Biology subjects

Clifton, S.

Publications and source records attributed to Clifton, S..

3 recordsLinked to original sources

bioRxiv2021

Epigenetic therapy suppresses endocrine-resistant breast tumour growth by re-wiring ER-mediated 3D chromatin interactions

Three-dimensional (3D) epigenome remodelling is an important mechanism of gene deregulation in cancer. However, its potential as a target to overcome therapy resistance remains largely unaddressed. Here we show that FDA-approved epigenetic therapy Decitabine (5-Aza-mC) suppresses tumour growth in preclinical metastatic ER+ breast tumour xenograft models. Decitabine-induced genome-wide DNA hypomethylation results in large-scale 3D epigenome deregulation, including de-compaction of higher order chromatin structure and loss of topologically associated domain boundary insulation. Significant DNA hypomethylation at ER-enhancer elements was associated with gain in ER binding, creation of ectopic 3D enhancer-promoter interactions and concordant activation of ER-mediated transcription pathways. Importantly long-term withdrawal of epigenetic therapy partially restores methylation at ER-enhancer elements, resulting in loss of ectopic 3D enhancer-promoter interactions and associated gene repression. Our study illustrates how epigenetic therapy has potential to target ER+ endocrine-resistant breast cancer by DNA methylation-dependent rewiring of 3D chromatin interactions associated with suppression of tumour growth.

molecular biology↗

bioRxiv2019

Modeling the control of bacterial infections via antibiotic-induced proviruses

Most bacteria and archaea are infected by latent viruses that change their physiology and responses to environmental stress. We use a population model of the bacteria-phage relationship to examine the role that latent phage play on the bacterial population over time in response to antibiotic treatment. We demonstrate that the stress induced by antibiotic administration, even if bacteria are resistant to killing by antibiotics, is sufficient to control the infection under certain conditions. This work expands the breadth of understanding of phage-antibiotic synergy to include both temperate and chronic viruses persisting in their latent form in bacterial populations.\n\nImportanceAntibiotic-resistance is a growing concern for management of common bacterial infections. Here we show that antibiotics can be effective at sub-inhibitory levels when bacteria carry latent phage. Our findings suggest that specific treatment strategies based on the identification of latent viruses in individual bacterial strains may be an effective personalized medicine approach to antibiotic stewardship.

ecology↗

bioRxiv2018

Enzyme Immunoassays May Be Inaccurate: Familiar Correlates of Male Testosterone (T) Replicate in Britons when T is Measured by Mass Spectrometry but Do Not Replicate in Americans When T is Measured by Enzyme Immunoassay

Several correlations have been reported between mens testosterone (T) and other characteristics, e.g., T declines during the day, declines with obesity, and declines with advancing age. We asked if these relationships hold in older men when T is assayed from saliva. Here seven familiar correlations are tested among older American men, their salivary T measured by enzyme immunoassay (EIA). Some correlations can also be tested among older British men, their salivary T assayed by liquid chromatography-tandem mass spectroscopy (LC-MS/MS), a technique noted for its specificity. Most of our attempts at replication failed in the American data but succeeded in the British data. We conclude that failure to replicate in Americans is likely due to inaccuracy of EIA values for T, and that most T correlations hold true in older men when salivary T is accurately measured by LC-MS/MS.

physiology↗