Dynamic intron retention modulates gene expression in the monocytic differentiation pathway

Immunology ◽  
2021 ◽  
Author(s):  
Renhua Song ◽  
Shweta Tikoo ◽  
Rohit Jain ◽  
Natalia Pinello ◽  
Amy YM Au ◽  
...  
Keyword(s):  
Gene Expression ◽  
Intron Retention ◽  
Monocytic Differentiation

scholarly journals Alternative splicing landscapes in Arabidopsis thaliana across tissues and stress conditions highlight major functional differences with animals

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Guiomar Martín ◽  
Yamile Márquez ◽  
Federica Mantica ◽  
Paula Duque ◽  
Manuel Irimia
Keyword(s):  
Gene Expression ◽  
Arabidopsis Thaliana ◽  
Alternative Splicing ◽  
Stress Responses ◽  
Target Genes ◽  
Intron Retention ◽  
Single Gene ◽  
Exon Skipping ◽  
Environmental Response ◽  
Biotic Stresses

Abstract Background Alternative splicing (AS) is a widespread regulatory mechanism in multicellular organisms. Numerous transcriptomic and single-gene studies in plants have investigated AS in response to specific conditions, especially environmental stress, unveiling substantial amounts of intron retention that modulate gene expression. However, a comprehensive study contrasting stress-response and tissue-specific AS patterns and directly comparing them with those of animal models is still missing. Results We generate a massive resource for Arabidopsis thaliana, PastDB, comprising AS and gene expression quantifications across tissues, development and environmental conditions, including abiotic and biotic stresses. Harmonized analysis of these datasets reveals that A. thaliana shows high levels of AS, similar to fruitflies, and that, compared to animals, disproportionately uses AS for stress responses. We identify core sets of genes regulated specifically by either AS or transcription upon stresses or among tissues, a regulatory specialization that is tightly mirrored by the genomic features of these genes. Unexpectedly, non-intron retention events, including exon skipping, are overrepresented across regulated AS sets in A. thaliana, being also largely involved in modulating gene expression through NMD and uORF inclusion. Conclusions Non-intron retention events have likely been functionally underrated in plants. AS constitutes a distinct regulatory layer controlling gene expression upon internal and external stimuli whose target genes and master regulators are hardwired at the genomic level to specifically undergo post-transcriptional regulation. Given the higher relevance of AS in the response to different stresses when compared to animals, this molecular hardwiring is likely required for a proper environmental response in A. thaliana.

scholarly journals c-sis but not c-fos gene expression is lineage specific in human myeloid cells

Blood ◽  
1988 ◽  
Vol 71 (2) ◽  
pp. 488-493
Author(s):  
E Sariban ◽  
T Mitchell ◽  
A Rambaldi ◽  
DW Kufe
Keyword(s):  
Gene Expression ◽  
Leukemic Cells ◽  
Monocytic Differentiation ◽  
Granulocytic Differentiation ◽  
Drug Induced ◽  
Monocytic Cells ◽  
Hexamethylene Bisacetamide ◽  
Gene Transcripts ◽  
Myelomonocytic Leukemia ◽  
Monocytic Lineage

Expression of both the c-fos and c-sis protooncogenes during myeloid differentiation has been detected in cells of the monocytic lineage. Since an increase in c-fos transcripts was not detected during dimethylsulfoxide induced HL-60 granulocytic differentiation, it was suggested that within the myeloid series c-fos gene expression might be lineage specific. In the present study, we have determined whether expression of the c-fos and c-sis genes is indeed specific for the monocytic pathway or rather common to both the granulocyte and monocyte pathways. C-fos and c-sis gene expression was analyzed in freshly isolated human granulocytes and monocytes, in human HL-60 promyelocytic leukemia cells induced to differentiate along the granulocytic or monocytic pathway, in myeloblasts from five patients with the M1 or M2 subtype of acute myeloblastic leukemia (AML) and in blasts from six patients with M4 myelomonocytic leukemia. The level of c-fos mRNA was fifteen times higher in granulocytes as compared with monocytes. An increase in c-fos expression was also found in HL-60 cells differentiated along the granulocytic pathway after exposure to hypoxanthine, hexamethylene bisacetamide, and the combination of retinoic acid and dibutyryl adenosine 3′5′ cyclic monophosphate. Three of 5 M1 and M2 leukemic myeloblast preparations depleted of lymphoid and monocytic cells and all six M4 leukemic cells expressed c-fos transcripts. In contrast, c-sis gene transcripts were detectable in monocytes and during drug induced monocytic differentiation of the HL- 60 cells but not in granulocytes during granulocytic differentiation of the HL-60 cells or in AML samples. Thus, in the myeloid series, c-sis gene expression is lineage specific while expression of the c-fos gene is found in both lineages and may be related to metabolic pathways common to both granulocytes and monocytes.

Posttranscriptional stabilization of c-fms mRNA by a labile protein during human monocytic differentiation

1989 ◽  
Vol 9 (2) ◽  
pp. 769-775
Author(s):  
B Weber ◽  
J Horiguchi ◽  
R Luebbers ◽  
M Sherman ◽  
D Kufe
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Half Life ◽  
Mrna Levels ◽  
Human Monocytes ◽  
Monocytic Differentiation ◽  
Transmembrane Glycoprotein ◽  
Inhibition Of Protein Synthesis ◽  
Monocytic Lineage ◽  
Posttranscriptional Level

The c-fms proto-oncogene encodes a transmembrane glycoprotein that is closely related or identical to the receptor for the monocyte colony-stimulating factor CSF-1. The present studies examined the mechanisms responsible for the regulation of c-fms gene expression during human monocytic differentiation. Levels of c-fms mRNA were undetectable in HL-60 promyelocytic leukemia cells, while 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced monocytic differentiation of these cells was associated with the appearance of these transcripts. Run-on transcription assays demonstrated that the c-fms gene was transcriptionally active in uninduced HL-60 cells and that the rate of transcription was unchanged after TPA treatment. These findings suggested that c-fms mRNA levels in HL-60 cells are controlled by posttranscriptional mechanisms. The half-life of c-fms transcripts in TPA-induced HL-60 cells was found to be at least 6 h, while inhibition of protein synthesis with cycloheximide (CHX) decreased this half-life to 4 h. Moreover, inhibition of protein synthesis was associated with decreases in c-fms mRNA levels and a block in the induction of c-fms transcripts by TPA. These findings indicated that the c-fms transcript is stabilized by a labile protein. In contrast to HL-60 cells, c-fms mRNA is constitutively expressed in resting human monocytes and is down-regulated by treatment of these cells with TPA. Run-on assays demonstrated that TPA-induced downregulation of c-fms mRNA levels in monocytes occurred at the posttranscriptional level. Moreover, the results demonstrate that levels of c-fms mRNA are regulated posttranscriptionally by a labile protein. In this regard, the half-life of the c-fms transcript was 6.1 h in monocytes, while treatment of these cells with CHX decreased the half-life to 30 min. Furthermore, this effect of CHX occurred in the absence of changes in the rate of c-fms gene transcription. Together, these findings indicate that c-fms gene expression is regulated at a posttranscriptional level both in HL-60 cells induced to differentiate along the monocytic lineage and in human monocytes. The findings also indicate that levels of c-fms mRNA are regulated by the synthesis of a labile protein which is involved in stabilization of the c-fms transcript.

scholarly journals Alternative Splicing During the Chlamydomonasreinhardtii Cell Cycle

2020 ◽  
Vol 10 (10) ◽  
pp. 3797-3810
Author(s):  
Manishi Pandey ◽  
Gary D. Stormo ◽  
Susan K. Dutcher
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Alternative Splicing ◽  
Chlamydomonas Reinhardtii ◽  
Intron Retention ◽  
Exon Skipping ◽  
Dark Phase ◽  
Periodic Patterns ◽  
Genome Wide ◽  
Splicing Pattern

Genome-wide analysis of transcriptome data in Chlamydomonas reinhardtii shows periodic patterns in gene expression levels when cultures are grown under alternating light and dark cycles so that G1 of the cell cycle occurs in the light phase and S/M/G0 occurs during the dark phase. However, alternative splicing, a process that enables a greater protein diversity from a limited set of genes, remains largely unexplored by previous transcriptome based studies in C. reinhardtii. In this study, we used existing longitudinal RNA-seq data obtained during the light-dark cycle to investigate the changes in the alternative splicing pattern and found that 3277 genes (19.75% of 17,746 genes) undergo alternative splicing. These splicing events include Alternative 5′ (Alt 5′), Alternative 3′ (Alt 3′) and Exon skipping (ES) events that are referred as alternative site selection (ASS) events and Intron retention (IR) events. By clustering analysis, we identified a subset of events (26 ASS events and 10 IR events) that show periodic changes in the splicing pattern during the cell cycle. About two-thirds of these 36 genes either introduce a pre-termination codon (PTC) or introduce insertions or deletions into functional domains of the proteins, which implicate splicing in altering gene function. These findings suggest that alternative splicing is also regulated during the Chlamydomonas cell cycle, although not as extensively as changes in gene expression. The longitudinal changes in the alternative splicing pattern during the cell cycle captured by this study provides an important resource to investigate alternative splicing in genes of interest during the cell cycle in Chlamydomonas reinhardtii and other eukaryotes.

Inhibition of EGR-1 and NF-κB gene expression by dexamethasone during phorbol ester-induced human monocytic differentiation

1992 ◽  
Vol 44 (8) ◽  
pp. 1569-1576 ◽  
Author(s):  
Ralf Hass ◽  
Marion Brach ◽  
Hisato Gunji ◽  
Surender Kharbanda ◽  
Donald Kufe
Keyword(s):  
Gene Expression ◽  
Phorbol Ester ◽  
Monocytic Differentiation

Intron retention and its impact on gene expression and protein diversity: A review and a practical guide

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
David F. Grabski ◽  
Lucile Broseus ◽  
Bandana Kumari ◽  
David Rekosh ◽  
Marie‐Louise Hammarskjold ◽  
...  
Keyword(s):  
Gene Expression ◽  
Intron Retention ◽  
Protein Diversity ◽  
Practical Guide

scholarly journals Alternative splicing landscapes in Arabidopsis thaliana across tissues and stress conditions highlight major functional differences with animals

2020 ◽  
Author(s):  
Guiomar Martín ◽  
Yamile Márquez ◽  
Federica Mantica ◽  
Paula Duque ◽  
Manuel Irimia
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Stress Responses ◽  
Target Genes ◽  
Intron Retention ◽  
Single Gene ◽  
Exon Skipping ◽  
Environmental Response ◽  
Biotic Stresses ◽  
External Stimuli

AbstractBackgroundAlternative splicing (AS) is a widespread regulatory mechanism in multicellular organisms. Numerous transcriptomic and single-gene studies in plants have investigated AS in response to specific conditions, especially environmental stress, unveiling substantial amounts of intron retention that modulate gene expression. However, a comprehensive study contrasting stress-response and tissue-specific AS patterns and directly comparing them with those of animal models is still missing.ResultsWe generated a massive resource for A. thaliana (PastDB; pastdb.crg.eu), comprising AS and gene expression quantifications across tissues, development and environmental conditions, including abiotic and biotic stresses. Harmonized analysis of these datasets revealed that A. thaliana shows high levels of AS (similar to fruitflies) and that, compared to animals, disproportionately uses AS for stress responses. We identified core sets of genes regulated specifically by either AS or transcription upon stresses or among tissues, a regulatory specialization that was tightly mirrored by the genomic features of these genes. Unexpectedly, non-intron retention events, including exon skipping, were overrepresented across regulated AS sets in A. thaliana, being also largely involved in modulating gene expression through NMD and uORF inclusion.ConclusionsNon-intron retention events have likely been functionally underrated in plants. AS constitutes a distinct regulatory layer controlling gene expression upon internal and external stimuli whose target genes and master regulators are hardwired at the genomic level to specifically undergo post-transcriptional regulation. Given the higher relevance of AS in the response to different stresses when compared to animals, this molecular hardwiring is likely required for a proper environmental response in A. thaliana.

scholarly journals Environmental perturbations lead to extensive directional shifts in RNA processing

2017 ◽  
Author(s):  
A. L. Richards ◽  
D. Watza ◽  
A. Findley ◽  
A. Alazizi ◽  
X. Wen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Rna Processing ◽  
Complex Traits ◽  
Intron Retention ◽  
Vast Number ◽  
Factor Binding ◽  
Environmental Perturbations ◽  
Exon Usage ◽  
The Impact

AbstractEnvironmental perturbations have large effects on both organismal and cellular traits, including gene expression, but the extent to which the environment affects RNA processing remains largely uncharacterized. Recent studies have identified a large number of genetic variants associated with variation in RNA processing that also have an important role in complex traits; yet we do not know in which contexts the different underlying isoforms are used. Here, we comprehensively characterized changes in RNA processing events across 89 environments in five human cell types and identified 15,300 event shifts (FDR = 15%) comprised of eight event types in over 4,000 genes. Many of these changes occur consistently in the same direction across conditions, indicative of global regulation by trans factors. Accordingly, we demonstrate that environmental modulation of splicing factor binding predicts shifts in intron retention, and that binding of transcription factors predicts shifts in AFE usage in response to specific treatments. We validated the mechanism hypothesized for AFE in two independent datasets. Using ATAC-seq, we found altered binding of 64 factors in response to selenium at sites of AFE shift, including ELF2 and other factors in the ETS family. We also performed AFE QTL mapping in 373 individuals and found an enrichment for SNPs predicted to disrupt binding of the ELF2 factor. Together, these results demonstrate that RNA processing is dramatically changed in response to environmental perturbations through specific mechanisms regulated by trans factors.Author SummaryChanges in a cell’s environment and genetic variation have been shown to impact gene expression. Here, we demonstrate that environmental perturbations also lead to extensive changes in alternative RNA processing across a large number of cellular environments that we investigated. These changes often occur in a non-random manner. For example, many treatments lead to increased intron retention and usage of the downstream first exon. We also show that the changes to first exon usage are likely dependent on changes in transcription factor binding. We provide support for this hypothesis by considering how first exon usage is affected by disruption of binding due to treatment with selenium. We further validate the role of a specific factor by considering the effect of genetic variation in its binding sites on first exon usage. These results help to shed light on the vast number of changes that occur in response to environmental stimuli and will likely aid in understanding the impact of compounds to which we are daily exposed.

scholarly journals Splicing Control in Normal and Aberrant Erythropoiesis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. SCI-47-SCI-47
Author(s):  
Esther Obeng
Keyword(s):  
Gene Expression ◽  
Rna Processing ◽  
Iron Transport ◽  
Rna Binding ◽  
Intron Retention ◽  
Point Mutations ◽  
Cytoskeletal Proteins ◽  
Mrna Splicing ◽  
Splice Sites ◽  
Erythroid Maturation

Abstract Alternative splicing is employed by all eukaryotic cells to increase proteome diversity and to regulate gene expression. RNA sequencing analysis of purified populations of erythroblasts at different stages of maturation has led to the identification of a dynamic alternative splicing program that directly modulates the protein isoform expression of cytoskeletal proteins and genes involved in RNA processing, heme biosynthesis, and iron transport. Regulated interactions of multiple RNA-binding proteins and cis-regulatory sequences located within exons or their flanking introns promote or inhibit functional spliceosome assembly at splice junctions, leading to altered exon inclusion or intron retention. Exon skipping regulates tissue and stage specific isoform expression of red cell membrane cytoskeletal proteins including EPB41, ankyrin, and band 3. Intron retention can lead to a frame shift during translation and introduction of a premature termination codon (PTC), that marks the transcript for degradation via the nonsense mediated decay pathway (NMD) upon export from the nucleus into the cytoplasm. Intron retention leading to posttranscriptional regulation of gene expression during terminal erythroid maturation has been identified in genes involved in RNA processing and iron transport including SF3B1, SNRNP70, SLC25A37 and SLC25A28. Mutations that alter mRNA splice sites or introduce PTCs lead to a variety of congenital anemias including beta thalassemia, hereditary pyropoikilocytosis, hereditary elliptocytosis, and hereditary spherocytosis. Aberrant mRNA splicing has subsequently been shown to lead to acquired anemias in subsets of patients with myelodysplastic syndromes (MDS). Somatic missense mutations in components of the spliceosome are the most common category of mutations in MDS. These point mutations lead to changes in the RNA binding specificity of the involved proteins and aberrant splicing of a subset of transcripts. Mutant SF3B1, the most commonly mutated splicing factor in MDS, has been shown to cause aberrant pre-mRNA splicing and an increase in transcripts predicted to undergo NMD due to use of upstream, cryptic 3' splice sites. Our group and others evaluating the strong genotype-phenotype association between SF3B1 point mutations and subtypes of MDS with ring sideroblasts have shown that the expression of the mitochondrial iron transporter, ABCB7, is decreased in samples from SF3B1-mutant MDS patients due to cryptic 3' splice site selection and introduction of a PTC between exons 8 and 9. The identification and functional validation of additional aberrantly spliced mutant-SF3B1 target genes is ongoing, with the goal of understanding how point mutations in a core component of the mRNA splicing machinery can lead to such specific effects on erythroid maturation. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document