scholarly journals Binding Sites of miR-1273 Family on the mRNA of Target Genes

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Anatoly Ivashchenko ◽  
Olga Berillo ◽  
Anna Pyrkova ◽  
Raigul Niyazova
Keyword(s):  
Binding Sites ◽  
Target Genes ◽  
Amino Acid Sequences ◽  
Mirna Binding Site ◽  
Maximum Value ◽  
Human Genes ◽  
High Conservation ◽  
Hybridization Energy ◽  
Homologous Amino Acid

This study examined binding sites of 2,578 miRNAs in the mRNAs of 12,175 human genes using the MirTarget program. It found that the miRNAs of miR-1273 family have between 33 and 1,074 mRNA target genes, with a free hybridization energy of 90% or more of its maximum value. The miR-1273 family consists of miR-1273a, miR-1273c, miR-1273d, miR-1273e, miR-1273f, miR-1273g-3p, miR-1273g-5p, miR-1273h-3p, and miR-1273h-5p. Unique miRNAs (miR-1273e, miR-1273f, and miR-1273g-3p) have more than 400 target genes. We established 99 mRNA nucleotide sequences that contain arranged binding sites for the miR-1273 family. High conservation of each miRNA binding site in the mRNA of the target genes was found. The arranged binding sites of the miR-1273 family are located in the 5′UTR, CDS, or 3′UTR of many mRNAs. Five repeating sites containing some of the miR-1273 family’s binding sites were found in the 3′UTR of several target genes. The oligonucleotide sequences of miR-1273 binding sites located in CDSs code for homologous amino acid sequences in the proteins of target genes. The biological role of unique miRNAs was also discussed.

scholarly journals miR-1322 Binding Sites in Paralogous and Orthologous Genes

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Raigul Niyazova ◽  
Olga Berillo ◽  
Shara Atambayeva ◽  
Anna Pyrkova ◽  
Aigul Alybayeva ◽  
...  
Keyword(s):  
Amino Acids ◽  
Transcription Factors ◽  
Amino Acid ◽  
Binding Site ◽  
Binding Sites ◽  
Target Genes ◽  
Amino Acid Sequences ◽  
Orthologous Genes ◽  
Start Position ◽  
Human Genes

We searched for 2,563 microRNA (miRNA) binding sites in 17,494 mRNA sequences of human genes. miR-1322 has more than 2,000 binding sites in 1,058 genes withΔG/ΔGmratio of 85% and more. miR-1322 has 1,889 binding sites in CDSs, 215 binding sites in 5′ UTRs, and 160 binding sites in 3′ UTRs. From two to 28 binding sites have arranged localization with the start position through three nucleotides of each following binding site. The nucleotide sequences of these sites in CDSs encode oligopeptides with the same and/or different amino acid sequences. We found that 33% of the target genes encoded transcription factors. miR-1322 has arranged binding sites in the CDSs of orthologousMAMLD1,MAML2, andMAML3genes. These sites encode a polyglutamine oligopeptide ranging from six to 47 amino acids in length. The properties of miR-1322 binding sites in orthologous and paralogous target genes are discussed.

scholarly journals The role of miRNA genes participating in VHL-HIF1α in clear cell renal cell carcinoma

2019 ◽  
Vol 6 (4) ◽  
pp. 36-41 ◽  
Author(s):  
V. N. Pavlov ◽  
I. R. Gilyazova ◽  
A. A. Izmailov ◽  
E. A. Klimentova ◽  
I. R. Sultanov ◽  
...  
Keyword(s):  
Binding Site ◽  
Binding Sites ◽  
Target Genes ◽  
Venous Blood ◽  
Mirna Binding Site ◽  
Cell Renal Cell Carcinoma ◽  
Vhl Gene ◽  
Increased Risk ◽  
Tsc1 Gene

Introduction. Much attention in ccRCC development is paid to VHL-HIF1α pathway genes. Numerous genes involved in the pathogenesis of ccRCC are targets for miRNA. Alteration in the nature of interaction with miRNA binding site as a result of a single nucleotide substitution may promote change the expression of target genes involved in the genesis and development of tumors.Purpose of research. Analysis of the role of polymorphic variants in the miRNA binding sites of the VHL-HIF1α gene pathways in ccRCC development.Materials and methods. We used 225 DNA samples isolated from the venous blood of ccRCC patients who are hospitalized to the Clinic of the Bashkir State Medical University, and 298 healthy individuals. The genotyping of miRNA binding site polymorphisms in VHL-HIFα-dependent pathway genes (rs10982724 of the DEC1 gene, rs406271 of the TFRC gene, rs10491534 of the TSC1 gene, rs1642742 of the VHL gene, rs3025033 of the VEGFA gene) was performed using Taq-man assays.Results. The frequency distribution of alleles and genotypes of rs1642742 of the VHL gene showed that rs1642742 *GG is a marker of the increased risk for ccRCC. In addition, rs10491534 * C allele was found to be the marker for severe ccRCC (p = 0.044; OR = 1.72 (CI = 1.012-2.911)), and rs10491534 * TT genotype (p = 0.044; OR = 0.55; (95% CI = 0.31–0.98)) of the TSC1 gene was shown to be a protective marker for ccRCC of severe duration.Conclusions. The study indicated the association of miRNA binding sites polymorphisms with the risk of ccRCC development and severity of disease. However, further studies of the genes are needed to establish their functional significance and role in the pathogenesis of ccRCC.

scholarly journals Low-affinity transcription factor binding sites shape morphogen responses and enhancer evolution

2013 ◽  
Vol 368 (1632) ◽  
pp. 20130018 ◽  
Author(s):  
Andrea I. Ramos ◽  
Scott Barolo
Keyword(s):  
Transcription Factor ◽  
Binding Affinity ◽  
Binding Sites ◽  
Target Genes ◽  
Gene Activation ◽  
Transcriptional Response ◽  
Morphogen Gradients ◽  
Weak Binding ◽  
Initial Hypothesis

In the era of functional genomics, the role of transcription factor (TF)–DNA binding affinity is of increasing interest: for example, it has recently been proposed that low-affinity genomic binding events, though frequent, are functionally irrelevant. Here, we investigate the role of binding site affinity in the transcriptional interpretation of Hedgehog (Hh) morphogen gradients . We noted that enhancers of several Hh-responsive Drosophila genes have low predicted affinity for Ci, the Gli family TF that transduces Hh signalling in the fly. Contrary to our initial hypothesis, improving the affinity of Ci/Gli sites in enhancers of dpp , wingless and stripe , by transplanting optimal sites from the patched gene, did not result in ectopic responses to Hh signalling. Instead, we found that these enhancers require low-affinity binding sites for normal activation in regions of relatively low signalling. When Ci/Gli sites in these enhancers were altered to improve their binding affinity, we observed patterning defects in the transcriptional response that are consistent with a switch from Ci-mediated activation to Ci-mediated repression. Synthetic transgenic reporters containing isolated Ci/Gli sites confirmed this finding in imaginal discs. We propose that the requirement for gene activation by Ci in the regions of low-to-moderate Hh signalling results in evolutionary pressure favouring weak binding sites in enhancers of certain Hh target genes.

ASXL2 Is a Novel Mediator of RUNX1-ETO Transcriptional Function and Collaborates with RUNX1-ETO to Promote Leukemogenesis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 302-302
Author(s):  
Jean-Baptiste Micol ◽  
Nicolas Duployez ◽  
Alessandro Pastore ◽  
Robert Williams ◽  
Eunhee Kim ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Line ◽  
Hematopoietic Stem Cell ◽  
Binding Sites ◽  
Target Genes ◽  
Cell Function ◽  
Rna Seq ◽  
Hematopoietic Stem

Abstract Mutations in Addition of Sex Combs Like 1 (ASXL1) are common in patients with myeloid leukemias. More recently, mutations in ASXL2, a paralog of ASXL1 with ~40% shared amino acid homology, have been discovered to occur specifically in patients with acute myeloid leukemia (AML) patients bearing the RUNX1-ETO (AML1-ETO; RUNX1-RUNX1T1) translocation and are amongst the most common mutations in RUNX1-ETO AML (mutated in 20-25% of patients). Although ASXL1 is critical for Polycomb Repressive Complex 2 function in myeloid hematopoietic cells and loss of Asxl1 recapitulates key aspects of myelodysplastic syndrome (MDS), the function of ASXL2 in normal or malignant hematopoiesis is unknown. We therefore set out to perform a functional comparison of ASXL1and ASXL2on hematopoiesis and transcription and determine the functional basis for frequent mutations in RUNX1-ETO AML. In vitro analyses of ASXL2 insertion/deletion mutations revealed that these mutations resulted in substantial reduction of ASXL2 protein expression, stability, and half-life. We therefore generated Asxl2 conditional knockout (cKO) mice to delineate the effect of ASXL2 loss on hematopoiesis. Competitive (Fig. 1A) and noncompetitive transplantation revealed that Asxl2 or compound Asxl1/2 loss resulted in cell-autonomous, rapid defects of hematopoietic stem cell function, self-renewal, and number with peripheral blood leukopenia and thrombocytopenia but without any obvious MDS features- phenotypes distinct from Asxl1 cKO mice. Mice with heterozygous deletion of Asxl2 demonstrated an intermediate phenotype between control and homozygous cKO mice indicating a gene dosage effect of Asxl2 loss. RNA sequencing (RNA-seq) of hematopoietic stem/progenitor cells from Asxl2- and Asxl1-deficient mice revealed twenty-fold greater differentially expressed genes in Asxl2 cKO mice relative to Asxl1 cKO mice. Interestingly, genes differentially expressed with Asxl2 loss significantly overlapped with direct transcriptional targets of RUNX1-ETO, findings not seen in Asxl1 cKO mice (Fig. 1B). Asxl2 target genes appeared to also be targets of RUNX1, a key gene repressed by RUNX1-ETO to promote leukemogenesis. Consistent with this, genome-wide analysis of Asxl2 binding sites through anti-Asxl2 ChIP-seq revealed that Asxl2 binding sites substantially overlap with those of Runx1. Overall, the above data suggest that Asxl2 may be a critical mediator of RUNX1-ETO mediated leukemogenesis by affecting the expression of RUNX1 and/or RUNX1-ETO target genes. RNA-seq of primary RUNX1-ETO AML patient samples revealed that ASXL2-mutant RUNX1-ETO patients form a distinct transcriptional subset of RUNX1-ETO AML (Fig. 1C) suggesting a specific role of ASXL2 in leukemogenesis. To functionally interrogate the role of ASXL2 loss in RUNX1-ETO mediated leukemogenesis we first utilized an in vitro model with RNAi-mediated depletion of ASXL1 or ASXL2 in the SKNO1 cell line (the only ASXL-wildtype human RUNX1-ETO cell line). RNA-seq revealed distinct target genes dysregulated by ASXL1 versus ASXL2 loss in these cells without any significant overlap. Anti-ASXL2, RUNX1, and RUNX1-ETO ChIPSeq in SKNO1 cells revealed significant co-occupancy of ASXL2 with RUNX1 and RUNX1-ETO binding sites. Moreover, analysis of histone modification ChIPSeq revealed an enrichment in intergenic and enhancer H3K4me1 abundance following ASXL2 loss in SKNO1 cells. Next, to understand the in vivo effects of Asxl2 loss in the context of RUNX1-ETO, we performed retroviral bone marrow (BM) transplantation assays using RUNX1-ETO9a in Asxl2 cKO mice. In contrast to the failure of hematopoietic stem cell function with Asxl2 deletion alone, mice reconstituted with BM cells expressing RUNX1-ETO9a in Asxl2-deficient background had a shortened leukemia-free survival compared to Asxl2 -wildtype control. Overall, these data reveal that ASXL2 is required for hematopoiesis and has differing biological and transcriptional functions from ASXL1. Moreover, this work identifies ASXL2 as a novel mediator of RUNX1-ETOtranscriptional function and provides a new model of penetrant RUNX1-ETO AML based on genetic events found in a substantial proportion of t(8;21) AML patients. Further interrogation of the enhancer alterations generated by ASXL2 loss in RUNX1-ETO AML may highlight new therapeutic approaches for this subset of AML. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Binding of Ca++ to Human Prothrombin

1975 ◽  
Author(s):  
R. Benarous ◽  
J. Elion
Keyword(s):  
Binding Sites ◽  
Equilibrium Dialysis ◽  
Specific Property ◽  
Binding Properties ◽  
Binding Ability ◽  
Ph Variation ◽  
Maximum Value ◽  
Number Of Binding Sites ◽  
Scatchard Plots

The Ca++ binding properties of human prothrombin were studied by equilibrium dialysis using 45 calcium chloride at +4° C with prothrombin concentration of about 1 mg/ml equilibrated in 0.025 M Tris HCl, 0.12 M NaCl buffer pH 7.4. Scatchard plots obtained were similar to those described by Steenflo (1973) for bovine prothrombin, suggesting a positive cooperativity in the binding of Ca++ with a maximum ratio of bound Ca++/free Ca++ of 3 moles of Ca++ bound per mole of protein.The total number of binding sites was found to be at about 7, less than 10 to 12 found for bovine prothrombin. Ca++ binding was dependent on pH variation of the buffer with a maximum value for pH 8.5. Chemical modifications of carboxyl groups of prothrombin according to Hoare and Koshland (1967) abolished the Ca++ binding ability of the molecule confirming the essential role of these residues in this specific property of prothrombin.

Bioinformatic Analysis of Transcriptional Regulation by Nur77 in Central Nervous System and Immune System

2021 ◽  
Author(s):  
Montserrat Olivares Costa ◽  
Fernando Faunes ◽  
María Estela Andrés
Keyword(s):  
Stem Cells ◽  
Central Nervous System ◽  
Nervous System ◽  
Transcription Factor ◽  
Immune Cells ◽  
Binding Sites ◽  
Target Genes ◽  
Bioinformatic Analysis ◽  
Neuronal Stem Cells

Abstract ObjectiveThe objectives of this work were to find genes regulated by Nur77 in neurons and to evaluate the possible common role of this transcription factor in neurons and lymphatic cells using published experimentally generated databases of ChIP-Seq and a microarray. We also characterized Nur77 binding throughout the genome. ResultsWe identified 113 Nur77 target genes in neuronal stem cells and 116 in neuronal cells. Cell adhesion and anchoring processes emerged as regulated by Nur77 in neurons and lymphatic cells. We found 9 common genes regulated by Nur77. Finally, we described a significant distribution of Nur77 binding sites in strong enhancers and active promoters. This work is a first step to understand the role of Nur77 and its common targets in neurons and immune cells.

Mechanisms of Transcriptional Regulation and Transformation by HOXA9

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. SCI-30-SCI-30
Author(s):  
Jay L. Hess ◽  
Cailin Collins ◽  
Joel Bronstein ◽  
Yuqing Sun ◽  
Surya Nagaraja
Keyword(s):  
Transcriptional Regulation ◽  
Transcription Factors ◽  
Transcriptional Activation ◽  
Binding Sites ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Hematopoietic Stem ◽  
A Genome ◽  
The Impact

Abstract Abstract SCI-30 HOXA9 plays important roles in both development and hematopoiesis and is overexpressed in more than 50 percent of acute myeloid leukemias (AML). Nearly all cases of AML with mixed lineage leukemia (MLL) translocations show increased HOXA9 expression, as well as cases with mutation of the nucleophosmin gene NPM1, overexpression of CDX2, and fusions of NUP98. In most cases, upregulation of HOXA9 is accompanied by upregulation of its homeodomain-containing cofactor MEIS1, which directly interacts with HOXA9. While HOXA9 alone is sufficient for transformation of hematopoietic stem cells in culture, the addition of MEIS1 increases the transformation efficiency and results in rapidly fatal leukemias in transplanted animals. Despite the crucial role that HOXA9 plays in development, hematopoiesis, and leukemia, its transcriptional targets and mechanisms of action are poorly understood. We have used ChIP-seq to identify Hoxa9 and Meis1 binding sites on a genome-wide level in myeloblastic cells, profiled their associated epigenetic modifications, identified the target genes regulated by HOXA9 and identified HOXA9 interacting proteins. HOXA9 and MEIS1 cobind at hundreds of promoter distal, highly evolutionarily conserved sites showing high levels of histone H3K4 monomethylation and CBP/P300 binding. These include many proleukemogenic gene loci, such as Erg, Flt3, Myb, Lmo2, and Sox4. In addition, HOXA9 binding sites overlap a subset of enhancers previously implicated in myeloid differentiation and inflammation. HOXA9 binding at enhancers stabilizes association of MEIS1 and lineage-restricted transcription factors, including C/EBPα, PU.1, and STAT5A/B thereby promoting CBP/p300 recruitment, histone acetylation, and transcriptional activation. Current efforts are focused on using both biochemical and genetic approaches to assess the role of HOXA9 “enhanceosome” components C/EBPα, PU.1, and STAT5A/B in transcriptional regulation and leukemogenesis. Studies to date suggest that C/EBPα and PU.1 binding can occur in the absence of HOXA9/MEIS1, supporting a model in which these proteins act as pioneer transcription factors for establishment of poised, but not activated, HOXA9-regulated enhancers. Work is under way to assess the impact of high-level HOXA9 and MEIS1 on enhanceosome assembly and the role of recruitment of transcriptional coactivators involved in target gene up- or downregulation, including histone acetyltransferases and chromatin remodeling complexes. Collectively, our findings suggest that HOXA9-regulated enhancers are a fundamental mechanism of HOX-mediated transcription in normal development that is deregulated in leukemia. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Nfib Regulates Transcriptional Networks That Control the Development of Prostatic Hyperplasia

Endocrinology ◽  
2015 ◽  
Vol 157 (3) ◽  
pp. 1094-1109 ◽  
Author(s):  
Magdalena M. Grabowska ◽  
Stephen M. Kelly ◽  
Amy L. Reese ◽  
Justin M. Cates ◽  
Tom C. Case ◽  
...  
Keyword(s):  
Binding Sites ◽  
Target Genes ◽  
Severe Disease ◽  
Family Members ◽  
Prostatic Hyperplasia ◽  
Transcriptional Networks ◽  
Small Subset ◽  
Published Data ◽  
Intermediate Cell

AbstractA functional complex consisting of androgen receptor (AR) and forkhead box A1 (FOXA1) proteins supports prostatic development, differentiation, and disease. In addition, the interaction of FOXA1 with cofactors such as nuclear factor I (NFI) family members modulates AR target gene expression. However, the global role of specific NFI family members has yet to be described in the prostate. In these studies, chromatin immunoprecipitation followed by DNA sequencing in androgen-dependent LNCaP prostate cancer cells demonstrated that 64.3% of NFIB binding sites are associated with AR and FOXA1 binding sites. Interrogation of published data revealed that genes associated with NFIB binding sites are predominantly induced after dihydrotestosterone treatment of LNCaP cells, whereas NFIB knockdown studies demonstrated that loss of NFIB drives increased AR expression and superinduction of a subset of AR target genes. Notably, genes bound by NFIB only are associated with cell division and cell cycle. To define the role of NFIB in vivo, mouse Nfib knockout prostatic tissue was rescued via renal capsule engraftment. Loss of Nfib expression resulted in prostatic hyperplasia, which did not resolve in response to castration, and an expansion of an intermediate cell population in a small subset of grafts. In human benign prostatic hyperplasia, luminal NFIB loss correlated with more severe disease. Finally, some areas of intermediate cell expansion were also associated with NFIB loss. Taken together, these results show a fundamental role for NFIB as a coregulator of AR action in the prostate and in controlling prostatic hyperplasia.

scholarly journals A direct and widespread role for the nuclear receptor EcR in mediating the response to ecdysone in Drosophila

2019 ◽  
Author(s):  
Christopher M. Uyehara ◽  
Daniel J. McKay
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Dna Binding ◽  
Nuclear Receptor ◽  
Binding Sites ◽  
Target Genes ◽  
Transcriptional Responses ◽  
Developmental Transitions ◽  
The Impact

ABSTRACTThe ecdysone pathway was amongst the first experimental systems employed to study the impact of steroid hormones on the genome. In Drosophila and other insects, ecdysone coordinates developmental transitions, including wholesale transformation of the larva into the adult during metamorphosis. Like other hormones, ecdysone controls gene expression through a nuclear receptor, which functions as a ligand-dependent transcription factor. Although it is clear that ecdysone elicits distinct transcriptional responses within its different target tissues, the role of its receptor, EcR, in regulating target gene expression is incompletely understood. In particular, EcR initiates a cascade of transcription factor expression in response to ecdysone, making it unclear which ecdysone-responsive genes are direct EcR targets. Here, we use the larval-to-prepupal transition of developing wings to examine the role of EcR in gene regulation. Genome-wide DNA binding profiles reveal that EcR exhibits widespread binding across the genome, including at many canonical ecdysone-response genes. However, the majority of its binding sites reside at genes with wing-specific functions. We also find that EcR binding is temporally dynamic, with thousands of binding sites changing over time. RNA-seq reveals that EcR acts as both a temporal gate to block precocious entry to the next developmental stage as well as a temporal trigger to promote the subsequent program. Finally, transgenic reporter analysis indicates that EcR regulates not only temporal changes in target enhancer activity but also spatial patterns. Together, these studies define EcR as a multipurpose, direct regulator of gene expression, greatly expanding its role in coordinating developmental transitions.SIGNIFICANCENuclear receptors (NRs) are sequence-specific DNA binding proteins that act as intracellular receptors for small molecules such as hormones. Prior work has shown that NRs function as ligand-dependent switches that initiate a cascade of gene expression changes. The extent to which NRs function as direct regulators of downstream genes in these hierarchies remains incompletely understood. Here, we study the role of the NR EcR in metamorphosis of the Drosophila wing. We find that EcR directly regulates many genes at the top of the hierarchy as well as at downstream genes. Further, we find that EcR binds distinct sets of target genes at different developmental times. This work helps inform how hormones elicit tissue- and temporal-specific responses in target tissues.

scholarly journals MicroRNA-binding site polymorphisms and risk of breast cancer

2020 ◽  
pp. 12-13
Author(s):  
М.А. Бермишева ◽  
И.Р. Гилязова ◽  
Г.Ф. Зиннатуллина ◽  
А.А. Богданова ◽  
Э.К. Хуснутдинова
Keyword(s):  
Breast Cancer ◽  
Risk Factors ◽  
Genetic Variants ◽  
Binding Sites ◽  
Target Genes ◽  
Case Control Study ◽  
Expression Of Genes ◽  
Brca1 Brca2 ◽  
Control Study

Рак молочной железы (РМЖ) - многофакторное, генетически гетерогенное заболевание. Результаты многочисленных исследований доказали важную роль микроРНК в прогрессии опухолей. Гены микроРНК являются высоко консервативными, и считается, что любые варианты в этих последовательностях, а также сайтах связывания микроРНК в генах-мишенях находятся под отрицательным селективным давлением. Предполагается, что такие изменения могут быть связаны с повышенным риском развития рака. Наше исследование направлено на выявление генетических вариантов в сайтах связывания микроРНК с мишенью, ассоциированных с риском развития РМЖ. Проведен анализ полиморфных вариантов, расположенных в 3’- нетранслируемых регионах генов BRCA1, BRCA2, BRIP1, RAD51, RAD52, MRE11A, NBN, ERBB4, PTEN у больных РМЖ и в группе контроля. Определено, что полиморфные варианты rs11895168/ERBB4 и rs7180135/RAD51 ассоциированы с риском развития РМЖ. Breast cancer (BC) is a complex, genetically heterogeneous disease. The results of numerous studies have proven the important role of miRNA in tumor progression. miRNA sequences are highly conserved. Any variants in these sequences as well as the binding sites of miRNA in the target genes are supposed to be under negative selective pressure. miRNA that alter the expression of genes have been identified to play a significant role in BC regulation. The present study is aimed at investigating the involvement of SNPs in miRNA-binding sites as risk factors for the development of BC. A case - control study was performed to evaluate genetic variants of BRCA1, BRCA2, BRIP1, RAD51, RAD52, MRE11A, NBN, ERBB4, PTEN genes as BC risk factors. The results of the present study suggest that genetic variants rs11895168 / ERBB4 and rs7180135 / RAD51 are associated with breast cancer risk.

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