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Article: DUX4 is a common driver of immune evasion and immunotherapy failure in metastatic cancers.

Pineda, Jose Mario Bello / Bradley, Robert K

bioRxiv : the preprint server for biology

2023

Abstract: Cancer immune evasion contributes to checkpoint immunotherapy failure in many patients with metastatic cancers. The embryonic transcription factor DUX4 was recently characterized as a suppressor of interferon-γ signaling and antigen presentation that is ... ...

Abstract	Cancer immune evasion contributes to checkpoint immunotherapy failure in many patients with metastatic cancers. The embryonic transcription factor DUX4 was recently characterized as a suppressor of interferon-γ signaling and antigen presentation that is aberrantly expressed in a small subset of primary tumors. Here, we report that
Language	English
Publishing date	2023-12-29
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.07.10.548412
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Article: Large overlap in neutrophil transcriptome between lupus and COVID-19 with limited lupus-specific gene expression.

Najjar, Rayan / Rogel, Noga / Pineda, Jose Mario Bello / Wang, Xiaoxing / Tran, Megan / Bays, Alison / Mustelin, Tomas

Lupus science & medicine

2024 Volume 11, Issue 1

Abstract: Objectives: To illuminate the poorly understood aetiology of SLE by comparing the gene expression profile of SLE neutrophils with that of neutrophils from patients infected by SARS-CoV-2, a disease (COVID-19) with well-defined antigens and a similar ... ...

Abstract	Objectives: To illuminate the poorly understood aetiology of SLE by comparing the gene expression profile of SLE neutrophils with that of neutrophils from patients infected by SARS-CoV-2, a disease (COVID-19) with well-defined antigens and a similar type I interferon response. Methods: RNA sequencing of neutrophils from patients with SLE (n=15) and healthy controls (n=12) was analysed for differential gene expression and modulated pathways. The same analyses were performed on a similar neutrophil dataset from patients with SARS-CoV-2 infection (n=30) and healthy controls (n=8). Next, we carried out comparative analyses to identify common and unique transcriptional changes between the two disease contexts, emphasising genes regulated in opposite directions. Results: We identified 372 differentially expressed genes in SLE neutrophils compared with healthy donor neutrophils (≥2 fold, p<0.05), 181 of which were concordant with transcriptional changes in SARS-CoV-2-infected individuals compared with their respective healthy controls. In contrast, 118 genes demonstrated statistically significant alterations exclusive to SLE, including 28 genes that were differentially expressed in opposite directions in the two diseases. Conclusions: The substantial overlap between neutrophil responses in SLE and COVID-19 suggests that the unknown cause of SLE is functionally similar to a viral infection and drives a similar immune activation and type I interferon response. Conversely, the genes regulated in the opposite direction represent responses unique to SLE. These include tyrosylprotein sulfotransferase-1 and nucleic acid deaminases of the APOBEC family, which can catalyse cytosine-to-uridine editing of both RNA and DNA, and other RNA-modifying enzymes.
MeSH term(s)	Humans ; Neutrophils ; Transcriptome ; COVID-19/genetics ; SARS-CoV-2/genetics ; SARS-CoV-2/metabolism ; Lupus Erythematosus, Systemic/genetics ; RNA/metabolism ; Interferon Type I/genetics
Chemical Substances	RNA (63231-63-0) ; Interferon Type I
Language	English
Publishing date	2024-01-31
Publishing country	England
Document type	Journal Article
ZDB-ID	2779620-6
ISSN	2053-8790
ISSN	2053-8790
DOI	10.1136/lupus-2023-001059
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Article ; Online: The proto-oncogene SRC phosphorylates cGAS to inhibit an antitumor immune response.

Dunker, William / Zaver, Shivam A / Pineda, Jose Mario Bello / Howard, Cameron J / Bradley, Robert K / Woodward, Joshua J

JCI insight

2023 Volume 8, Issue 12

Abstract: Cyclic GMP-AMP synthase (cGAS) is a DNA sensor and responsible for inducing an antitumor immune response. Recent studies reveal that cGAS is frequently inhibited in cancer, and therapeutic targets to promote antitumor cGAS function remain elusive. SRC is ...

Abstract	Cyclic GMP-AMP synthase (cGAS) is a DNA sensor and responsible for inducing an antitumor immune response. Recent studies reveal that cGAS is frequently inhibited in cancer, and therapeutic targets to promote antitumor cGAS function remain elusive. SRC is a proto-oncogene tyrosine kinase and is expressed at elevated levels in numerous cancers. Here, we demonstrate that SRC expression in primary and metastatic bladder cancer negatively correlates with innate immune gene expression and immune cell infiltration. We determine that SRC restricts cGAS signaling in human cell lines through SRC small molecule inhibitors, depletion, and overexpression. cGAS and SRC interact in cells and in vitro, while SRC directly inhibits cGAS enzymatic activity and DNA binding in a kinase-dependent manner. SRC phosphorylates cGAS, and inhibition of cGAS Y248 phosphorylation partially reduces SRC inhibition. Collectively, our study demonstrates that cGAS antitumor signaling is hindered by the proto-oncogene SRC and describes how cancer-associated proteins can regulate the innate immune system.
MeSH term(s)	Humans ; Nucleotidyltransferases/metabolism ; Immunity, Innate ; Neoplasms/genetics ; DNA/metabolism ; Proto-Oncogenes
Chemical Substances	Nucleotidyltransferases (EC 2.7.7.-) ; DNA (9007-49-2)
Language	English
Publishing date	2023-06-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.167270
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Article ; Online: The proto-oncogene SRC phosphorylates cGAS to inhibit an antitumor immune response

William Dunker / Shivam A. Zaver / Jose Mario Bello Pineda / Cameron J. Howard / Robert K. Bradley / Joshua J. Woodward

JCI Insight, Vol 8, Iss

2023 Volume 12

Abstract	Cyclic GMP-AMP synthase (cGAS) is a DNA sensor and responsible for inducing an antitumor immune response. Recent studies reveal that cGAS is frequently inhibited in cancer, and therapeutic targets to promote antitumor cGAS function remain elusive. SRC is a proto-oncogene tyrosine kinase and is expressed at elevated levels in numerous cancers. Here, we demonstrate that SRC expression in primary and metastatic bladder cancer negatively correlates with innate immune gene expression and immune cell infiltration. We determine that SRC restricts cGAS signaling in human cell lines through SRC small molecule inhibitors, depletion, and overexpression. cGAS and SRC interact in cells and in vitro, while SRC directly inhibits cGAS enzymatic activity and DNA binding in a kinase-dependent manner. SRC phosphorylates cGAS, and inhibition of cGAS Y248 phosphorylation partially reduces SRC inhibition. Collectively, our study demonstrates that cGAS antitumor signaling is hindered by the proto-oncogene SRC and describes how cancer-associated proteins can regulate the innate immune system.
Keywords	Immunology ; Oncology ; Medicine ; R
Subject code	570
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
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Article ; Online: Most human introns are recognized via multiple and tissue-specific branchpoints.

Pineda, Jose Mario Bello / Bradley, Robert K

Genes & development

2018 Volume 32, Issue 7-8, Page(s) 577–591

Abstract: Although branchpoint recognition is an essential component of intron excision during the RNA splicing process, the branchpoint itself is frequently assumed to be a basal, rather than regulatory, sequence feature. However, this assumption has not been ... ...

Abstract	Although branchpoint recognition is an essential component of intron excision during the RNA splicing process, the branchpoint itself is frequently assumed to be a basal, rather than regulatory, sequence feature. However, this assumption has not been systematically tested due to the technical difficulty of identifying branchpoints and quantifying their usage. Here, we analyzed ∼1.31 trillion reads from 17,164 RNA sequencing data sets to demonstrate that almost all human introns contain multiple branchpoints. This complexity holds even for constitutive introns, 95% of which contain multiple branchpoints, with an estimated five to six branchpoints per intron. Introns upstream of the highly regulated ultraconserved poison exons of SR genes contain twice as many branchpoints as the genomic average. Approximately three-quarters of constitutive introns exhibit tissue-specific branchpoint usage. In an extreme example, we observed a complete switch in branchpoint usage in the well-studied first intron of
MeSH term(s)	Alternative Splicing ; Exons ; Gene Expression ; Humans ; Introns ; Molecular Sequence Annotation ; Organ Specificity ; RNA Splice Sites ; Sequence Analysis, RNA
Chemical Substances	RNA Splice Sites
Language	English
Publishing date	2018-04-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	806684-x
ISSN	1549-5477 ; 0890-9369
ISSN (online)	1549-5477
ISSN	0890-9369
DOI	10.1101/gad.312058.118
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Article ; Online: GPATCH8 modulates mutant SF3B1 mis-splicing and pathogenicity in hematologic malignancies.

Molecular cell

2024

Abstract: Mutations in the RNA splicing factor gene SF3B1 are common across hematologic and solid cancers and result in widespread alterations in splicing, yet there is currently no therapeutic means to correct this mis-splicing. Here, we utilize synthetic introns ...

Abstract	Mutations in the RNA splicing factor gene SF3B1 are common across hematologic and solid cancers and result in widespread alterations in splicing, yet there is currently no therapeutic means to correct this mis-splicing. Here, we utilize synthetic introns uniquely responsive to mutant SF3B1 to identify trans factors required for aberrant mutant SF3B1 splicing activity. This revealed the G-patch domain-containing protein GPATCH8 as required for mutant SF3B1-induced splicing alterations and impaired hematopoiesis. GPATCH8 is involved in quality control of branchpoint selection, interacts with the RNA helicase DHX15, and functionally opposes SURP and G-patch domain containing 1 (SUGP1), a G-patch protein recently implicated in SF3B1-mutant diseases. Silencing of GPATCH8 corrected one-third of mutant SF3B1-dependent splicing defects and was sufficient to improve dysfunctional hematopoiesis in SF3B1-mutant mice and primary human progenitors. These data identify GPATCH8 as a novel splicing factor required for mis-splicing by mutant SF3B1 and highlight the therapeutic impact of correcting aberrant splicing in SF3B1-mutant cancers.
Language	English
Publishing date	2024-04-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2024.04.006
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Article ; Online: Disentangling strictly self-serving mutations from win-win mutations in a mutualistic microbial community.

Hart, Samuel Frederick Mock / Pineda, Jose Mario Bello / Chen, Chi-Chun / Green, Robin / Shou, Wenying

eLife

2019 Volume 8

Abstract: Mutualisms can be promoted by pleiotropic win-win mutations which directly benefit self (self-serving) and partner (partner-serving). Intuitively, partner-serving phenotype could be quantified as an individual's benefit supply rate to partners. Here, we ... ...

Abstract	Mutualisms can be promoted by pleiotropic win-win mutations which directly benefit self (self-serving) and partner (partner-serving). Intuitively, partner-serving phenotype could be quantified as an individual's benefit supply rate to partners. Here, we demonstrate the inadequacy of this thinking, and propose an alternative. Specifically, we evolved well-mixed mutualistic communities where two engineered yeast strains exchanged essential metabolites lysine and hypoxanthine. Among cells that consumed lysine and released hypoxanthine, a chromosome duplication mutation seemed win-win: it improved cell's affinity for lysine (self-serving), and increased hypoxanthine release rate per cell (partner-serving). However, increased release rate was due to increased cell size accompanied by increased lysine utilization per birth. Consequently, total hypoxanthine release rate per lysine utilization (defined as 'exchange ratio') remained unchanged. Indeed, this mutation did not increase the steady state growth rate of partner, and is thus solely self-serving during long-term growth. By extension, reduced benefit production rate by an individual may not imply cheating.
MeSH term(s)	Hypoxanthine/metabolism ; Lysine/metabolism ; Microbial Interactions ; Mutation ; Symbiosis ; Yeasts/genetics ; Yeasts/growth & development ; Yeasts/metabolism
Chemical Substances	Hypoxanthine (2TN51YD919) ; Lysine (K3Z4F929H6)
Language	English
Publishing date	2019-06-04
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.44812
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Article ; Online: Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia.

Takao, Sumiko / Forbes, Lauren / Uni, Masahiro / Cheng, Shuyuan / Pineda, Jose Mario Bello / Tarumoto, Yusuke / Cifani, Paolo / Minuesa, Gerard / Chen, Celine / Kharas, Michael G / Bradley, Robert K / Vakoc, Christopher R / Koche, Richard P / Kentsis, Alex

eLife

2021 Volume 10

Abstract: Dysregulated gene expression contributes to most prevalent features in human cancers. Here, we show that most subtypes of acute myeloid leukemia (AML) depend on the aberrant assembly of MYB transcriptional co-activator complex. By rapid and selective ... ...

Abstract	Dysregulated gene expression contributes to most prevalent features in human cancers. Here, we show that most subtypes of acute myeloid leukemia (AML) depend on the aberrant assembly of MYB transcriptional co-activator complex. By rapid and selective peptidomimetic interference with the binding of CBP/P300 to MYB, but not CREB or MLL1, we find that the leukemic functions of MYB are mediated by CBP/P300 co-activation of a distinct set of transcription factor complexes. These MYB complexes assemble aberrantly with LYL1, E2A, C/EBP family members, LMO2, and SATB1. They are organized convergently in genetically diverse subtypes of AML and are at least in part associated with inappropriate transcription factor co-expression. Peptidomimetic remodeling of oncogenic MYB complexes is accompanied by specific proteolysis and dynamic redistribution of CBP/P300 with alternative transcription factors such as RUNX1 to induce myeloid differentiation and apoptosis. Thus, aberrant assembly and sequestration of MYB:CBP/P300 complexes provide a unifying mechanism of oncogenic gene expression in AML. This work establishes a compelling strategy for their pharmacologic reprogramming and therapeutic targeting for diverse leukemias and possibly other human cancers caused by dysregulated gene control.
MeSH term(s)	Cell Line, Tumor ; Gene Expression Regulation, Leukemic ; Humans ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Matrix Attachment Region Binding Proteins ; Oncogenes ; Peptidomimetics ; Proto-Oncogene Proteins c-myb/genetics ; Proto-Oncogene Proteins c-myb/metabolism ; p300-CBP Transcription Factors/genetics
Chemical Substances	MYB protein, human ; Matrix Attachment Region Binding Proteins ; Peptidomimetics ; Proto-Oncogene Proteins c-myb ; p300-CBP Transcription Factors (EC 2.3.1.48)
Language	English
Publishing date	2021-02-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.65905
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Article ; Online: Uncovering and resolving challenges of quantitative modeling in a simplified community of interacting cells.

Hart, Samuel F M / Mi, Hanbing / Green, Robin / Xie, Li / Pineda, Jose Mario Bello / Momeni, Babak / Shou, Wenying

PLoS biology

2019 Volume 17, Issue 2, Page(s) e3000135

Abstract: Quantitative modeling is useful for predicting behaviors of a system and for rationally constructing or modifying the system. The predictive power of a model relies on accurate quantification of model parameters. Here, we illustrate challenges in ... ...

Abstract	Quantitative modeling is useful for predicting behaviors of a system and for rationally constructing or modifying the system. The predictive power of a model relies on accurate quantification of model parameters. Here, we illustrate challenges in parameter quantification and offer means to overcome these challenges, using a case example in which we quantitatively predict the growth rate of a cooperative community. Specifically, the community consists of two Saccharomyces cerevisiae strains, each engineered to release a metabolite required and consumed by its partner. The initial model, employing parameters measured in batch monocultures with zero or excess metabolite, failed to quantitatively predict experimental results. To resolve the model-experiment discrepancy, we chemically identified the correct exchanged metabolites, but this did not improve model performance. We then remeasured strain phenotypes in chemostats mimicking the metabolite-limited community environments, while mitigating or incorporating effects of rapid evolution. Almost all phenotypes we measured, including death rate, metabolite release rate, and the amount of metabolite consumed per cell birth, varied significantly with the metabolite environment. Once we used parameters measured in a range of community-like chemostat environments, prediction quantitatively agreed with experimental results. In summary, using a simplified community, we uncovered and devised means to resolve modeling challenges that are likely general to living systems.
MeSH term(s)	Coculture Techniques ; Computer Simulation ; Metabolic Engineering/methods ; Microbial Interactions/genetics ; Models, Biological ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/growth & development ; Saccharomyces cerevisiae/metabolism
Language	English
Publishing date	2019-02-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2126776-5
ISSN	1545-7885 ; 1544-9173
ISSN (online)	1545-7885
ISSN	1544-9173
DOI	10.1371/journal.pbio.3000135
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Article ; Online: Disentangling strictly self-serving mutations from win-win mutations in a mutualistic microbial community

Samuel Frederick Mock Hart / Jose Mario Bello Pineda / Chi-Chun Chen / Robin Green / Wenying Shou

eLife, Vol

2019 Volume 8

Abstract: Mutualisms can be promoted by pleiotropic win-win mutations which directly benefit self (self-serving) and partner (partner-serving). Intuitively, partner-serving phenotype could be quantified as an individual’s benefit supply rate to partners. Here, we ... ...

Abstract	Mutualisms can be promoted by pleiotropic win-win mutations which directly benefit self (self-serving) and partner (partner-serving). Intuitively, partner-serving phenotype could be quantified as an individual’s benefit supply rate to partners. Here, we demonstrate the inadequacy of this thinking, and propose an alternative. Specifically, we evolved well-mixed mutualistic communities where two engineered yeast strains exchanged essential metabolites lysine and hypoxanthine. Among cells that consumed lysine and released hypoxanthine, a chromosome duplication mutation seemed win-win: it improved cell’s affinity for lysine (self-serving), and increased hypoxanthine release rate per cell (partner-serving). However, increased release rate was due to increased cell size accompanied by increased lysine utilization per birth. Consequently, total hypoxanthine release rate per lysine utilization (defined as ‘exchange ratio’) remained unchanged. Indeed, this mutation did not increase the steady state growth rate of partner, and is thus solely self-serving during long-term growth. By extension, reduced benefit production rate by an individual may not imply cheating.
Keywords	mutualism ; benefit ; cost ; evolution ; partner-serving ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2019-06-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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