scholarly journals Regulation of Gene Expression by Telomere Position Effect

2021 ◽  
Vol 22 (23) ◽  
pp. 12807
Author(s):  
Kyung-Ha Lee ◽  
Do-Yeon Kim ◽  
Wanil Kim
Keyword(s):  
Gene Expression ◽  
Structural Changes ◽  
Genome Rearrangement ◽  
Malignant Tumors ◽  
Human Life ◽  
Position Effect ◽  
Regulation Of Gene Expression ◽  
The Elderly ◽  
Cellular Aging ◽  
Telomere Shortening

Many diseases that involve malignant tumors in the elderly affect the quality of human life; therefore, the relationship between aging and pathogenesis in geriatric diseases must be under-stood to develop appropriate treatments for these diseases. Recent reports have shown that epigenetic regulation caused by changes in the local chromatin structure plays an essential role in aging. This review provides an overview of the roles of telomere shortening on genomic structural changes during an age-dependent shift in gene expression. Telomere shortening is one of the most prominent events that is involved in cellular aging and it affects global gene expression through genome rearrangement. This review provides novel insights into the roles of telomere shortening in disease-affected cells during pathogenesis and suggests novel therapeutic approaches.

scholarly journals Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances

2014 ◽  
Vol 28 (22) ◽  
pp. 2464-2476 ◽  
Author(s):  
Jérôme D. Robin ◽  
Andrew T. Ludlow ◽  
Kimberly Batten ◽  
Frédérique Magdinier ◽  
Guido Stadler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Position Effect ◽  
Regulation Of Gene Expression ◽  
Telomere Shortening ◽  
Telomere Position Effect

scholarly journals MKL-1 regulates the stem cell marker. CD44 in breast cancer cells

2019 ◽  
Vol 78 ◽  
pp. 01002
Author(s):  
Zhou-Tong Dai ◽  
Ao Yao ◽  
Yuan Xiang ◽  
Jia Peng Li ◽  
Wei Guo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Malignant Tumors ◽  
Regulation Of Gene Expression ◽  
Gene Promoter ◽  
Expression Regulation ◽  
Stem Cell Marker ◽  
Luciferase Reporter ◽  
Regulation Mechanism ◽  
Luciferase Reporter Gene ◽  
Factors Affecting

CD44, cluster of differentiation 44 is a typical marker of stem cells. At present, it has been found that CD44 is prevalent in various human malignant tumors, but its expression regulation mechanism is still not clear. The initiation of gene expression, the modification of RNA levels, and the regulation of protein levels are the main factors affecting the expression level of genes, and the most critical one is the regulation of gene expression by signaling pathways. Up to now, there has been no report on the role of MKL-1 in the cloning of the cd44 promoter. Therefore, this study intends to clone the cd44 gene promoter, construct its luciferase reporter gene vector, transfect the MKL-1 overexpression vector, and analyze how it affects transcriptional activity, in order to further study the expression regulation of cd44. The mechanism provides a powerful tool in the future.

Copy number variation and expression of CT-genes in patients with colorectal cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16104-e16104
Author(s):  
Yuriy A. Gevorkyan ◽  
Denis S. Kutilin ◽  
Oleg I. Kit ◽  
Natalya V. Soldatkina ◽  
Dmitry A. Kharagezov ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Copy Number ◽  
Tumor Tissue ◽  
Malignant Tumors ◽  
Regulation Of Gene Expression ◽  
Rank Correlation ◽  
Normal Colon ◽  
Aberrant Expression ◽  
Spearman’S Rank Correlation

e16104 Background: Cancer-testis antigens (CTAs) can be used for immunotherapeutic approaches and early detection of malignant tumors. Despite numerous studies of CTA expression in various tumors, including colon tumors, the mechanisms of transcriptional activity regulation in colorectal cancer (CRC) remain poorly studied. One of the possible mechanisms of regulation of gene expression is a change in their copy number (CNV). The aim of the study was to analyze the changes in the copy number and expression of CT-genes in patients with CRC. Methods: Tumor and normal colon tissues of 81 patients were used in the study. DNA was isolated by phenol-chloroform extraction. RNA was isolated by the Chomczynski&Sacchi method (2006). The REVERTA-L reagent kit was used for the cDNA synthesis. Determination of expression and copy number of 16 CT genes ( MAGE-A1, -A2, -A3, -A4, MAGE-B1, -B2, GAGE-1, -3, -4, MAGEC1, BAGE, XAGE3, NYESO1, SSX2, SCP1, PRAME1) was performed using the Real-Time qPCR method (reference genes - GAPDH and GUSB). Differences were evaluated using the Mann-Whitney test, correlation analysis - using Spearman's rank correlation coefficient (r). Results: An analysis of CT-gene expression and CNV in tumor and normal colon tissues (n = 81) revealed a statistically significant (p < 0.05) difference between these parameters in tumor tissue relative to normal one: for MAGEB1 an increase of 2.0 and 2.7 times, GAGE3 an increase of 2.0 and 2.5 times, GAGE4 decreased by 5.0 and 6.8 times, BAGE decreased by 2.4 and 1.7 times, SSX2 increased by 1.8 and 2.1 times, SCP1 increased copy number by 4.4 times and PRAME1 increased expression and copy number by 2.9 and 2.3 times, respectively. When comparing CNV and expression of 16 CT genes, a positive correlation was observed (r = 0.875). Conclusions: Thus, the aberrant expression of MAGEB1, GAGE3, GAGE4, BAGE, SSX2 and PRAME1 found in the tumor tissue of CRC patients depends on the copy number of these CT-genes.

BCR-ABL Cooperates With a “Telomere-Associated Secretory Phenotype” (TASP) To Facilitate Malignant Proliferation Of Hematopoietic Stem Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3976-3976
Author(s):  
Tim H. Brümmendorf ◽  
Nora Pällmann ◽  
Michael Preukschas ◽  
Doris Steinemann ◽  
Winfried Hofmann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Disease Progression ◽  
Blast Crisis ◽  
Position Effect ◽  
Chronic Phase ◽  
Telomere Shortening ◽  
Hematopoietic Stem ◽  
Secretory Phenotype ◽  
G2 Cells

Abstract Chronic myeloid leukemia (CML) is a hematopoietic stem cell (HSC) disease caused by the reciprocal translocation t(9;22). Although there is clear evidence that the resulting oncogenic tyrosine kinase BCR-ABL is the key event of leukemia initiation which drives stem cell proliferation and expansion of myeloid progenitors in early chronic phase (CP), the mechanism leading to advanced phases remains elusive. Recently, we could show that telomere attrition correlates with disease stages due to increased leukemic stem cell turnover. Here, we could provide first time evidence that this can functionally contribute to disease progression in CML. In our study we made use of the well-described telomerase knockout mouse model (mTR-/-), lacking the RNA subunit of telomerase and resulting in significant telomere shortening with each generation, and retrovirally introduced BCR-ABL into primary bone marrow cells of different generation. Although all CML-like cultures (hereafter referred to as “CML”) grew exponentially and growth factor independently in vitro, they showed remarkable differences in cellular growth kinetics depending on the generation of mTR-/-mice the cells were derived from. CML-HSCs of generation iG4 (CML-iG4) are functionally impaired with respect to their growth properties and ceased to proliferate due to a robust senescent-like cell cycle arrest. Interestingly, they did not show overt genomic instability, but and are less susceptible to Imatinib-induced apoptosis compared to wildtype cells (CML-WT). In sharp contrast, CML-G2 cells with only pre-shortened telomere lengths grew most rapidly and presented with an impressive proliferation advantage compared to CML-WT and -iG4 cells, while they still retain Imatinib sensitivity. Notably, we uncovered that this growth advantage is related to a “telomere-associated secretory phenotype” (TASP), comprising the upregulation and secretion of chemokines, interleukins and other growth factors, thereby potentiating oncogene-driven growth in an autocrine fashion. In line with those observations, we found that conditioned supernatant of CML-G2 cells markedly enhanced proliferation of CML-WT and pre-senescent CML-iG4 HSCs. To investigate if a TPE (telomere position effect)-related mechanism is responsible for inducing inflammatory gene expression in BCR-ABL positive cells, we mapped selected TASP genes for their chromosomal location. However, although they are frequently found in well-known cluster (e.g. chemokines), TASP genes are not preferentially located close to the (sub-) telomere. This suggests that a yet unknown mechanism controls TASP gene expression upon telomere shortening. Most importantly, a similar inflammatory mRNA expression pattern was found in CML patients of accelerated phase (AP), but not in blast crisis (BC). Taken together, those data support the hypothesis that accelerated telomere shortening contributes to disease progression in BCR-ABL-driven leukemogenesis by the expression of an inflammatory signature, while telomere-induced senescence needs to be bypassed (e.g. by upregulation of telomerase) in order for leukemic cells to be able to progress to blast crisis (BC) CML. Disclosures: Brümmendorf: Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding; Ariad: Consultancy.

Regulation of transcription factor activity during cellular aging

1996 ◽  
Vol 74 (4) ◽  
pp. 523-534 ◽  
Author(s):  
Keith Wheaton ◽  
Peter Atadja ◽  
Karl Riabowol
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Serum Response Factor ◽  
Regulation Of Gene Expression ◽  
Cellular Aging ◽  
Regulation Of Transcription ◽  
Transcription Factor Activity ◽  
Factor Activity ◽  
Altered Gene

Several lines of evidence suggest that the limited replication potential of normal human cells is due to the presence of an intrinsic genetic programme. This "senescence programme" is believed to reduce the incidence of cancer by limiting the growth of most of the transformed cells arising in vivo, although some cells do escape senescence becoming both immortalized and transformed. Here we review the literature that describes the senescence process in terms of gene expression and the regulation of gene expression by a variety of mechanisms affecting transcription factor activity. We focus on regulation of the c-fos gene through posttranslational modification of the serum response factor (SRF) as an example of altered gene expression during cellular aging.Key words: cellular aging, transcription, Fos, SRF, phosphorylation.

scholarly journals Imaging assay to probe the role of telomere length shortening on telomere-gene interactions in single cells

Chromosoma ◽  
2021 ◽  
Vol 130 (1) ◽  
pp. 61-73
Author(s):  
Ning Zhang ◽  
Yanhui Li ◽  
Tsung-Po Lai ◽  
Jerry W. Shay ◽  
Gaudenz Danuser
Keyword(s):  
Gene Expression ◽  
Telomere Length ◽  
Single Cells ◽  
Position Effect ◽  
Regulation Of Gene Expression ◽  
Telomeric Sequence ◽  
Long Distance ◽  
Position Effects ◽  
Age Progression

AbstractTelomeres are repetitive non-coding nucleotide sequences (TTAGGGn) capping the ends of chromosomes. Progressive telomere shortening with increasing age has been associated with shifts in gene expression through models such as the telomere position effect (TPE), which suggests reduced interference of the telomere with transcriptional activity of increasingly more distant genes. A modification of the TPE model, referred to as Telomere Position Effects over Long Distance (TPE-OLD), explains why some genes 1–10 MB from a telomere are still affected by TPE, but genes closer to the telomere are not. Here, we describe an imaging approach to systematically examine the occurrence of TPE-OLD at the single cell level. Compared to existing methods, the pipeline allows rapid analysis of hundreds to thousands of cells, which is necessary to establish TPE-OLD as an acceptable mechanism of gene expression regulation. We examined two human genes, ISG15 and TERT, for which TPE-OLD has been described before. For both genes, we found less interaction with the telomere on the same chromosome in old cells compared to young cells; and experimentally elongated telomeres in old cells rescued the level of telomere interaction for both genes. However, the dependency of the interactions on the age progression from young to old cells varied. One model for the differences between ISG15 and TERT may relate to the markedly distinct interstitial telomeric sequence arrangement in the two genes. Overall, this provides a strong rationale for the role of telomere length shortening in the regulation of gene expression.

Linking transcription, RNA polymerase II elongation and alternative splicing

2020 ◽  
Vol 477 (16) ◽  
pp. 3091-3104 ◽  
Author(s):  
Luciana E. Giono ◽  
Alberto R. Kornblihtt
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Rna Polymerase Ii ◽  
Environmental Changes ◽  
Transcription Elongation ◽  
Single Gene ◽  
Regulation Of Gene Expression ◽  
Regulation Of Transcription ◽  
Stepping Stones ◽  
Eukaryotic Transcription

Gene expression is an intricately regulated process that is at the basis of cell differentiation, the maintenance of cell identity and the cellular responses to environmental changes. Alternative splicing, the process by which multiple functionally distinct transcripts are generated from a single gene, is one of the main mechanisms that contribute to expand the coding capacity of genomes and help explain the level of complexity achieved by higher organisms. Eukaryotic transcription is subject to multiple layers of regulation both intrinsic — such as promoter structure — and dynamic, allowing the cell to respond to internal and external signals. Similarly, alternative splicing choices are affected by all of these aspects, mainly through the regulation of transcription elongation, making it a regulatory knob on a par with the regulation of gene expression levels. This review aims to recapitulate some of the history and stepping-stones that led to the paradigms held today about transcription and splicing regulation, with major focus on transcription elongation and its effect on alternative splicing.

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