Biology subjects

Fay, M. M.

Publications and source records attributed to Fay, M. M..

4 recordsLinked to original sources

bioRxiv2023

RxRx3: Phenomics Map of Biology

The combination of modern genetic perturbation techniques with high content screening has enabled genome-scale cell microscopy experiments that can be leveraged to construct maps of biology. These are built by processing microscopy images to produce readouts in unified and relatable representation space to capture known biological relationships and discover new ones. To further enable the scientific community to develop methods and insights from map-scale data, here we release RxRx3, the first ever public high-content screening dataset combining genome-scale CRISPR knockouts with multiple-concentration screening of small molecules (a set of FDA approved and commercially available bioactive compounds). The dataset contains 6-channel fluorescent microscopy images and associated deep learning embeddings from over 2.2 million wells that span 17,063 CRISPR knockouts and 1,674 compounds at 8 doses each. RxRx3 is one of the largest collections of cellular screening data, and as far as we know, the largest generated consistently via a common experimental protocol within a single laboratory. Our goal in releasing RxRx3 is to demonstrate the benefits of generating consistent data, enable the development of the machine learning methods on this scale of data and to foster research, methods development, and collaboration. For more information about RxRx3 please visit RxRx.ai/rxrx3

systems biology↗

bioRxiv2021

Mechanisms of translation inhibition and suppression of Stress Granule formation by cisplatin

Platinum-based antineoplastic drugs, such as cisplatin, are commonly used to induce tumor cell death. Cisplatin is believed to induce apoptosis as a result of cisplatin-DNA adducts that inhibit DNA and RNA synthesis. Although idea that DNA damage underlines anti-proliferative effects of cisplatin is dominant in cancer research, there is a poor correlation between the degree of the cell sensitivity to cisplatin and the extent of DNA platination. Here, we propose a novel mechanism of cisplatin-mediated cytotoxicity. We show that cisplatin suppresses formation of Stress Granules (SGs), pro-survival RNA granules with multiple roles in cellular metabolism. Mechanistically, cisplatin inhibits cellular translation to promote disassembly of polysomes and aggregation of ribosomal subunits. As SGs are in equilibrium with polysomes, cisplatin-induced shift towards ribosomal aggregation suppresses SG formation and promotes cellular death. Our data also explain nephrotoxic, neurotoxic and ototoxic effects of cisplatin treatment.

cell biology↗

bioRxiv2019

Multiple ribonuclease A family members cleave transfer RNAs in response to stress

During stress, changes in gene expression are critical for cell survival. Stress-induced tRNA cleavage has been implicated in various cellular processes, where tRNA fragments play diverse regulatory roles. Angiogenin (ANG), a member of the RNase A superfamily, induces cleavage of tRNAs resulting in the formation of tRNA-derived stress-induced RNAs (tiRNAs) that contribute to translational reprogramming aiming at cell survival. The role of other stress-induced RNases in tRNA cleavage is poorly understood. Using gene editing and biochemical approaches, we show that other members of the RNase A family are capable of targeting tRNAs in stress-responsive manner. We show that in the absence of ANG, these RNases also promote the production of tiRNAs. Moreover, specific stresses (such as treatment with sodium arsenite) activate cleavage of universal 3-CCA termini of tRNAs in ANG-independent fashion in living cells. We conclude that multiple RNase A family members are capable of targeting tRNAs in a stress-specific manner in vivo.

molecular biology↗

bioRxiv2019

Bisphenol A promotes stress granule assembly and modulates the integrated stress response

Bisphenol-A (BPA) is a ubiquitous precursor of polycarbonate plastics that is found in the blood and serum of >92% of Americans. While BPA has been well documented to act as a weak estrogen receptor (ER) agonist, its effects on cellular stress are unclear. Here, we demonstrate that high-dose BPA causes stress granules (SGs) in human cells. A common estrogen derivative, {beta}-estradiol, does not trigger SGs, indicating the mechanism of SG induction is not via the ER pathway. We also tested other structurally related environmental contaminants including the common BPA substitutes BPS and BPF, the industrial chemical 4-nonylphenol (4-NP) and structurally related compounds 4-EP and 4-VP, and the pesticide 2,4-dichlorophenoxyacetic acid (2,4-D). The variable results from these related compounds suggest that structural homology is not a reliable predictor of the capacity of a compound to cause SGs. Also, we demonstrate that BPA acts primarily through the PERK pathway to generate canonical SGs. Finally, we show that chronic exposure to a low physiologically relevant dose of BPA disrupts SG assembly by inhibiting SGs upon additional acute stress. Our work identifies additional effects of BPA beyond endocrine disruption that may have consequences for human health.

cell biology↗