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Article: Deleteome-Tools: Utilizing a compendium of yeast deletion strain transcriptomes to identify co-functional genes.

Neal, Maxwell L / Choudhry, Sanjeev K / Aitchison, John D

bioRxiv : the preprint server for biology

2024

Abstract: We developed an R codebase that uses a publicly-available compendium of transcriptomes from yeast single-gene deletion strains - the Deleteome - to predict gene function. Primarily, the codebase provides functions for identifying similarities between the ...

Abstract	We developed an R codebase that uses a publicly-available compendium of transcriptomes from yeast single-gene deletion strains - the Deleteome - to predict gene function. Primarily, the codebase provides functions for identifying similarities between the transcriptomic signatures of deletion strains, thereby associating genes of interest with others that may be functionally related. We describe how our tool predicted a novel relationship between the yeast nucleoporin Nup170 and the Ctf18-RFC complex, which was confirmed experimentally, revealing a previously unknown link between nuclear pore complexes and the DNA replication machinery. We also discuss how our strategy for quantifying similarity between deletion strains differs from other approaches and why it has the potential to identify functional relationships that similar approaches may not. Deleteome-Tools is implemented in R and is freely available at https://github.com/AitchisonLab/Deleteome-Tools .
Language	English
Publishing date	2024-02-08
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.05.578946
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Article: Predicting host-based, synthetic lethal antiviral targets from omics data.

Staheli, Jeannette P / Neal, Maxwell L / Navare, Arti / Mast, Fred D / Aitchison, John D

bioRxiv : the preprint server for biology

2023

Abstract: Traditional antiviral therapies often have limited effectiveness due to toxicity and development of drug resistance. Host-based antivirals, while an alternative, may lead to non-specific effects. Recent evidence shows that virus-infected cells can be ... ...

Abstract	Traditional antiviral therapies often have limited effectiveness due to toxicity and development of drug resistance. Host-based antivirals, while an alternative, may lead to non-specific effects. Recent evidence shows that virus-infected cells can be selectively eliminated by targeting synthetic lethal (SL) partners of proteins disrupted by viral infection. Thus, we hypothesized that genes depleted in CRISPR KO screens of virus-infected cells may be enriched in SL partners of proteins altered by infection. To investigate this, we established a computational pipeline predicting SL drug targets of viral infections. First, we identified SARS-CoV-2-induced changes in gene products via a large compendium of omics data. Second, we identified SL partners for each altered gene product. Last, we screened CRISPR KO data for SL partners required for cell viability in infected cells. Despite differences in virus-induced alterations detected by various omics data, they share many predicted SL targets, with significant enrichment in CRISPR KO-depleted datasets. Comparing data from SARS-CoV-2 and influenza infections, we found possible broad-spectrum, host-based antiviral SL targets. This suggests that CRISPR KO data are replete with common antiviral targets due to their SL relationship with virus-altered states and that such targets can be revealed from analysis of omics datasets and SL predictions.
Language	English
Publishing date	2023-08-16
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.15.553430
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Article ; Online: SUMOylation at the inner nuclear membrane facilitates nuclear envelope biogenesis during mitosis.

Saik, Natasha O / Ptak, Christopher / Rehman, Saif / Aitchison, John D / Montpetit, Ben / Wozniak, Richard W

The Journal of cell biology

2023 Volume 222, Issue 8

Abstract: As eukaryotic cells progress through cell division, the nuclear envelope (NE) membrane must expand to accommodate the formation of progeny nuclei. In Saccharomyces cerevisiae, closed mitosis allows visualization of NE biogenesis during mitosis. During ... ...

Abstract	As eukaryotic cells progress through cell division, the nuclear envelope (NE) membrane must expand to accommodate the formation of progeny nuclei. In Saccharomyces cerevisiae, closed mitosis allows visualization of NE biogenesis during mitosis. During this period, the SUMO E3 ligase Siz2 binds the inner nuclear membrane (INM) and initiates a wave of INM protein SUMOylation. Here, we show these events increase INM levels of phosphatidic acid (PA), an intermediate of phospholipid biogenesis, and are necessary for normal mitotic NE membrane expansion. The increase in INM PA is driven by the Siz2-mediated inhibition of the PA phosphatase Pah1. During mitosis, this results from the binding of Siz2 to the INM and dissociation of Spo7 and Nem1, a complex required for the activation of Pah1. As cells enter interphase, the process is then reversed by the deSUMOylase Ulp1. This work further establishes a central role for temporally controlled INM SUMOylation in coordinating processes, including membrane expansion, that regulate NE biogenesis during mitosis.
MeSH term(s)	Cell Nucleus/metabolism ; Mitosis ; Nuclear Envelope/metabolism ; Nuclear Proteins/metabolism ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Sumoylation ; Organelle Biogenesis
Chemical Substances	Nem1 protein, S cerevisiae ; Nuclear Proteins ; Saccharomyces cerevisiae Proteins ; Siz2 protein, S cerevisiae ; ULP1 protein, S cerevisiae (EC 3.4.22.68) ; SPO7 protein, S cerevisiae ; PAH1 protein, S cerevisiae (EC 3.1.3.4)
Language	English
Publishing date	2023-07-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.202208137
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Article: Autophagy as a Mechanism for Adaptive Prediction-Mediated Emergence of Drug Resistance.

Nivedita, Nivedita / Aitchison, John D / Baliga, Nitin S

Frontiers in microbiology

2021 Volume 12, Page(s) 712631

Abstract: Drug resistance is a major problem in treatment of microbial infections and cancers. There is growing evidence that a transient drug tolerant state may precede and potentiate the emergence of drug resistance. Therefore, understanding the mechanisms ... ...

Abstract	Drug resistance is a major problem in treatment of microbial infections and cancers. There is growing evidence that a transient drug tolerant state may precede and potentiate the emergence of drug resistance. Therefore, understanding the mechanisms leading to tolerance is critical for combating drug resistance and for the development of effective therapeutic strategy. Through laboratory evolution of yeast, we recently demonstrated that adaptive prediction (AP), a strategy employed by organisms to anticipate and prepare for a future stressful environment, can emerge within 100 generations by linking the response triggered by a neutral cue (caffeine) to a mechanism of protection against a lethal agent (5-fluoroorotic acid, 5-FOA). Here, we demonstrate that mutations selected across multiple laboratory-evolved lines had linked the neutral cue response to core genes of autophagy. Across these evolved lines, conditional activation of autophagy through AP conferred tolerance, and potentiated subsequent selection of mutations in genes specific to overcoming the toxicity of 5-FOA. These results offer a new perspective on how extensive genome-wide genetic interactions of autophagy could have facilitated the emergence of AP over short evolutionary timescales to potentiate selection of 5-FOA resistance-conferring mutations.
Language	English
Publishing date	2021-09-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587354-4
ISSN	1664-302X
ISSN	1664-302X
DOI	10.3389/fmicb.2021.712631
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Article: Automated, image-based quantification of peroxisome characteristics with

Neal, Maxwell L / Shukla, Nandini / Mast, Fred D / Farré, Jean-Claude / Pacio, Therese M / Raney-Plourde, Katelyn E / Prasad, Sumedh / Subramani, Suresh / Aitchison, John D

bioRxiv : the preprint server for biology

2024

Abstract: perox-per- ... ...

Abstract	perox-per-cell
Language	English
Publishing date	2024-04-12
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.08.588597
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Article ; Online: ODELAM: Rapid Sequence-independent Detection of Drug Resistance in

Herricks, Thurston / Donczew, Magdalena / Sherman, David R / Aitchison, John D

Bio-protocol

2021 Volume 11, Issue 10, Page(s) e4027

Abstract: Antimicrobial- ... ...

Abstract	Antimicrobial-resistant
Language	English
Publishing date	2021-05-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2833269-6
ISSN	2331-8325 ; 2331-8325
ISSN (online)	2331-8325
ISSN	2331-8325
DOI	10.21769/BioProtoc.4027
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Article: Characterization of Peroxisomal Regulation Networks.

Mast, Fred D / Aitchison, John D

Sub-cellular biochemistry

2018 Volume 89, Page(s) 367–382

Abstract: Peroxisome proliferation involves signal recognition and computation by molecular networks that direct molecular events of gene expression, metabolism, membrane biogenesis, organelle proliferation, protein import, and organelle inheritance. Peroxisome ... ...

Abstract	Peroxisome proliferation involves signal recognition and computation by molecular networks that direct molecular events of gene expression, metabolism, membrane biogenesis, organelle proliferation, protein import, and organelle inheritance. Peroxisome biogenesis in yeast has served as a model system for exploring the regulatory networks controlling this process. Yeast is an outstanding model system to develop tools and approaches to study molecular networks and cellular responses and because the mechanisms of peroxisome biogenesis and key aspects of the transcriptional regulatory networks are remarkably conserved from yeast to humans. In this chapter, we focus on the complex regulatory networks that respond to environmental cues leading to peroxisome assembly and the molecular events of organelle assembly. Ultimately, understanding the mechanisms of the entire peroxisome biogenesis program holds promise for predictive modeling approaches and for guiding rational intervention strategies that could treat human conditions associated with peroxisome function.
MeSH term(s)	Humans ; Metabolic Networks and Pathways ; Models, Biological ; Peroxisomes/chemistry ; Peroxisomes/genetics ; Peroxisomes/metabolism ; Protein Transport ; Saccharomyces cerevisiae/cytology ; Saccharomyces cerevisiae/metabolism
Language	English
Publishing date	2018-10-30
Publishing country	United States
Document type	Journal Article ; Review
ISSN	0306-0225 ; 0096-8757
ISSN	0306-0225 ; 0096-8757
DOI	10.1007/978-981-13-2233-4_16
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Article ; Online: Peroxisome prognostications: Exploring the birth, life, and death of an organelle.

Mast, Fred D / Rachubinski, Richard A / Aitchison, John D

The Journal of cell biology

2020 Volume 219, Issue 3

Abstract: Peroxisomes play a central role in human health and have biochemical properties that promote their use in many biotechnology settings. With a primary role in lipid metabolism, peroxisomes share a niche with lipid droplets within the endomembrane- ... ...

Abstract	Peroxisomes play a central role in human health and have biochemical properties that promote their use in many biotechnology settings. With a primary role in lipid metabolism, peroxisomes share a niche with lipid droplets within the endomembrane-secretory system. Notably, factors in the ER required for the biogenesis of peroxisomes also impact the formation of lipid droplets. The dynamic interface between peroxisomes and lipid droplets, and also between these organelles and the ER and mitochondria, controls their metabolic flux and their dynamics. Here, we review our understanding of peroxisome biogenesis to propose and reframe models for understanding how peroxisomes are formed in cells. To more fully understand the roles of peroxisomes and to take advantage of their many properties that may prove useful in novel therapeutics or biotechnology applications, we recast mechanisms controlling peroxisome biogenesis in a framework that integrates inference from these models with experimental data.
MeSH term(s)	Animals ; Endoplasmic Reticulum/metabolism ; Endosomal Sorting Complexes Required for Transport/metabolism ; Energy Metabolism ; Humans ; Lipid Droplets/metabolism ; Mitochondria/metabolism ; Organelle Biogenesis ; Peroxins/metabolism ; Peroxisomes/metabolism ; Peroxisomes/pathology ; Protein Transport ; Signal Transduction
Chemical Substances	Endosomal Sorting Complexes Required for Transport ; Peroxins
Language	English
Publishing date	2020-06-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.201912100
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Article ; Online: Preimmunization correlates of protection shared across malaria vaccine trials in adults.

Neal, Maxwell L / Duffy, Fergal J / Du, Ying / Aitchison, John D / Stuart, Kenneth D

NPJ vaccines

2022 Volume 7, Issue 1, Page(s) 5

Abstract: Identifying preimmunization biological characteristics that promote an effective vaccine response offers opportunities for illuminating the critical immunological mechanisms that confer vaccine-induced protection, for developing adjuvant strategies, and ... ...

Abstract	Identifying preimmunization biological characteristics that promote an effective vaccine response offers opportunities for illuminating the critical immunological mechanisms that confer vaccine-induced protection, for developing adjuvant strategies, and for tailoring vaccination regimens to individuals or groups. In the context of malaria vaccine research, studying preimmunization correlates of protection can help address the need for a widely effective malaria vaccine, which remains elusive. In this study, common preimmunization correlates of protection were identified using transcriptomic data from four independent, heterogeneous malaria vaccine trials in adults. Systems-based analyses showed that a moderately elevated inflammatory state prior to immunization was associated with protection against malaria challenge. Functional profiling of protection-associated genes revealed the importance of several inflammatory pathways, including TLR signaling. These findings, which echo previous studies that associated enhanced preimmunization inflammation with protection, illuminate common baseline characteristics that set the stage for an effective vaccine response across diverse malaria vaccine strategies in adults.
Language	English
Publishing date	2022-01-14
Publishing country	England
Document type	Journal Article
ISSN	2059-0105
ISSN (online)	2059-0105
DOI	10.1038/s41541-021-00425-1
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Article ; Online: Multiple receptor tyrosine kinases regulate dengue infection of hepatocytes.

Bourgeois, Natasha M / Wei, Ling / Ho, Nhi N T / Neal, Maxwell L / Seferos, Denali / Tongogara, Tinotenda / Mast, Fred D / Aitchison, John D / Kaushansky, Alexis

Frontiers in cellular and infection microbiology

2024 Volume 14, Page(s) 1264525

Abstract: Introduction: Dengue is an arboviral disease causing severe illness in over 500,000 people each year. Currently, there is no way to constrain dengue in the clinic. Host kinase regulators of dengue virus (DENV) infection have the potential to be ... ...

Abstract	Introduction: Dengue is an arboviral disease causing severe illness in over 500,000 people each year. Currently, there is no way to constrain dengue in the clinic. Host kinase regulators of dengue virus (DENV) infection have the potential to be disrupted by existing therapeutics to prevent infection and/or disease progression. Methods: To evaluate kinase regulation of DENV infection, we performed kinase regression (KiR), a machine learning approach that predicts kinase regulators of infection using existing drug-target information and a small drug screen. We infected hepatocytes with DENV Results: Thirty-six kinases were predicted to have a functional role. Intriguingly, seven of the predicted kinases - EPH receptor A4 (EPHA4), EPH receptor B3 (EPHB3), EPH receptor B4 (EPHB4), erb-b2 receptor tyrosine kinase 2 (ERBB2), fibroblast growth factor receptor 2 (FGFR2), Insulin like growth factor 1 receptor (IGF1R), and ret proto-oncogene (RET) - belong to the receptor tyrosine kinase (RTK) family, which are already therapeutic targets in the clinic. We demonstrate that predicted RTKs are expressed at higher levels in DENV infected cells. Knockdown of EPHB4, ERBB2, FGFR2, or IGF1R reduces DENV infection in hepatocytes. Finally, we observe differential temporal induction of ERBB2 and IGF1R following DENV infection, highlighting their unique roles in regulating DENV. Discussion: Collectively, our findings underscore the significance of multiple RTKs in DENV infection and advocate further exploration of RTK-oriented interventions against dengue.
MeSH term(s)	Humans ; Dengue ; Dengue Virus/physiology ; Receptor, EphA1 ; Hepatocytes/metabolism ; Tyrosine ; Virus Replication
Chemical Substances	Receptor, EphA1 (EC 2.7.10.1) ; Tyrosine (42HK56048U)
Language	English
Publishing date	2024-03-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2024.1264525
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