Subgroup-specific gene expression profiles and mixed epistasis in chronic lymphocytic leukemia

Despite the extensive catalogue of recurrent mutations in chronic lymphocytic leukaemia (CLL), the diverse molecular driving events and the resulting range of disease phenotypes remain incompletely understood. To study the molecular heterogeneity of CLL, we performed RNA-sequencing on 184 CLL patient samples. Unsupervised analysis revealed two major independent axes of gene expression variation: the first one aligned with the mutational status of the immunoglobulin heavy variable (IGHV) genes, and concomitantly, with the three-group stratification of CLL by global DNA methylation pattern, and affected biological functions including B- and T-cell receptor signaling. The second one aligned with trisomy 12 status and affected chemokine signaling. Furthermore, we searched for differentially expressed genes associated with gene mutations and copy-number aberrations and detected strong signatures for TP53, BRAF and SF3B1, as well as for del(11)(q22.3), del(17)(p13) and del(13)(q14) beyond the dosage effect. We discovered strong non-additive effects (i.e., genetic interactions, or epistasis) of IGHV mutation status and trisomy 12 on multiple phenotypes, including the expression of 893 genes. Multiple types of epistasis were observed, including synergy, buffering, suppression and inversion. Our study reveals previously underappreciated gene expression signatures for (epi)genomic variants in CLL and the presence of epistasis between them. The findings will serve as a reference for a functional resolution of CLL molecular heterogeneity.

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Molecular Heterogeneity of Multiple Myeloma: Pathogenesis, Prognosis, and Therapeutic Implications

Journal of Clinical Oncology ◽

10.1200/jco.2010.32.8435 ◽

2011 ◽

Vol 29 (14) ◽

pp. 1893-1897 ◽

Cited By ~ 42

Author(s):

Avet-Loiseau Hervé ◽

Magrangeas Florence ◽

Moreau Philippe ◽

Attal Michel ◽

Facon Thierry ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Chromosome 17 ◽

Comparative Genomic ◽

Specific Gene ◽

Molecular Heterogeneity ◽

Significant Heterogeneity ◽

Hodgkin's Lymphomas

Multiple myeloma (MM) is characterized by a significant heterogeneity at the molecular level. The first level is the chromosomal one. Although cytogenetics is difficult to assess in MM, patients can be divided into two categories: hyperdiploidy and non-hyperdiploidy (about half in each group). Using molecular cytogenetic techniques, several subgroups of patients are identified, particularly on the basis of 14q32 translocations. This chromosomal heterogeneity is confirmed by genomic techniques (gene expression profiling or single nucleotide polymorphism/comparative genomic hybridization arrays). Unsupervised analyses of gene expression profiles identified several subgroups of patients, essentially on the basis of chromosomal abnormalities such as hyperdiploidy or 14q32 translocations. However, these analyses failed to separate MM into subentities, which could lead to specific therapeutic approaches, as is the case for non-Hodgkin's lymphomas. Nevertheless, these chromosomal/genomic data can be used for prognostication of patients. Specific chromosomal changes, such as loss of the short arm of chromosome 17, or specific gene expression profiles clearly identify patients with short survival. No molecular change so far has been associated with long survival or even cure, probably because of the short follow-up observed in all studies. So far, it is unclear how to use this massive amount of data to treat patients. Because of the complex and heterogeneous picture of the molecular profiles, it is unexpected that targeted therapies might play a role in MM. The only recognized indication is to propose bortezomib-based approaches for the treatment of patients displaying the translocation t(4;14).

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Faculty Opinions recommendation of Ketamine and Imipramine Reverse Transcriptional Signatures of Susceptibility and Induce Resilience-Specific Gene Expression Profiles.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726695455.793533096 ◽

2017 ◽

Author(s):

E Ronald de Kloet ◽

Lisa van Weert ◽

Onno Meijer

Keyword(s):

Gene Expression ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Specific Gene ◽

Specific Gene Expression

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Single-cell immune repertoire and transcriptome sequencing reveals that clonally expanded and transcriptionally distinct lymphocytes populate the aged central nervous system in mice

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2020.2793 ◽

2021 ◽

Vol 288 (1945) ◽

pp. 20202793

Author(s):

Alexander Yermanos ◽

Daniel Neumeier ◽

Ioana Sandu ◽

Mariana Borsa ◽

Ann Cathrin Waindok ◽

...

Keyword(s):

Gene Expression ◽

Central Nervous System ◽

Nervous System ◽

B Cells ◽

Single Cell ◽

Somatic Hypermutation ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Cell Receptor ◽

The Central Nervous System

Neuroinflammation plays a crucial role during ageing and various neurological conditions, including Alzheimer's disease, multiple sclerosis and infection. Technical limitations, however, have prevented an integrative analysis of how lymphocyte immune receptor repertoires and their accompanying transcriptional states change with age in the central nervous system. Here, we leveraged single-cell sequencing to simultaneously profile B cell receptor and T cell receptor repertoires and accompanying gene expression profiles in young and old mouse brains. We observed the presence of clonally expanded B and T cells in the central nervous system of aged male mice. Furthermore, many of these B cells were of the IgM and IgD isotypes, and had low levels of somatic hypermutation. Integrating gene expression information additionally revealed distinct transcriptional profiles of these clonally expanded lymphocytes. Our findings implicate that clonally related T and B cells in the CNS of elderly mice may contribute to neuroinflammation accompanying homeostatic ageing.

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Convergent evolution of venom gland transcriptomes across Metazoa

10.1101/2021.07.04.451048 ◽

2021 ◽

Author(s):

Giulia Zancolli ◽

Maarten Reijnders ◽

Robert Waterhouse ◽

Marc Robinson-Rechavi

Keyword(s):

Gene Expression ◽

Regulatory Networks ◽

Molecular Mechanisms ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Venom Gland ◽

Bioactive Molecules ◽

Specific Gene ◽

Animal Kingdom ◽

Venom Glands

Animals have repeatedly evolved specialized organs and anatomical structures to produce and deliver a cocktail of potent bioactive molecules to subdue prey or predators: venom. This makes it one of the most widespread convergent functions in the animal kingdom. Whether animals have adopted the same genetic toolkit to evolved venom systems is a fascinating question that still eludes us. Here, we performed the first comparative analysis of venom gland transcriptomes from 20 venomous species spanning the main Metazoan lineages, to test whether different animals have independently adopted similar molecular mechanisms to perform the same function. We found a strong convergence in gene expression profiles, with venom glands being more similar to each other than to any other tissue from the same species, and their differences closely mirroring the species phylogeny. Although venom glands secrete some of the fastest evolving molecules (toxins), their gene expression does not evolve faster than evolutionarily older tissues. We found 15 venom gland specific gene modules enriched in endoplasmic reticulum stress and unfolded protein response pathways, indicating that animals have independently adopted stress response mechanisms to cope with mass production of toxins. This, in turns, activates regulatory networks for epithelial development, cell turnover and maintenance which seem composed of both convergent and lineage-specific factors, possibly reflecting the different developmental origins of venom glands. This study represents the first step towards an understanding of the molecular mechanisms underlying the repeated evolution of one of the most successful adaptive traits in the animal kingdom.

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Dimethyl fumarate induces ferroptosis and impairs NF-κB/STAT3 signaling in DLBCL

Blood ◽

10.1182/blood.2020009404 ◽

2021 ◽

Author(s):

Anja Schmitt ◽

Wendan Xu ◽

Philip Bucher ◽

Melanie Grimm ◽

Martina Konantz ◽

...

Keyword(s):

Cell Death ◽

B Cell ◽

Expression Profiles ◽

Therapeutic Option ◽

Gene Expression Profiles ◽

B Cell Lymphoma ◽

Dimethyl Fumarate ◽

Specific Gene ◽

Molecular Heterogeneity ◽

Stat3 Signaling

Despite the development of novel targeted drugs, the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) still poses a major therapeutic challenge. DLBCL can be classified into at least two major subtypes, i.e. germinal center B-cell-like (GCB) and the aggressive activated B-cell-like (ABC) DLBCL, each characterized by specific gene expression profiles and mutation patterns. Here we demonstrate a broad anti-tumor effect of dimethyl fumarate (DMF) on both DLBCL subtypes, which is mediated by the induction of ferroptosis, a form of cell death driven by the peroxidation of phospholipids. Due to high expression of arachidonate 5-lipoxygenase in concert with low glutathione and glutathione peroxidase 4 levels, DMF induces lipid peroxidation and thus ferroptosis particularly in GCB DLBCL. In ABC DLBCL cells, which are addicted to NF-κB and STAT3 survival signaling, DMF treatment efficiently inhibits the activity of the IKK complex and JAK kinases. Interestingly, the BCL-2 specific BH3 mimetic ABT-199 and an inhibitor of ferroptosis suppressor protein 1 synergize with DMF in inducing cell death in DLBCL. Collectively, our findings identify the clinically approved drug DMF as a promising novel therapeutic option in the treatment of both GCB and ABC DLBCL.

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In Vivo mRNA Profiling of Uropathogenic Escherichia coli from Diverse Phylogroups Reveals Common and Group-Specific Gene Expression Profiles

mBio ◽

10.1128/mbio.01075-14 ◽

2014 ◽

Vol 5 (4) ◽

Cited By ~ 39

Author(s):

Piotr Bielecki ◽

Uthayakumar Muthukumarasamy ◽

Denitsa Eckweiler ◽

Agata Bielecka ◽

Sarah Pohl ◽

...

Keyword(s):

Gene Expression ◽

Escherichia Coli ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Specific Gene ◽

Content Type ◽

E Coli ◽

Human Host ◽

Tract Infections

ABSTRACTmRNA profiling of pathogens during the course of human infections gives detailed information on the expression levels of relevant genes that drive pathogenicity and adaptation and at the same time allows for the delineation of phylogenetic relatedness of pathogens that cause specific diseases. In this study, we used mRNA sequencing to acquire information on the expression ofEscherichia colipathogenicity genes during urinary tract infections (UTI) in humans and to assign the UTI-associatedE. coliisolates to different phylogenetic groups. Whereas thein vivogene expression profiles of the majority of genes were conserved among 21E. colistrains in the urine of elderly patients suffering from an acute UTI, the specific gene expression profiles of the flexible genomes was diverse and reflected phylogenetic relationships. Furthermore, genes transcribedin vivorelative to laboratory media included well-described virulence factors, small regulatory RNAs, as well as genes not previously linked to bacterial virulence. Knowledge on relevant transcriptional responses that drive pathogenicity and adaptation of isolates to the human host might lead to the introduction of a virulence typing strategy into clinical microbiology, potentially facilitating management and prevention of the disease.IMPORTANCEUrinary tract infections (UTI) are very common; at least half of all women experience UTI, most of which are caused by pathogenicEscherichia colistrains. In this study, we applied massive parallel cDNA sequencing (RNA-seq) to provide unbiased, deep, and accurate insight into the nature and the dimension of the uropathogenicE. coligene expression profile during an acute UTI within the human host. This work was undertaken to identify key players in physiological adaptation processes and, hence, potential targets for new infection prevention and therapy interventions specifically aimed at sabotaging bacterial adaptation to the human host.

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Establishment of Cell Lines That Exhibit Correct Ontogenic Stage-Specific Gene Expression Profiles From Tissues of Yeast Artificial Chromosome Transgenic Mice Using Chemically Induced Growth Signals

YAC Protocols ◽

10.1385/1-59745-158-4:163 ◽

2006 ◽

pp. 163-174

Author(s):

C. Anthony Blau ◽

Kenneth R. Peterson

Keyword(s):

Gene Expression ◽

Transgenic Mice ◽

Cell Lines ◽

Yeast Artificial Chromosome ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Artificial Chromosome ◽

Specific Gene ◽

Specific Gene Expression ◽

Chemically Induced

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In Silico Discovery of Candidate Drugs against Covid-19

Viruses ◽

10.3390/v12040404 ◽

2020 ◽

Vol 12 (4) ◽

pp. 404 ◽

Cited By ~ 42

Author(s):

Claudia Cava ◽

Gloria Bertoli ◽

Isabella Castiglioni

Keyword(s):

Gene Expression ◽

In Silico ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Interaction Network ◽

Enrichment Analysis ◽

Basic Mechanism ◽

Cell Receptor ◽

The Cancer Genome Atlas ◽

Pathway Enrichment Analysis

Previous studies reported that Angiotensin converting enzyme 2 (ACE2) is the main cell receptor of SARS-CoV and SARS-CoV-2. It plays a key role in the access of the virus into the cell to produce the final infection. In the present study we investigated in silico the basic mechanism of ACE2 in the lung and provided evidences for new potentially effective drugs for Covid-19. Specifically, we used the gene expression profiles from public datasets including The Cancer Genome Atlas, Gene Expression Omnibus and Genotype-Tissue Expression, Gene Ontology and pathway enrichment analysis to investigate the main functions of ACE2-correlated genes. We constructed a protein-protein interaction network containing the genes co-expressed with ACE2. Finally, we focused on the genes in the network that are already associated with known drugs and evaluated their role for a potential treatment of Covid-19. Our results demonstrate that the genes correlated with ACE2 are mainly enriched in the sterol biosynthetic process, Aryldialkylphosphatase activity, adenosylhomocysteinase activity, trialkylsulfonium hydrolase activity, acetate-CoA and CoA ligase activity. We identified a network of 193 genes, 222 interactions and 36 potential drugs that could have a crucial role. Among possible interesting drugs for Covid-19 treatment, we found Nimesulide, Fluticasone Propionate, Thiabendazole, Photofrin, Didanosine and Flutamide.

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