNRNPA2B1-depleted cells PC cells, we identified HNRNPA2B1-mediated down-regulation of UPR genes including the master ER-stress sensor IRE1, which induces ER proteostasis. Consistent with IRE1 down-regulation in HNRNPA2B1-depleted cells, we observed reduced splicing of the IRE1-target and key UPR effector XBP1s. Furthermore, HNRNPA2B1 depletion up-regulates expression of the IRE1-dependent decay (RIDD) target gene BLOC1S1, which is degraded by activated IRE1. We identify a HNRNPA2B1-IRE1-XBP1-controlled four gene prognostic biomarker signature (HIX) which classifies a subgroup of primary PC patients at high risk of disease relapse. Pharmacological targeting of IRE1 attenuated HNRNAPA2-driven PC cell growth. Taken together, our data reveal a putative novel mechanism of UPR activation in PC by HNRNPA2B1, which may promote an IRE1-dependent yet potentially-targetable recurrent disease phenotype.

cancer biology↗

bioRxiv2018

Single-cell in situ transcriptomic map of astrocyte cortical layer diversity

During organogenesis, patterns and gradients of gene expression underlie organization and diversified cell specification to generate complex tissue architecture. While the cerebral cortex is organized into six excitatory neuronal layers, it is unclear whether glial cells are diversified to mimic neuronal laminae or show distinct layering. To determine the molecular architecture of the mammalian cortex, we developed a high content pipeline that can quantify single-cell gene expression in situ. The Large-area Spatial Transcriptomic (LaST) map confirmed expected cortical neuron layer organization and also revealed a novel neuronal identity signature. Screening 46 candidate genes for astrocyte diversity across the cortex, we identified grey matter superficial, mid and deep astrocyte identities in gradient layer patterns that were distinct from neurons. Astrocyte layers formed in early postnatal cortex and mostly persisted in adult mouse and human cortex. Mutations that shifted neuronal post-mitotic identity or organization were sufficient to alter glial layering, indicating an instructive role for neuronal cues. In normal mouse cortex, astrocyte layer patterns showed area diversity between functionally distinct cortical regions. These findings indicate that excitatory neurons and astrocytes cells are organized into distinct lineage-associated laminae, which give rise to higher order neuroglial complexity of cortical architecture.

neuroscience↗