Biology subjects

Williams, R. S.

Publications and source records attributed to Williams, R. S..

3 recordsLinked to original sources

bioRxiv2025

Apathy as a Loss of Prior Precision on Action Outcomes

Apathy is common in neurological disease, associated with poor prognosis and limited treatments. Current models posit that goal-directed actions are reduced because costs or effort outweigh the expected reward. We highlight an alternative account of apathy, based on the reduction in precision of prior beliefs about action outcomes. In this preregistered study, we test the hypothesis that precision is encoded in the GABAergic gain of prefrontal superficial pyramidal neurons. Fifty healthy adults undertook a goal-directed task during magnetoencephalography. Estimates of synaptic efficacy or gain were obtained by dynamic causal modelling of induced responses. There was strong evidence of a negative correlation between prior precision and apathy (Bayes Factor=12, p<0.01), and that prior precision was associated with gain in prefrontal and premotor neuronal populations (Posterior probability>0.99). The importance of prior precision and GABAergic gain for goal-directed actions opens new avenues to advance the understanding and treatment of apathy.

neuroscience↗

bioRxiv2024

Topological regulation of the estrogen transcriptional response by ZATT-mediated inhibition of TOP2B activity

Human type-II topoisomerases, TOP2A and TOP2B, remove transcription associated DNA supercoiling, thereby affecting gene-expression programs, and have recently been associated with 3D genome architecture. Here, we study the regulatory roles of TOP2 paralogs in response to estrogen, which triggers an acute transcriptional induction that involves rewiring of genome organization. We find that, whereas TOP2A facilitates transcription, as expected for a topoisomerase, TOP2B limits the estrogen response. Consistent with this, TOP2B activity is locally downregulated upon estrogen treatment to favor the establishment and stabilization of regulatory chromatin contacts, likely through an accumulation of DNA supercoiling. We show that estrogen-mediated inhibition of TOP2B requires estrogen receptor (ER), a non-catalytic function of TOP2A, and the action of the atypical SUMO-ligase ZATT. This mechanism of topological transcriptional-control, which may be shared by additional gene-expression circuits, highlights the relevance of DNA topoisomerases as central actors of genome dynamics.

molecular biology↗

bioRxiv2019

A genetic map of the response to DNA damage in human cells

The response to DNA damage is critical for cellular homeostasis, tumor suppression, immunity and gametogenesis. In order to provide an unbiased and global view of the DNA damage response in human cells, we undertook 28 CRISPR/Cas9 screens against 25 genotoxic agents in the retinal pigment epithelium-1 (RPE1) cell line. These screens identified 840 genes whose loss causes either sensitivity or resistance to DNA damaging agents. Mining this dataset, we uncovered that ERCC6L2, which is mutated in a bone-marrow failure syndrome, codes for a canonical non-homologous end-joining pathway factor; that the RNA polymerase II component ELOF1 modulates the response to transcription-blocking agents and that the cytotoxicity of the G-quadruplex ligand pyridostatin involves trapping topoisomerase II on DNA. This map of the DNA damage response provides a rich resource to study this fundamental cellular system and has implications for the development and use of genotoxic agents in cancer therapy.

cancer biology↗