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1.
Trends Immunol ; 44(7): 493-495, 2023 07.
Article in English | MEDLINE | ID: mdl-37270301

ABSTRACT

Genomic studies are transforming knowledge about the epigenetic, transcription factor, and 3D landscapes of the genome. However, comprehensive information is lacking about the effector domains used by transcription factors to influence gene expression. Addressing this gap, DelRosso et al. developed a high-throughput screen to discover effector domains in human regulatory factors.


Subject(s)
Gene Expression Regulation , Transcription Factors , Humans , Transcription Factors/genetics , Transcription Factors/metabolism , Genome , Genomics
2.
Cell Rep ; 39(5): 110769, 2022 05 03.
Article in English | MEDLINE | ID: mdl-35508135

ABSTRACT

Distinguishing between conserved and divergent regulatory mechanisms is essential for translating preclinical research from mice to humans, yet there is a lack of information about how evolutionary genome rearrangements affect the regulation of the immune response, a rapidly evolving system. The current model is topologically associating domains (TADs) are conserved between species, buffering evolutionary rearrangements and conserving long-range interactions within a TAD. However, we find that TADs frequently span evolutionary translocation and inversion breakpoints near genes with species-specific expression in immune cells, creating unique enhancer-promoter interactions exclusive to the mouse or human genomes. This includes TADs encompassing immune-related transcription factors, cytokines, and receptors. For example, we uncover an evolutionary rearrangement that created a shared LPS-inducible regulatory module between OASL and P2RX7 in human macrophages that is absent in mice. Therefore, evolutionary genome rearrangements disrupt TAD boundaries, enabling sequence-conserved enhancer elements from divergent genomic locations between species to create unique regulatory modules.


Subject(s)
Chromatin , Genome, Human , Animals , Enhancer Elements, Genetic/genetics , Evolution, Molecular , Gene Rearrangement/genetics , Genomics , Humans , Mice
3.
Trends Immunol ; 42(12): 1077-1087, 2021 12.
Article in English | MEDLINE | ID: mdl-34740529

ABSTRACT

Model organisms such as mice are important for basic research and serve as valuable tools in preclinical translational studies. A challenge with translating findings from mice to humans is identifying and separating evolutionarily conserved mechanisms in the immune system from those diverging between species. A significant emphasis has been placed on defining conserved gene regulation principles, with divergent mechanisms often overlooked. We put forward the perspective that both conserved and divergent mechanisms that regulate gene expression programs are of equal importance. With recent advances and availability of datasets, immunologists should take a closer look at the role for genetic diversity in altering gene expression programs between mouse and human immune cells.


Subject(s)
Gene Expression Regulation , Immune System , Animals , Humans , Mice
4.
PLoS Pathog ; 16(2): e1008269, 2020 02.
Article in English | MEDLINE | ID: mdl-32032393

ABSTRACT

In mammalian cells, widespread acceleration of cytoplasmic mRNA degradation is linked to impaired RNA polymerase II (Pol II) transcription. This mRNA decay-induced transcriptional repression occurs during infection with gammaherpesviruses including Kaposi's sarcoma-associated herpesvirus (KSHV) and murine gammaherpesvirus 68 (MHV68), which encode an mRNA endonuclease that initiates widespread RNA decay. Here, we show that MHV68-induced mRNA decay leads to a genome-wide reduction of Pol II occupancy at mammalian promoters. This reduced Pol II occupancy is accompanied by down-regulation of multiple Pol II subunits and TFIIB in the nucleus of infected cells, as revealed by mass spectrometry-based global measurements of protein abundance. Viral genes, despite the fact that they require Pol II for transcription, escape transcriptional repression. Protection is not governed by viral promoter sequences; instead, location on the viral genome is both necessary and sufficient to escape the transcriptional repression effects of mRNA decay. We propose a model in which the ability to escape from transcriptional repression is linked to the localization of viral DNA within replication compartments, providing a means for these viruses to counteract decay-induced transcript loss.


Subject(s)
Herpesviridae Infections/metabolism , Herpesvirus 8, Human/physiology , Promoter Regions, Genetic , RNA Polymerase II/metabolism , RNA Stability , Rhadinovirus/physiology , Virus Replication , Animals , Endonucleases/genetics , Endonucleases/metabolism , Genome, Viral , Herpesviridae Infections/genetics , Mice , NIH 3T3 Cells , RNA Polymerase II/genetics , Transcription Factor TFIIB/genetics , Transcription Factor TFIIB/metabolism , Viral Proteins/genetics , Viral Proteins/metabolism
5.
Elife ; 72018 10 03.
Article in English | MEDLINE | ID: mdl-30281021

ABSTRACT

Alterations in global mRNA decay broadly impact multiple stages of gene expression, although signals that connect these processes are incompletely defined. Here, we used tandem mass tag labeling coupled with mass spectrometry to reveal that changing the mRNA decay landscape, as frequently occurs during viral infection, results in subcellular redistribution of RNA binding proteins (RBPs) in human cells. Accelerating Xrn1-dependent mRNA decay through expression of a gammaherpesviral endonuclease drove nuclear translocation of many RBPs, including poly(A) tail-associated proteins. Conversely, cells lacking Xrn1 exhibited changes in the localization or abundance of numerous factors linked to mRNA turnover. Using these data, we uncovered a new role for relocalized cytoplasmic poly(A) binding protein in repressing recruitment of TATA binding protein and RNA polymerase II to promoters. Collectively, our results show that changes in cytoplasmic mRNA decay can directly impact protein localization, providing a mechanism to connect seemingly distal stages of gene expression.


Subject(s)
Gene Expression Regulation , Protein Transport , RNA Stability , RNA Transport , RNA, Messenger/metabolism , RNA-Binding Proteins/metabolism , Transcription, Genetic , Exoribonucleases/metabolism , HEK293 Cells , Humans , Mass Spectrometry , Microtubule-Associated Proteins/metabolism , Poly(A)-Binding Proteins/metabolism , Promoter Regions, Genetic , Protein Binding , RNA Polymerase II/metabolism , Staining and Labeling , TATA-Box Binding Protein/metabolism
6.
Cell Host Microbe ; 18(2): 243-53, 2015 Aug 12.
Article in English | MEDLINE | ID: mdl-26211836

ABSTRACT

Gamma-herpesviruses encode a cytoplasmic mRNA-targeting endonuclease, SOX, that cleaves most cellular mRNAs. Cleaved fragments are subsequently degraded by the cellular 5'-3' mRNA exonuclease Xrn1, thereby suppressing cellular gene expression and facilitating viral evasion of host defenses. We reveal that mammalian cells respond to this widespread cytoplasmic mRNA decay by altering RNA Polymerase II (RNAPII) transcription in the nucleus. Measuring RNAPII recruitment to promoters and nascent mRNA synthesis revealed that the majority of affected genes are transcriptionally repressed in SOX-expressing cells. The transcriptional feedback does not occur in response to the initial viral endonuclease-induced cleavage, but instead to degradation of the cleaved fragments by cellular exonucleases. In particular, Xrn1 catalytic activity is required for transcriptional repression. Notably, viral mRNA transcription escapes decay-induced repression, and this escape requires Xrn1. Collectively, these results indicate that mRNA decay rates impact transcription and that gamma-herpesviruses use this feedback mechanism to facilitate viral gene expression.


Subject(s)
Feedback , Gammaherpesvirinae/enzymology , Host-Pathogen Interactions , RNA Stability , Ribonucleases/metabolism , Transcription, Genetic , Cell Line , Exoribonucleases/metabolism , Gene Expression Profiling , Humans , Microtubule-Associated Proteins/metabolism , Molecular Sequence Data , RNA Polymerase II/antagonists & inhibitors , Sequence Analysis, DNA
7.
Nat Immunol ; 15(10): 957-64, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25194422

ABSTRACT

Despite the increasing knowledge of the molecular events that induce the glycolysis pathway in effector T cells, very little is known about the transcriptional mechanisms that dampen the glycolysis program in quiescent cell populations such as memory T cells. Here we found that the transcription factor Bcl-6 directly repressed genes encoding molecules involved in the glycolysis pathway, including Slc2a1, Slc2a3, Pkm and Hk2, in type 1 helper T cells (TH1 cells) exposed to low concentrations of interleukin 2 (IL-2). Thus, Bcl-6 had a role opposing the IL-2-sensitive glycolytic transcriptional program that the transcription factors c-Myc and HIF-1α promote in effector T cells. Additionally, the TH1 lineage-specifying factor T-bet functionally antagonized the Bcl-6-dependent repression of genes encoding molecules in the glycolysis pathway, which links the molecular balance of these two factors to regulation of the metabolic gene program.


Subject(s)
CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , DNA-Binding Proteins/genetics , Glycolysis/genetics , Metabolic Networks and Pathways/genetics , Animals , Blotting, Western , CD4-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/drug effects , Cell Line, Tumor , Cells, Cultured , DNA-Binding Proteins/metabolism , Gene Expression/drug effects , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Interleukin-2/pharmacology , Mice , Mice, Inbred C57BL , Mice, Knockout , Proto-Oncogene Proteins c-bcl-6 , Reverse Transcriptase Polymerase Chain Reaction
8.
J Nurs Educ ; 46(1): 28-32, 2007 01.
Article in English | MEDLINE | ID: mdl-17302097

ABSTRACT

Registered nurses and nurse educators are often unaware of how nursing students experience the nursing profession. In the current practice climate of increased workloads, reduced funding, and higher patient acuity, nurse educators are likely to hear from colleagues how unprepared newly qualified nurses are for the needs of practice. It is difficult for many nursing students to see value in their practice because they become preoccupied with their perceived lack of knowledge and technical skills. Nurses and nurse educators should be aware of how this brands new graduates and informs their sense of developing professional identity. Despite their feelings of deficit in terms of skills and knowledge, it is clear that many nursing students are, in fact, effectively negotiating relational ethics. This article presents a collaborative account of the important relational work being undertaken by one group of nursing students in New Zealand.


Subject(s)
Attitude of Health Personnel , Clinical Competence/standards , Morals , Nurse-Patient Relations , Students, Nursing/psychology , Transcultural Nursing/ethics , Ceremonial Behavior , Cultural Diversity , Education, Nursing, Baccalaureate/organization & administration , Empathy , Health Knowledge, Attitudes, Practice , Health Services Needs and Demand , Holistic Health , Humans , New Zealand , Nurse's Role/psychology , Nursing Assessment/ethics , Nursing Methodology Research , Patient Advocacy/ethics , Patient Advocacy/psychology , Patient Care Planning/ethics , Power, Psychological , Practice Guidelines as Topic , Principle-Based Ethics , Self Efficacy , Semantics , Transcultural Nursing/education , Transcultural Nursing/organization & administration
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