Biology subjects

Shah, R.

Publications and source records attributed to Shah, R..

4 recordsLinked to original sources

bioRxiv2018

Genetic variability in response to Aβ deposition influences Alzheimer’s risk

Genetic analysis of late-onset Alzheimers disease risk has previously identified a network of largely microglial genes that form a transcriptional network. In transgenic mouse models of amyloid deposition we have previously shown that the expression of many of the mouse orthologs of these genes are co-ordinately up-regulated by amyloid deposition. Here we investigate whether systematic analysis of other members of this mouse amyloid-responsive network predicts other Alzheimers risk loci. This statistical comparison of the mouse amyloid-response network with Alzheimers disease genome-wide association studies identifies 5 other genetic risk loci for the disease (OAS1, CXCL10, LAPTM5, ITGAM and LILRB4). This work suggests that genetic variability in the microglial response to amyloid deposition is a major determinant for Alzheimers risk.\n\nOne Sentence SummaryIdentification of 5 new risk loci for Alzheimers by statistical comparison of mouse A{beta} microglial response with gene-based SNPs from human GWAS

neuroscience↗

bioRxiv2018

Mathematical modelling reveals how MeCP2 restrains transcriptional elongation in human neurons

Patterns of gene expression are primarily determined by proteins that locally enhance or repress transcription. While many transcription factors target a restricted number of genes, others appear to modulate transcription levels globally. An example is MeCP2, an abundant methylated-DNA binding protein that is mutated in the neurological disorder Rett Syndrome. Despite much research, the molecular mechanism by which MeCP2 regulates gene expression is not fully resolved. Here we integrate quantitative, multi-dimensional experimental analysis and mathematical modelling to show that MeCP2 is a novel type of global transcriptional regulator whose binding to DNA creates "slow sites" in gene bodies. Waves of slowed-down RNA polymerase II formed behind these sites travel backward and indirectly affect initiation, reminiscent of defect-induced shock waves in non-equilibrium physics transport models. This mechanism differs from conventional gene regulation mechanisms, which often involve direct modulation of transcription initiation. Our findings uncover a genome-wide function of DNA methylation that may account for the reversibility of Rett syndrome in mice. Moreover, our combined theoretical and experimental approach provides a general method for understanding how global gene expression patterns are choreographed.

biophysics↗

bioRxiv2018

G-quadruplex DNA drives genomic instability and represents a targetable molecular abnormality in ATRX-deficient malignant glioma

Mutational inactivation of ATRX (-thalassemia mental retardation X-linked) represents a defining molecular alteration in large subsets of malignant glioma. Yet the pathogenic consequences of ATRX deficiency remain unclear, as do tractable mechanisms for its therapeutic targeting. Here we report that ATRX loss in isogenic glioma model systems induces replication stress and DNA damage by way of G-quadruplex (G4) DNA secondary structure. Moreover, these effects are associated with the acquisition of disease-relevant copy number alterations over time. We then demonstrate, both in vitro and in vivo, that ATRX deficiency selectively enhances DNA damage and cell death following chemical G4 stabilization. Finally, we show that G4 stabilization synergizes with other DNA-damaging therapies, including ionizing radiation, in the ATRX-deficient context. Our findings reveal novel pathogenic mechanisms driven by ATRX deficiency in glioma, while also pointing to tangible strategies for drug development.

cancer biology↗

bioRxiv2017

Signaling architectures that transmit unidirectional information despite retroactivity

A signaling pathway transmits information from an upstream system to downstream systems, ideally in a unidirectional fashion. A key obstacle to unidirectional transmission is retroactivity, the additional reaction flux that affects a system once its species interact with those of downstream systems. This raises the fundamental question of whether signaling pathways have developed specialized architectures that overcome retroactivity and transmit unidirectional signals. Here, we propose a general procedure based on mathematical analysis that provides an answer to this question. Using this procedure, we analyze the ability of a variety of signaling architectures to transmit one-way (from upstream to downstream) signals, as key biological parameters are tuned. We find that single stage phosphorylation and phosphotransfer systems that transmit signals from a kinase show a stringent design trade-off that hampers their ability to overcome retroactivity. Interestingly, cascades of these architectures, which are highly represented in nature, can overcome this trade-off and thus enable unidirectional transmission. By contrast, phosphotransfer systems, and single and double phosphorylation cycles that transmit signals from a substrate are unable to mitigate retroactivity effects, even when cascaded, and hence are not well suited for unidirectional information transmission. Our results identify signaling architectures that, allowing unidirectional transmission of signals, embody modular processes that conserve their input/output behavior across multiple contexts. These findings can be used to decompose natural signal transduction networks into modules, and, at the same time, they establish a library of devices that can be used in synthetic biology to facilitate modular circuit design.

biophysics↗