scholarly journals Disruption of the topological associated domain at Xp21.2 is related to gonadal dysgenesis: A general mechanism of pathogenesis

2020 ◽  
Author(s):  
Ana Paula dos Santos ◽  
Jakob A. Meinel ◽  
Cristiane dos Santos Cruz Piveta ◽  
Juliana Gabriel Ribeiro de Andrade ◽  
Helena Fabbri-Scallet ◽  
...  
Keyword(s):  
Gonadal Dysgenesis ◽  
Gene Dosage ◽  
Copy Number Variations ◽  
Ctcf Binding ◽  
General Mechanism ◽  
Ctcf Binding Site ◽  
Xy Gonadal Dysgenesis ◽  
Binding Factor ◽  
Increase Gene Dosage ◽  
Intermediate Expression

AbstractDuplications of dosage sensitive sex-locus Xp21.2 including NR0B1 have been linked to 46,XY gonadal dysgenesis (GD) and their effects are attributed merely to increase gene dosage of NR0B1 (DAX1). Here we present a general mechanism how deletions, duplications, triplications or inversions with or without NR0B1 at Xp21.2 can lead to partial or complete GD by disrupting the cognate topological associated domain (TAD) in the vincinity of NR0B1. Our model is supported by three unrelated patients: two showing a 287kb overlapping duplication at the Xp21.2 locus upstream of NR0B1 containing CXorf21 and GK and one patient having a large new triplication of Xp21.2 as the most likely cause of GD. Whole Genome sequencing uncovered the exact structural rearrangements of the duplications and the triplication. Comparison with a previously published deletion upstream of NR0B1 revealed a common 35kb overlap between the deletion, our newly reported NR0B1 upstream duplications and the triplication as well as all other copy number variations (CNVs) at Xp21.2 reported so far. This overlap contains a strong CCCTC-binding factor (CTCF) binding site representing one boundary of the NR0B1 TAD. All three CNVs at Xp21.2 most likely disrupt this TAD boundary, which isolates NR0B1 from CXorf21 and GK and putatively results in GK and CXorf21 enhancer adoption and ensuing ectopic NR0B1 expression. As a result, the patients’ transcriptomes developed an intermediate expression pattern with both ovarian and testicular features and greatly reduced expression of spermatogenesis-related genes. This model not only allows better diagnosis of GD displaying CNVs at Xp21.2, but also gives deeper insight how spatiotemporal activation of developmental genes can be disrupted by reorganized TADs also in other rare diseases.

scholarly journals A Variably Occupied CTCF Binding Site in the Ultrabithorax Gene in the Drosophila Bithorax Complex

2014 ◽  
Vol 35 (1) ◽  
pp. 318-330 ◽  
Author(s):  
Jose Paolo Magbanua ◽  
Estelle Runneburger ◽  
Steven Russell ◽  
Robert White
Keyword(s):  
Imaginal Disc ◽  
Normal Function ◽  
Ctcf Binding ◽  
Ctcf Binding Site ◽  
Content Type ◽  
Variable Site ◽  
Binding Factor ◽  
Context Specific ◽  
Transposon Insertions ◽  
Ctcf Site

Although the majority of genomic binding sites for the insulator protein CCCTC-binding factor (CTCF) are constitutively occupied, a subset show variable occupancy. Such variable sites provide an opportunity to assess context-specific CTCF functions in gene regulation. Here, we have identified a variably occupied CTCF site in theDrosophila Ultrabithorax(Ubx) gene. This site is occupied in tissues whereUbxis active (third thoracic leg imaginal disc) but is not bound in tissues where theUbxgene is repressed (first thoracic leg imaginal disc). Using chromatin conformation capture, we show that this site preferentially interacts with theUbxpromoter region in the active state. The site lies close toUbxenhancer elements and is also close to the locations of severalgypsytransposon insertions that disruptUbxexpression, leading to thebxmutant phenotype.gypsyinsertions carry the Su(Hw)-dependentgypsyinsulator and were found to affect both CTCF binding at the variable site and the chromatin topology. This suggests that insertion of thegypsyinsulator in this region interferes with CTCF function and supports a model for the normal function of the variable CTCF site as a chromatin loop facilitator, promoting interaction betweenUbxenhancers and theUbxtranscription start site.

scholarly journals Analysis of Sequence Upstream of the Endogenous H19 Gene Reveals Elements Both Essential and Dispensable for Imprinting

2002 ◽  
Vol 22 (8) ◽  
pp. 2450-2462 ◽  
Author(s):  
Joanne L. Thorvaldsen ◽  
Mellissa R. W. Mann ◽  
Okechukwu Nwoko ◽  
Kristen L. Duran ◽  
Marisa S. Bartolomei
Keyword(s):  
Repetitive Elements ◽  
Ctcf Binding ◽  
Ctcf Binding Site ◽  
Insulator Activity ◽  
Binding Factor ◽  
Additional Sequence ◽  
H19 Gene ◽  
Full Activation ◽  
Ctcf Site

ABSTRACT Imprinting of the linked and oppositely expressed mouse H19 and Igf2 genes requires a 2-kb differentially methylated domain (DMD) that is located 2 kb upstream of H19. This element is postulated to function as a methylation-sensitive insulator. Here we test whether an additional sequence 5′ of H19 is required for H19 and Igf2 imprinting. Because repetitive elements have been suggested to be important for genomic imprinting, the requirement of a G-rich repetitive element that is located immediately 3′ to the DMD was first tested in two targeted deletions: a 2.9-kb deletion (ΔDMDΔG) that removes the DMD and G-rich repeat and a 1.3-kb deletion (ΔG) removing only the latter. There are also four 21-bp GC-rich repetitive elements within the DMD that bind the insulator-associated CTCF (CCCTC-binding factor) protein and are implicated in mediating methylation-sensitive insulator activity. As three of the four repeats of the 2-kb DMD were deleted in the initial 1.6-kb ΔDMD allele, we analyzed a 3.8-kb targeted allele (Δ3.8kb-5′H19), which deletes the entire DMD, to test the function of the fourth repeat. Comparative analysis of the 5′ deletion alleles reveals that (i) the G-rich repeat element is dispensable for imprinting, (ii) the ΔDMD and ΔDMDΔG alleles exhibit slightly more methylation upon paternal transmission, (iii) removal of the 5′ CTCF site does not further perturb H19 and Igf2 imprinting, suggesting that one CTCF-binding site is insufficient to generate insulator activity in vivo, (iv) the DMD sequence is required for full activation of H19 and Igf2, and (v) deletion of the DMD disrupts H19 and Igf2 expression in a tissue-specific manner.

scholarly journals A Loss of Insulin-like Growth Factor-2 Imprinting Is Modulated by CCCTC-binding Factor Down-regulation at Senescence in Human Epithelial Cells

2004 ◽  
Vol 279 (50) ◽  
pp. 52218-52226 ◽  
Author(s):  
Vivian X. Fu ◽  
Steven R. Schwarze ◽  
Michelle L. Kenowski ◽  
Scott LeBlanc ◽  
John Svaren ◽  
...  
Keyword(s):  
Growth Factor ◽  
De Novo ◽  
Cellular Aging ◽  
Ctcf Binding ◽  
Paternal Allele ◽  
Ctcf Binding Site ◽  
Insulin Like Growth Factor ◽  
Down Regulation ◽  
Prostate Cell ◽  
Binding Factor

The imprinted insulin-like growth factor-2 (IGF2) gene is an auto/paracrine growth factor expressed only from the paternal allele in adult tissues. In tissues susceptible to aging-related cancers, including the prostate, a relaxation ofIGF2imprinting is found, suggesting a permissive role for epigenetic alterations in cancer development. To determine whetherIGF2imprinting is altered in cellular aging and senescence, human prostate epithelial and urothelial cells were passaged serially in culture to senescence. Allelic analyses using anIGF2polymorphism demonstrated a complete conversion of theIGF2imprint status from monoallelic to biallelic, in which the development of senescence was associated with a 10-fold increase inIGF2expression. As a mechanism, a 2-fold decrease in the binding of the enhancer-blocking element CCCTC-binding factor (CTCF) within the intergenicIGF2-H19region was found to underlie this switch to biallelicIGF2expression in senescent cells. This decrease in CTCF binding was associated with reduced CTCF expression in senescent cells. Node novoincreases in methylation at theIGF2CTCF binding site were seen. The forced down-regulation of CTCF expression using small interfering RNA in imprinted prostate cell lines resulted in an increase inIGF2expression and a relaxation of imprinting. Our data suggest a novel mechanism forIGF2imprinting regulation, that is, the reduction of CTCF expression in the control ofIGF2imprinting. We also demonstrate that altered imprinting patterns contribute to changes in gene expression in aging cells.

scholarly journals LncRNA:DNA triplex-forming sites are positioned at specific areas of genome organization and are predictors for Topologically Associated Domains

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Benjamin Soibam ◽  
Ayzhamal Zhamangaraeva
Keyword(s):  
Genome Organization ◽  
Chromatin Organization ◽  
Ctcf Binding ◽  
General Mechanism ◽  
Promoter Regions ◽  
Cellular Processes ◽  
A Genome ◽  
Topologically Associated Domains ◽  
Multiple Cell ◽  
Genomic Regions

Abstract Background Chromosomes are organized into units called topologically associated domains (TADs). TADs dictate regulatory landscapes and other DNA-dependent processes. Even though various factors that contribute to the specification of TADs have been proposed, the mechanism is not fully understood. Understanding the process for specification and maintenance of these units is essential in dissecting cellular processes and disease mechanisms. Results In this study, we report a genome-wide study that considers the idea of long noncoding RNAs (lncRNAs) mediating chromatin organization using lncRNA:DNA triplex-forming sites (TFSs). By analyzing the TFSs of expressed lncRNAs in multiple cell lines, we find that they are enriched in TADs, their boundaries, and loop anchors. However, they are evenly distributed across different regions of a TAD showing no preference for any specific portions within TADs. No relationship is observed between the locations of these TFSs and CTCF binding sites. However, TFSs are located not just in promoter regions but also in intronic, intergenic, and 3’UTR regions. We also show these triplex-forming sites can be used as predictors in machine learning models to discriminate TADs from other genomic regions. Finally, we compile a list of important “TAD-lncRNAs” which are top predictors for TADs identification. Conclusions Our observations advocate the idea that lncRNA:DNA TFSs are positioned at specific areas of the genome organization and are important predictors for TADs. LncRNA:DNA triplex formation most likely is a general mechanism of action exhibited by some lncRNAs, not just for direct gene regulation but also to mediate 3D chromatin organization.

Clinical and Pathologic Spectrum of 46,XY Gonadal Dysgenesis

Medicine ◽  
1991 ◽  
Vol 70 (6) ◽  
pp. 375-383 ◽  
Author(s):  
Gary D. Berkovitz ◽  
Patricia Y. Fechner ◽  
Howard W. Zacur ◽  
John A. Rock ◽  
Howard M. Snyder ◽  
...  
Keyword(s):  
Gonadal Dysgenesis ◽  
Xy Gonadal Dysgenesis

scholarly journals Swyer Syndrome

2020 ◽  
Vol 11 (3) ◽  
pp. 65-68
Author(s):  
G. R. Gazizova ◽  
F. V. Valeeva ◽  
M. R. Shaydullina ◽  
E. I. Akbirova
Keyword(s):  
Gonadal Dysgenesis ◽  
Clinical Observation ◽  
Clinical Symptoms ◽  
Objective Data ◽  
Xy Gonadal Dysgenesis ◽  
Swyer Syndrome ◽  
Swyer’S Syndrome

A clinical observation of a patient with Swyer's syndrome is presented. The article presents anamnesis data, phenotypic signs, clinical symptoms and objective data of the patient, the results of instrumental and hormonal studies, on the basis of which doctors of different specialties may suspect a violation of sex formation with XY gonadal dysgenesis.

scholarly journals Spontaneous HTLV-1 transcription is accompanied by distinct epigenetic changes in the 5′ and 3′ long terminal repeats

2018 ◽  
Vol 3 ◽  
pp. 105 ◽  
Author(s):  
Michi Miura ◽  
Paola Miyazato ◽  
Yorifumi Satou ◽  
Yuetsu Tanaka ◽  
Charles R.M. Bangham
Keyword(s):  
Histone Modifications ◽  
Insertion Site ◽  
Rapid Change ◽  
Epigenetic Modifications ◽  
The Body ◽  
Ctcf Binding ◽  
Ctcf Binding Site ◽  
Long Terminal Repeats ◽  
Terminal Repeats ◽  
The Impact

Background:The human retrovirus HTLV-1 inserts the viral complementary DNA of 9 kb into the host genome. Both plus- and minus-strands of the provirus are transcribed, respectively from the 5′ and 3′ long terminal repeats (LTR). Plus-strand expression is rapid and intense once activated, whereas the minus-strand is transcribed at a lower, more constant level. To identify how HTLV-1 transcription is regulated, we investigated the epigenetic modifications associated with the onset of spontaneous plus-strand expression and the potential impact of the host factor CTCF.Methods:Patient-derived peripheral blood mononuclear cells (PBMCs) and in vitro HTLV-1-infected T cell clones were examined. Cells were stained for the plus-strand-encoded viral protein Tax, and sorted into Tax+and Tax–populations. Chromatin immunoprecipitation and methylated DNA immunoprecipitation were performed to identify epigenetic modifications in the provirus. Bisulfite-treated DNA fragments from the HTLV-1 LTRs were sequenced. Single-molecule RNA-FISH was performed, targeting HTLV-1 transcripts, for the estimation of transcription kinetics. The CRISPR/Cas9 technique was applied to alter the CTCF-binding site in the provirus, to test the impact of CTCF on the epigenetic modifications.Results:Changes in the histone modifications H3K4me3, H3K9Ac and H3K27Ac were strongly correlated with plus-strand expression. DNA in the body of the provirus was largely methylated except for the pX and 3′ LTR regions, regardless of Tax expression. The plus-strand promoter was hypomethylated when Tax was expressed. Removal of CTCF had no discernible impact on the viral transcription or epigenetic modifications.Conclusions:The histone modifications H3K4me3, H3K9Ac and H3K27Ac are highly dynamic in the HTLV-1 provirus: they show rapid change with the onset of Tax expression, and are reversible. The HTLV-1 provirus has an intrinsic pattern of epigenetic modifications that is independent of both the provirus insertion site and the chromatin architectural protein CTCF which binds to the HTLV-1 provirus.

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