Pre-print on cardiomyocyte response to novel anti-cancer drug CX-5461 now published! Includes new gene expression response data at higher CX doses. Response to micromolar CX doses starts to mimic DOX responses, suggesting that off-target effects on the heart should be considered for this drug.
Together, we identified a drug-induced gene regulatory response propagated to the proteome that underlies early cardiotoxicity. We believe our multi-level network architecture provides insight into genetically mediated susceptibility to drug-induced stress. [6/6]
Integration of the protein network with GWAS across hundreds of CV traits identified a preserved protein module enriched for genetic risk of atrial fibrillation, PR interval, and longitudinal strain. This module also associates with impaired calcium handling in iPSC-CMs. [5/6]
The most preserved RNA module is enriched for p53 motifs in associated active regulatory regions and p53 target genes, which propagates to enrichment of p53 targets in the most drug-responsive preserved protein module. [4/6]
Integration with an RNA co-expression network generated from paired transcriptomic data revealed that the two most drug-responsive protein modules are preserved in the RNA network. [3/6]
We generated proteomics data from iPSC-CMs from 6 individuals treated with 3 anthracyclines across 2 timepoints. We constructed a co-expression network consisting of 19 modules. 4 modules contain proteins that respond to all drugs. [2/6]
Our latest work led by MD/PhD student Omar: βConserved RNA-protein modules link early anthracycline responses to atrial fibrillation riskβ. [1/6]
www.biorxiv.org/content/10.6...
Our results suggest an altered cell state following repair of double-strand breaks that is distinct from pre-exposed cells. DOX response genes with persistent changes in expression can be applied to the design of toxicity biomarkers or therapeutic targets. [6/6]
While chronic response genes are enriched for p53 target genes and DNA damage response genes, the majority of known DOX-toxicity associated genes are acute response genes. [5/6]
Concomitantly, thousands of genes respond acutely to DOX and return to baseline expression after DOX removal; however 501 genes show a chronic response. 163 of these genes become increasingly responsive over time. [4/6]
DNA damage, determined by Ξ³H2AX expression, is induced following DOX treatment and is resolved a week following DOX removal. [3/6]
Doxorubicin is known to induce cardiotoxicity in some cancer patients. To understand the long-term effects of cardiomyocyte exposure to DOX, we profiled the global gene expression response to DOX over time. [2/6]
Happy to share graduate student Emmaβs first paper: βProgressive suppression of DNA repair genes with persistent p53 activation in Doxorubicin-treated cardiomyocytesβ. [1/6] www.biorxiv.org/content/10.6...
We're hiring for multiple open rank positions in the broad areas of biochemistry, molecular biology, and computational biology. With the recruitment of a new chair our Departmental strengths now include nuclear architecture, genomics and ancient DNA.
jobs.sciencecareers.org/job/676677/b...
To showcase science youβre interested in seeing at ASHG26 in Montreal, submit a proposal for a Featured Symposium. Deadline is Jan 20th. Topics of interest include βevolutionary approaches to biological and clinical insights from phylogeny or recent human/primate lineages'.
Thank you to the reviewers for helping us focus and strengthen the manuscript, and the editors for a smooth publication process. [3/3]
We found large-scale rewiring of the chromatin landscape across related drugs that coincide with TOP2B binding, neighboring gene expression changes and loci associated with atrial fibrillation. [2/3]
Our preprint on chromatin accessibility changes in response to DNA-damaging agents in cardiomyocytes is now published. Congrats to Renee et al and two first time co-authors! [1/3]
journals.plos.org/plosgenetics...
Happy to be at ASHG!
2 students in the lab will present posters on gene regulatory evolution in primates on Thurs:
Emma focuses on responses to stimuli: 9109T
John focuses on transposable elements: 6036T
Please stop by if interested #ASHG25
We believe this work provides insight into the role of topoisomerase II beta in gene regulation, and cancer patient risk for cardiovascular disease. [4/4]
We compared the effects of CX and DOX in human cardiomyocytes. CX is 20-fold less toxic than DOX and induces an order of magnitude fewer changes in gene expression despite a shared target. However, CX-induced transcriptional changes are shared with DOX. [3/4]
DOX is an effective anti-cancer drug. However, it inhibits the DNA topology regulator topoisomerase II beta in the heart leading to increased risk for cardiovascular disease. CX-5461 is a promising novel anti-cancer compound that was recently shown to target the same protein. [2/4]
Project led by Sayan investigating the effects of CX-5461, an anti-cancer drug currently in clinical trials, on cardiomyocytes: βTopoisomerase II inhibitors CX-5461 and Doxorubicin differ in their cardiotoxicity profiles.β [1/4] www.biorxiv.org/content/10.1...
Happy to share our work led by Renee: βAnthracyclines induce global changes in cardiomyocyte chromatin accessibility that overlap with cardiovascular disease loci.β
www.biorxiv.org/content/10.1...
Congrats Anat, Nehal and Guy!
Congrats Ben!
Happy to share the published version of Omar & Sayanβs paper. We generated a DNA-damage-associated cardiomyocyte protein co-expression network to gain insights into tolerance to genetic variation and disease. www.sciencedirect.com/science/arti...
Congrats Tauras!
Come join us at #ASHG25 in Boston Oct 14-18! Abstract submission site (ashg.org/submit) is now live. Abstracts due June 9th.
