scholarly journals Loop competition and extrusion model predicts CTCF interaction specificity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wang Xi ◽  
Michael A. Beer
Keyword(s):  
Binding Site ◽  
Critical Role ◽  
Three Dimensional ◽  
Ctcf Binding ◽  
Chromatin Interaction ◽  
Ctcf Binding Site ◽  
Loop Formation ◽  
Critical Determinant ◽  
Frequency Changes ◽  
Transcriptional Gene Regulation

AbstractThree-dimensional chromatin looping interactions play an important role in constraining enhancer–promoter interactions and mediating transcriptional gene regulation. CTCF is thought to play a critical role in the formation of these loops, but the specificity of which CTCF binding events form loops and which do not is difficult to predict. Loops often have convergent CTCF binding site motif orientation, but this constraint alone is only weakly predictive of genome-wide interaction data. Here we present an easily interpretable and simple mathematical model of CTCF mediated loop formation which is consistent with Cohesin extrusion and can predict ChIA-PET CTCF looping interaction measurements with high accuracy. Competition between overlapping loops is a critical determinant of loop specificity. We show that this model is consistent with observed chromatin interaction frequency changes induced by CTCF binding site deletion, inversion, and mutation, and is also consistent with observed constraints on validated enhancer–promoter interactions.

scholarly journals Loop extrusion model predicts CTCF interaction specificity

2020 ◽  
Author(s):  
Wang Xi ◽  
Michael A Beer
Keyword(s):  
Binding Site ◽  
Critical Role ◽  
Three Dimensional ◽  
Ctcf Binding ◽  
Chromatin Interaction ◽  
Ctcf Binding Site ◽  
Loop Formation ◽  
Critical Determinant ◽  
Frequency Changes ◽  
Transcriptional Gene Regulation

AbstractThree-dimensional chromatin looping interactions play an important role in constraining enhancer-promoter interactions and mediating transcriptional gene regulation. CTCF is thought to play a critical role in the formation of these loops, but the specificity of which CTCF binding events form loops and which do not is difficult to predict. Loops often have convergent CTCF binding site motif orientation, but this constraint alone is only weakly predictive of genome-wide interaction data. Here we present an easily interpretable and simple mathematical model of CTCF mediated loop formation which is consistent with Cohesin extrusion and can predict ChIA-PET CTCF looping interaction measurements with high accuracy. Competition between overlapping loops is a critical determinant of loop specificity. We show that this model is consistent with observed chromatin interaction frequency changes induced by CTCF binding site deletion, inversion, and mutation, and is also consistent with observed constraints on validated enhancer-promoter interactions.

scholarly journals Increased Epstein-Barr virus C-promoter activity with CTCF-binding site deletion is associated with elevated EBNA2 recruitment

2018 ◽  
Author(s):  
Ian J Groves ◽  
Martin J Allday
Keyword(s):  
Binding Site ◽  
Epstein Barr Virus ◽  
Three Dimensional ◽  
Fold Increase ◽  
Transcript Level ◽  
Ctcf Binding ◽  
Ctcf Binding Site ◽  
Regulation Of Transcription ◽  
Barr Virus ◽  
Epstein Barr

AbstractThe regulation of transcription from Epstein-Barr virus promoters is known to involve the association of the host CCCTC-binding factor (CTCF) protein. This control involves direct binding of CTCF across the EBV genome and the formation of three-dimensional loops between virus promoters and enhancers. We sought to address how the deletion of a CTCF binding site upstream of the C-promoter (Cp) affected viral transcription in infected lymphoblastoid cell lines (LCLs) and how binding of the EBV trans-activating protein EBNA2 was changed across this promoter. Transcript level from Cp was up-regulated with CTCF binding site deletion, and transcription from other promoters (Wp and Qp) was decreased, while transcript levels were largely unchanged by independent mutation of a Cp-RBPJκ binding site. In turn, expression of EBNA2 protein was also increased, likely driven by increases in polycistronic EBNA2-encoding transcripts. Finally, Cp up-regulation was associated with an 8-fold increase in EBNA2 enrichment across Cp, concomitant with increased association of the associated cellular factor RBPJκ, probably due to a more accessible three-dimensional chromatin conformation upstream of Cp. Overall, the data presented here confirm that binding of CTCF directly upstream of Cp is important for the regulation of transcription from this and other EBV promoters.

scholarly journals 3'HS1 CTCF binding site in human β-globin locus regulates fetal hemoglobin expression

2021 ◽  
Author(s):  
Pamela Himadewi ◽  
Xue Qing David Wang ◽  
Fan Feng ◽  
Haley Gore ◽  
Yushuai Liu ◽  
...  
Keyword(s):  
Binding Site ◽  
Progenitor Cells ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Ctcf Binding ◽  
Ctcf Binding Site ◽  
Distal Enhancer ◽  
Erythroid Progenitor ◽  
Hematopoietic Stem ◽  
Ctcf Site

Mutations in the adult β-globin gene can lead to a variety of hemoglobinopathies, including sickle cell disease and β-thalassemia. An increase in fetal hemoglobin expression throughout adulthood, a condition named Hereditary Persistence of Fetal Hemoglobin (HPFH), has been found to ameliorate hemoglobinopathies. Deletional HPFH occurs through the excision of a significant portion of the 3 prime end of the β-globin locus, including a CTCF binding site termed 3'HS1. Here, we show that the deletion of this CTCF site alone induces fetal hemoglobin expression in both adult CD34+ hematopoietic stem and progenitor cells and HUDEP-2 erythroid progenitor cells. This induction is driven by the ectopic access of a previously postulated distal enhancer located in the OR52A1 gene downstream of the locus, which can also be insulated by the inversion of the 3'HS1 CTCF site. This suggests that genetic editing of this binding site can have therapeutic implications to treat hemoglobinopathies.

Allele-specific methylation of a functional CTCF binding site upstream of MEG3 in the human imprinted domain of 14q32

2005 ◽  
Vol 13 (8) ◽  
pp. 809-818 ◽  
Author(s):  
Alberto L. Rosa ◽  
Yuan-Qing Wu ◽  
Bernard Kwabi-Addo ◽  
Karen J. Coveler ◽  
V. Reid Sutton ◽  
...  
Keyword(s):  
Binding Site ◽  
Ctcf Binding ◽  
Ctcf Binding Site ◽  
Allele Specific ◽  
Allele Specific Methylation

scholarly journals CTCFBSDB: a CTCF-binding site database for characterization of vertebrate genomic insulators

2007 ◽  
Vol 36 (Database) ◽  
pp. D83-D87 ◽  
Author(s):  
L. Bao ◽  
M. Zhou ◽  
Y. Cui
Keyword(s):  
Binding Site ◽  
Ctcf Binding ◽  
Ctcf Binding Site

scholarly journals HTLV-1 inserts an ectopic CTCF-binding site into the human genome

Retrovirology ◽  
2015 ◽  
Vol 12 (S1) ◽  
Author(s):  
Yorifumi Satou ◽  
Miyazato Paola ◽  
Ko Ishihara ◽  
Asami Fukuda ◽  
Kisato Nosaka ◽  
...  
Keyword(s):  
Binding Site ◽  
Human Genome ◽  
Ctcf Binding ◽  
Ctcf Binding Site

scholarly journals Loss of imprinting control of the lncRNA H19-fetal mitogen IGF2 gene cluster in the decidual microenvironment of patients with idiopathic spontaneous miscarriages

2021 ◽  
Author(s):  
Xue Wen ◽  
Qi Zhang ◽  
Lei Zhou ◽  
Zhaozhi Li ◽  
Xue Wei ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Noncoding Rna ◽  
Recurrent Miscarriage ◽  
Critical Role ◽  
Ctcf Binding ◽  
Ctcf Binding Site ◽  
Monoallelic Expression ◽  
Endometrial Stromal Cells ◽  
Control Center ◽  
Loss Of Imprinting

Abstract Miscarriage, the spontaneous loss of a pregnancy before the fetus achieves viability, is a common complication of pregnancy. Decidualization plays a critical role in the implantation of the embryo. To search for molecular factors underlying miscarriage, we explored the role of long noncoding RNAs (lncRNAs) in the decidual microenvironment, where the molecular crosstalk at the feto–maternal interface occurs. By integrating RNA-seq data from recurrent miscarriage patients and decidualized endometrial stromal cells, we identified H19 , a noncoding RNA that exhibits paternally imprinted monoallelic expression in normal tissues, as the most upregulated lncRNA associated with miscarriage. Aberrant upregulation of H19 lncRNA was observed in decidual tissues derived from patients with spontaneous miscarriage as well as decidualized endometrial stromal cells. The maternally imprinted fetal mitogen Igf2, which is usually reciprocally co-regulated with H19 in the same imprinting cluster, was also upregulated. Notably, both genes underwent loss of imprinting, as H19 and IGF2 were actively transcribed from both parental alleles in decidual tissues. Mechanistically, this loss of imprinting in decidual tissues was associated with the loss of the H3K27m3 suppression marker in the IGF2 promoter, CpG hypomethylation at the central CTCF binding site in the imprinting control center (ICR) that is located between IGF2 and H19 , and the loss of CTCF-mediated intrachromosomal looping. These data provide the first evidence that aberrant control of the ICR epigenotype-intrachromosomal looping- H19/IGF2 imprinting pathway may be a critical epigenetic risk factor in the abnormal decidualization related to miscarriage.

scholarly journals CTCF modulates allele-specific sub-TAD organization and imprinted gene activity at the mouse Dlk1-Dio3 and Igf2-H19 domains

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
David Llères ◽  
Benoît Moindrot ◽  
Rakesh Pathak ◽  
Vincent Piras ◽  
Mélody Matelot ◽  
...  
Keyword(s):  
Gene Activation ◽  
Three Dimensional ◽  
Ctcf Binding ◽  
Differentially Methylated Region ◽  
Ctcf Binding Site ◽  
Mammalian Development ◽  
Imprinted Gene ◽  
Maternal Chromosome ◽  
Additional Layer ◽  
Allele Specific

Abstract Background Genomic imprinting is essential for mammalian development and provides a unique paradigm to explore intra-cellular differences in chromatin configuration. So far, the detailed allele-specific chromatin organization of imprinted gene domains has mostly been lacking. Here, we explored the chromatin structure of the two conserved imprinted domains controlled by paternal DNA methylation imprints—the Igf2-H19 and Dlk1-Dio3 domains—and assessed the involvement of the insulator protein CTCF in mouse cells. Results Both imprinted domains are located within overarching topologically associating domains (TADs) that are similar on both parental chromosomes. At each domain, a single differentially methylated region is bound by CTCF on the maternal chromosome only, in addition to multiple instances of bi-allelic CTCF binding. Combinations of allelic 4C-seq and DNA-FISH revealed that bi-allelic CTCF binding alone, on the paternal chromosome, correlates with a first level of sub-TAD structure. On the maternal chromosome, additional CTCF binding at the differentially methylated region adds a further layer of sub-TAD organization, which essentially hijacks the existing paternal-specific sub-TAD organization. Perturbation of maternal-specific CTCF binding site at the Dlk1-Dio3 locus, using genome editing, results in perturbed sub-TAD organization and bi-allelic Dlk1 activation during differentiation. Conclusions Maternal allele-specific CTCF binding at the imprinted Igf2-H19 and the Dlk1-Dio3 domains adds an additional layer of sub-TAD organization, on top of an existing three-dimensional configuration and prior to imprinted activation of protein-coding genes. We speculate that this allele-specific sub-TAD organization provides an instructive or permissive context for imprinted gene activation during development.

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