A Genome‐wide Screen for Transcription Factors Involved in Programmed Cell Death in the Yeast, Candida albicans

Abstract Key message This study showed the systematic identification of long non-coding RNAs (lncRNAs) involving in flag leaf senescence of rice, providing the possible lncRNA-mRNA regulatory relationships and lncRNA-miRNA-mRNA ceRNA networks during leaf senescence. Abstract LncRNAs have been reported to play crucial roles in diverse biological processes. However, no systematic identification of lncRNAs associated with leaf senescence in plants has been studied. In this study, a genome-wide high throughput sequencing analysis was performed using rice flag leaves developing from normal to senescence. A total of 3953 lncRNAs and 38757 mRNAs were identified, of which 343 lncRNAs and 9412 mRNAs were differentially expressed. Through weighted gene co-expression network analysis (WGCNA), 22 continuously down-expressed lncRNAs targeting 812 co-expressed mRNAs and 48 continuously up-expressed lncRNAs targeting 1209 co-expressed mRNAs were considered to be significantly associated with flag leaf senescence. Gene Ontology results suggested that the senescence-associated lncRNAs targeted mRNAs involving in many biological processes, including transcription, hormone response, oxidation–reduction process and substance metabolism. Additionally, 43 senescence-associated lncRNAs were predicted to target 111 co-expressed transcription factors. Interestingly, 8 down-expressed lncRNAs and 29 up-expressed lncRNAs were found to separately target 12 and 20 well-studied senescence-associated genes (SAGs). Furthermore, analysis on the competing endogenous RNA (CeRNA) network revealed that 6 down-expressed lncRNAs possibly regulated 51 co-expressed mRNAs through 15 miRNAs, and 14 up-expressed lncRNAs possibly regulated 117 co-expressed mRNAs through 21 miRNAs. Importantly, by expression validation, a conserved miR164-NAC regulatory pathway was found to be possibly involved in leaf senescence, where lncRNA MSTRG.62092.1 may serve as a ceRNA binding with miR164a and miR164e to regulate three transcription factors. And two key lncRNAs MSTRG.31014.21 and MSTRG.31014.36 also could regulate the abscisic-acid biosynthetic gene BGIOSGA025169 (OsNCED4) and BGIOSGA016313 (NAC family) through osa-miR5809. The possible regulation networks of lncRNAs involving in leaf senescence were discussed, and several candidate lncRNAs were recommended for prior transgenic analysis. These findings will extend the understanding on the regulatory roles of lncRNAs in leaf senescence, and lay a foundation for functional research on candidate lncRNAs.

Download Full-text

A genome-wide survey on basic helix-loop-helix transcription factors in rat and mouse

Mammalian Genome ◽

10.1007/s00335-009-9176-7 ◽

2009 ◽

Vol 20 (4) ◽

pp. 236-246 ◽

Cited By ~ 29

Author(s):

X. Zheng ◽

Y. Wang ◽

Q. Yao ◽

Z. Yang ◽

K. Chen

Keyword(s):

Transcription Factors ◽

Basic Helix Loop Helix ◽

Helix Loop Helix ◽

Genome Wide ◽

A Genome ◽

Genome Wide Survey

Download Full-text

SEC24A identified as an essential mediator of thapsigargin-induced cell death in a genome-wide CRISPR/Cas9 screen

Cell Death Discovery ◽

10.1038/s41420-018-0135-5 ◽

2018 ◽

Vol 4 (1) ◽

Cited By ~ 6

Author(s):

Tamutenda Chidawanyika ◽

Elizabeth Sergison ◽

Michael Cole ◽

Kenneth Mark ◽

Surachai Supattapone

Keyword(s):

Cell Death ◽

Genome Wide ◽

A Genome

Download Full-text

Intracellular Staphylococcus aureus Perturbs the Host Cell Ca2+ Homeostasis To Promote Cell Death

mBio ◽

10.1128/mbio.02250-20 ◽

2020 ◽

Vol 11 (6) ◽

pp. e02250-20

Author(s):

Kathrin Stelzner ◽

Ann-Cathrin Winkler ◽

Chunguang Liang ◽

Aziza Boyny ◽

Carsten P. Ade ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Cell Death ◽

Host Cell ◽

Intracellular Bacterium ◽

Tissue Destruction ◽

Content Type ◽

Host Cell Death ◽

Genome Wide ◽

A Genome ◽

Spread Of Infection

ABSTRACTThe opportunistic human pathogen Staphylococcus aureus causes serious infectious diseases that range from superficial skin and soft tissue infections to necrotizing pneumonia and sepsis. While classically regarded as an extracellular pathogen, S. aureus is able to invade and survive within human cells. Host cell exit is associated with cell death, tissue destruction, and the spread of infection. The exact molecular mechanism employed by S. aureus to escape the host cell is still unclear. In this study, we performed a genome-wide small hairpin RNA (shRNA) screen and identified the calcium signaling pathway as being involved in intracellular infection. S. aureus induced a massive cytosolic Ca2+ increase in epithelial host cells after invasion and intracellular replication of the pathogen. This was paralleled by a decrease in endoplasmic reticulum Ca2+ concentration. Additionally, calcium ions from the extracellular space contributed to the cytosolic Ca2+ increase. As a consequence, we observed that the cytoplasmic Ca2+ rise led to an increase in mitochondrial Ca2+ concentration, the activation of calpains and caspases, and eventually to cell lysis of S. aureus-infected cells. Our study therefore suggests that intracellular S. aureus disturbs the host cell Ca2+ homeostasis and induces cytoplasmic Ca2+ overload, which results in both apoptotic and necrotic cell death in parallel or succession.IMPORTANCE Despite being regarded as an extracellular bacterium, the pathogen Staphylococcus aureus can invade and survive within human cells. The intracellular niche is considered a hideout from the host immune system and antibiotic treatment and allows bacterial proliferation. Subsequently, the intracellular bacterium induces host cell death, which may facilitate the spread of infection and tissue destruction. So far, host cell factors exploited by intracellular S. aureus to promote cell death are only poorly characterized. We performed a genome-wide screen and found the calcium signaling pathway to play a role in S. aureus invasion and cytotoxicity. The intracellular bacterium induces a cytoplasmic and mitochondrial Ca2+ overload, which results in host cell death. Thus, this study first showed how an intracellular bacterium perturbs the host cell Ca2+ homeostasis.

Download Full-text

RicetissueTFDB: A Genome‐Wide Identification of Tissue‐Specific Transcription Factors in Rice

The Plant Genome ◽

10.3835/plantgenome2017.09.0081 ◽

2019 ◽

Vol 12 (1) ◽

pp. 170081 ◽

Cited By ~ 2

Author(s):

Weiying Chen ◽

Zhenyong Chen ◽

Fuyan Luo ◽

Mingli Liao ◽

Shuhong Wei ◽

...

Keyword(s):

Transcription Factors ◽

Tissue Specific ◽

Genome Wide ◽

A Genome

Download Full-text

Applying genome-wide CRISPR-Cas9 screens for therapeutic discovery in facioscapulohumeral muscular dystrophy

Science Translational Medicine ◽

10.1126/scitranslmed.aay0271 ◽

2020 ◽

Vol 12 (536) ◽

pp. eaay0271 ◽

Cited By ~ 6

Author(s):

Angela Lek ◽

Yuanfan Zhang ◽

Keryn G. Woodman ◽

Shushu Huang ◽

Alec M. DeSimone ◽

...

Keyword(s):

Cell Death ◽

Muscular Dystrophy ◽

Phenotypic Selection ◽

Facioscapulohumeral Muscular Dystrophy ◽

Loss Of Function ◽

Hypoxia Response ◽

Genome Wide ◽

A Genome ◽

Structural And Functional Properties ◽

Cellular Hypoxia

The emergence of CRISPR-Cas9 gene-editing technologies and genome-wide CRISPR-Cas9 libraries enables efficient unbiased genetic screening that can accelerate the process of therapeutic discovery for genetic disorders. Here, we demonstrate the utility of a genome-wide CRISPR-Cas9 loss-of-function library to identify therapeutic targets for facioscapulohumeral muscular dystrophy (FSHD), a genetically complex type of muscular dystrophy for which there is currently no treatment. In FSHD, both genetic and epigenetic changes lead to misexpression of DUX4, the FSHD causal gene that encodes the highly cytotoxic DUX4 protein. We performed a genome-wide CRISPR-Cas9 screen to identify genes whose loss-of-function conferred survival when DUX4 was expressed in muscle cells. Genes emerging from our screen illuminated a pathogenic link to the cellular hypoxia response, which was revealed to be the main driver of DUX4-induced cell death. Application of hypoxia signaling inhibitors resulted in increased DUX4 protein turnover and subsequent reduction of the cellular hypoxia response and cell death. In addition, these compounds proved successful in reducing FSHD disease biomarkers in patient myogenic lines, as well as improving structural and functional properties in two zebrafish models of FSHD. Our genome-wide perturbation of pathways affecting DUX4 expression has provided insight into key drivers of DUX4-induced pathogenesis and has identified existing compounds with potential therapeutic benefit for FSHD. Our experimental approach presents an accelerated paradigm toward mechanistic understanding and therapeutic discovery of a complex genetic disease, which may be translatable to other diseases with well-established phenotypic selection assays.

Download Full-text

Lentiviral (HIV)-based RNA interference screen in human B-cell receptor regulatory networks reveals MCL1-induced oncogenic pathways

Blood ◽

10.1182/blood-2007-09-110601 ◽

2008 ◽

Vol 111 (3) ◽

pp. 1665-1676 ◽

Cited By ~ 11

Author(s):

Antonio Ruiz-Vela ◽

Mohit Aggarwal ◽

Paloma de la Cueva ◽

Cezary Treda ◽

Beatriz Herreros ◽

...

Keyword(s):

Cell Death ◽

Rna Interference ◽

Programmed Cell Death ◽

B Cell ◽

Cell Receptor ◽

B Cell Receptor ◽

B Cell Lymphomas ◽

Clonal Deletion ◽

A Genome ◽

Human B Cell

AbstractAberrant inhibition of B-cell receptor (BCR)-induced programmed cell death pathways is frequently associated with the development of human auto-reactive B-cell lymphomas. Here, we integrated loss-of-function, genomic, and bioinformatics approaches for the identification of oncogenic mechanisms linked to the inhibition of BCR-induced clonal deletion pathways in human B-cell lymphomas. Lentiviral (HIV)-based RNA interference screen identified MCL1 as a key survival molecule linked to BCR signaling. Loss of MCL1 by RNA interference rendered human B-cell lymphomas sensitive to BCR-induced programmed cell death. Conversely, MCL1 overexpression blocked programmed cell death on BCR stimulation. To get insight into the mechanisms of MCL1-induced survival and transformation, we screened 41 000 human genes in a genome-wide gene expression profile analysis of MCL1-overexpressing B-cell lymphomas. Bioinformatic gene network reconstruction illustrated reprogramming of relevant oncoproteins within β-catenin–T-cell factor signaling pathways induced by enforced MCL1 expression. Overall, our findings not only illustrate MCL1 as an aberrantly expressed reprogramming oncoprotein in follicular lymphomas but also highlight MCL1 as key therapeutic target.

Download Full-text