scholarly journals Analysis of the Vertebrate Insulator Protein CTCF-Binding Sites in the Human Genome

Cell ◽  
2007 ◽  
Vol 128 (6) ◽  
pp. 1231-1245 ◽  
Author(s):  
Tae Hoon Kim ◽  
Ziedulla K. Abdullaev ◽  
Andrew D. Smith ◽  
Keith A. Ching ◽  
Dmitri I. Loukinov ◽  
...  
Keyword(s):  
Human Genome ◽  
Binding Sites ◽  
Ctcf Binding ◽  
Insulator Protein

scholarly journals Comprehensive Identification and Annotation of Cell Type-Specific and Ubiquitous CTCF-Binding Sites in the Human Genome

PLoS ONE ◽  
2012 ◽  
Vol 7 (7) ◽  
pp. e41374 ◽  
Author(s):  
Hebing Chen ◽  
Yao Tian ◽  
Wenjie Shu ◽  
Xiaochen Bo ◽  
Shengqi Wang
Keyword(s):  
Human Genome ◽  
Binding Sites ◽  
Ctcf Binding ◽  
Cell Type ◽  
Cell Type Specific

CTCF, cohesin, and histone variants: connecting the genome

2011 ◽  
Vol 89 (5) ◽  
pp. 505-513 ◽  
Author(s):  
Jean-François Millau ◽  
Luc Gaudreau
Keyword(s):  
Human Genome ◽  
Binding Sites ◽  
Genome Organization ◽  
Histone Variants ◽  
Ctcf Binding ◽  
Recent Advances ◽  
Genome Wide ◽  
Gene Regulations

During the last decades our view of the genome organization has changed. We moved from a linear view to a looped view of the genome. It is now well established that inter- and intra-connections occur between chromosomes and play a major role in gene regulations. These interconnections are mainly orchestrated by the CTCF protein, which is also known as the “master weaver” of the genome. Recent advances in sequencing and genome-wide studies revealed that CTCF binds to DNA at thousands of sites within the human genome, providing the possibility to form thousands of genomic connection hubs. Strikingly, two histone variants, namely H2A.Z and H3.3, strongly co-localize at CTCF binding sites. In this article, we will review the recent advances in CTCF biology and discuss the role of histone variants H2A.Z and H3.3 at CTCF binding sites.

scholarly journals Transcription Factor Binding Sites Are Genetic Determinants of Retroviral Integration in the Human Genome

PLoS ONE ◽  
2009 ◽  
Vol 4 (2) ◽  
pp. e4571 ◽  
Author(s):  
Barbara Felice ◽  
Claudia Cattoglio ◽  
Davide Cittaro ◽  
Anna Testa ◽  
Annarita Miccio ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Human Genome ◽  
Binding Sites ◽  
Transcription Factor Binding Sites ◽  
Transcription Factor Binding ◽  
Genetic Determinants ◽  
Retroviral Integration ◽  
Factor Binding

Abstract P531: FOXO3 , a Cardiovascular Protector, is at the Hub of a 46-gene Cell Resilience “Gene Factory” on Human Chromosome 6

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Brian J Morris ◽  
Timothy A Donlon ◽  
Randi Chen ◽  
Kamal H Masaki ◽  
Richard C Allsopp ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Cell Lines ◽  
Binding Sites ◽  
Healthy Aging ◽  
Nutrient Sensing ◽  
Physical Contact ◽  
Ctcf Binding ◽  
Lymphoblastoid Cell Lines ◽  
Chromosome 6 ◽  
Disease Etiology

The transcription factor FoxO3 regulates multiple genes involved in cell resilience. We have previously implicated variation in non-coding DNA of the FoxO3 gene ( FOXO3 ) with lower blood pressure, reduced inflammation, less hypertension, reduced coronary heart disease mortality, and longevity. The aim of the present study was to determine transcriptional, genetic and genomic mechanisms involving FOXO3 . By DNA sequencing of chromosome 6q21 in lymphoblastoid cell lines of 95 men who had survived to ≥ 95 years of age we identified 110 FOXO3 single nucleotide polymorphisms (SNPs). Thirteen SNPs were at binding sites for 18 transcription factors. Those SNPs appeared to be in physical contact, via RNA polymerase II binding chromatin looping, with sites in the FOXO3 promoter, and likely function together as a cis -regulatory unit. At the chromosome level, FOXO3 was located at the center of a 7.3 Mb 46-gene chromatin domain flanked by gene deserts. We identified distant contact points between FOXO3 and these 46 neighboring genes, through long-range physical contacts via CCCTC-binding factor zinc finger protein (CTCF) binding sites. The genes in this “archipelago” of neighbourhood genes mediate a similar repertoire of functions as FoxO3, including stress resistance, nutrient sensing, cell proliferation, autophagy, apoptosis and stem cell maintenance. The 7.3 Mb gene domain was highly conserved across species, indicating evolutionary importance. We believe that FOXO3 serves as the hub for an “interactome” involved in healthy aging, including cardiovascular disease reduction, in those with favorable FOXO3 genotypes. In support, we found that cellular stress (H 2 O 2 ) could stimulate FOXO3 expression in 20 lymphoblastoid cell lines, being 3-fold stronger for those with a favorable FOXO3 genotype. In FISH experiments, stress-induced activation of FOXO3 caused it to move towards its neighboring genes as suggested by our genomic data. In conclusion, we have shown, for the first time, that FOXO3 is at the central hub of a gene network on chromosome 6 involved in cell protection and healthy aging. The concept of “gene factories” may apply more broadly to genome and genetic mechanisms involved in cardiovascular disease etiology.

scholarly journals Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes

2015 ◽  
Vol 112 (47) ◽  
pp. E6456-E6465 ◽  
Author(s):  
Adrian L. Sanborn ◽  
Suhas S. P. Rao ◽  
Su-Chen Huang ◽  
Neva C. Durand ◽  
Miriam H. Huntley ◽  
...  
Keyword(s):  
Genome Editing ◽  
Binding Sites ◽  
Physical Structure ◽  
Ctcf Binding ◽  
Binding Motifs ◽  
Physical Simulations ◽  
Chromatin Folding ◽  
Mammalian Genomes ◽  
Single Base Pair ◽  
Fractal Globule

We recently used in situ Hi-C to create kilobase-resolution 3D maps of mammalian genomes. Here, we combine these maps with new Hi-C, microscopy, and genome-editing experiments to study the physical structure of chromatin fibers, domains, and loops. We find that the observed contact domains are inconsistent with the equilibrium state for an ordinary condensed polymer. Combining Hi-C data and novel mathematical theorems, we show that contact domains are also not consistent with a fractal globule. Instead, we use physical simulations to study two models of genome folding. In one, intermonomer attraction during polymer condensation leads to formation of an anisotropic “tension globule.” In the other, CCCTC-binding factor (CTCF) and cohesin act together to extrude unknotted loops during interphase. Both models are consistent with the observed contact domains and with the observation that contact domains tend to form inside loops. However, the extrusion model explains a far wider array of observations, such as why loops tend not to overlap and why the CTCF-binding motifs at pairs of loop anchors lie in the convergent orientation. Finally, we perform 13 genome-editing experiments examining the effect of altering CTCF-binding sites on chromatin folding. The convergent rule correctly predicts the affected loops in every case. Moreover, the extrusion model accurately predicts in silico the 3D maps resulting from each experiment using only the location of CTCF-binding sites in the WT. Thus, we show that it is possible to disrupt, restore, and move loops and domains using targeted mutations as small as a single base pair.

scholarly journals Functions of Gtf2i and Gtf2ird1 in the developing brain: transcription, DNA-binding, and long term behavioral consequences

2019 ◽  
Author(s):  
Nathan D. Kopp ◽  
Kayla R. Nygaard ◽  
Katherine B. McCullough ◽  
Susan E. Maloney ◽  
Harrison W. Gabel ◽  
...  
Keyword(s):  
Dna Binding ◽  
Binding Sites ◽  
Conditioned Fear ◽  
Developing Brain ◽  
Ctcf Binding ◽  
Microdeletion Syndrome ◽  
Behavioral Phenotypes ◽  
Marble Burying ◽  
And Behavior

AbstractGtf2ird1 and Gtf2i may mediate aspects of the cognitive and behavioral phenotypes of Williams Syndrome (WS) – a microdeletion syndrome encompassing these transcription factors (TFs). Knockout mouse models of each TF show behavioral phenotypes. Here we identify their genomic binding sites in the developing brain, and test for additive effects of their mutation on transcription and behavior. Both TFs target constrained chromatin modifier and synaptic protein genes, including a significant number of ASD genes. They bind promoters, strongly overlap CTCF binding and TAD boundaries, and moderately overlap each other, suggesting epistatic effects. We used single and double mutants to test whether mutating both TFs will modify transcriptional and behavioral phenotypes of single Gtf2ird1 mutants. Despite little difference in DNA-binding and transcriptome-wide expression, Gtf2ird1 mutation caused balance, marble burying, and conditioned fear phenotypes. However, mutating Gtf2i in addition to Gtf2ird1 did not further modify transcriptomic or most behavioral phenotypes, suggesting Gtf2ird1 mutation alone is sufficient.

scholarly journals CTCF and cohesin promote focal detachment of DNA from the nuclear lamina

2021 ◽  
Author(s):  
Tom van Schaik ◽  
Ning Qing Liu ◽  
Stefano G. Manzo ◽  
Daan Peric-Hupkes ◽  
Elzo de Wit ◽  
...  
Keyword(s):  
Stem Cells ◽  
Histone Modifications ◽  
Binding Sites ◽  
Embryonic Stem ◽  
Nuclear Lamina ◽  
Fine Tuning ◽  
Ctcf Binding ◽  
Strongly Correlated ◽  
Sharp Transition ◽  
Genomic Regions

Lamina associated domains (LADs) are large genomic regions that are positioned at the nuclear lamina (NL). It has remained largely unclear what drives the positioning and demarcation of LADs. Because the insulator protein CTCF is enriched at LAD borders, it was postulated that CTCF binding could position a subset of LAD boundaries, possibly through its function in stalling cohesin and hence preventing cohesin to invade into the LAD. To test this, we mapped genome - NL interactions in mouse embryonic stem cells after rapid depletion of CTCF and other perturbations of cohesin dynamics. CTCF and cohesin contribute to a sharp transition in NL interactions at LAD borders, whilst LADs are maintained after depletion of these proteins, also at borders marked by CTCF. CTCF and cohesin may thus reinforce LAD borders, but do not position these. CTCF binding sites within LADs are locally detached from the NL and enriched for accessible DNA and active histone modifications. Remarkably, even though NL positioning is strongly correlated with genome inactivity, this DNA remains accessible after the local detachment is lost following CTCF depletion. At a chromosomal scale, cohesin depletion and cohesin stabilization (depletion of the unloading factor WAPL) quantitatively affect NL interactions, indicative of perturbed chromosomal positioning in the nucleus. Finally, while H3K27me3 is locally enriched at CTCF-marked LAD borders, we find no evidence for an interplay between CTCF and H3K27me3 on NL interactions. Combined, these findings illustrate that CTCF and cohesin do not shape LAD patterns. Rather, these proteins mediate fine-tuning of NL interactions.

scholarly journals DNA methylation marks inter-nucleosome linker regions throughout the human genome

2013 ◽  
Author(s):  
Benjamin P. Berman ◽  
Yaping Liu ◽  
Theresa K. Kelly
Keyword(s):  
Dna Methylation ◽  
Human Genome ◽  
Ctcf Binding ◽  
Gene Promoters ◽  
Cpg Dinucleotides ◽  
Sequencing Technologies ◽  
Nucleosome Organization ◽  
Genome Wide ◽  
A Genome ◽  
Sequencing Studies

Background: Nucleosome organization and DNA methylation are two mechanisms that are important for proper control of mammalian transcription, as well as epigenetic dysregulation associated with cancer. Whole-genome DNA methylation sequencing studies have found that methylation levels in the human genome show periodicities of approximately 190 bp, suggesting a genome-wide relationship between the two marks. A recent report (Chodavarapu et al., 2010) attributed this to higher methylation levels of DNA within nucleosomes. Here, we analyzed a number of published datasets and found a more compelling alternative explanation, namely that methylation levels are highest in linker regions between nucleosomes. Results: Reanalyzing the data from (Chodavarapu et al., 2010), we found that nucleosome-associated methylation could be strongly confounded by known sequence-related biases of the next-generation sequencing technologies. By accounting for these biases and using an unrelated nucleosome profiling technology, NOMe-seq, we found that genome-wide methylation was actually highest within linker regions occurring between nucleosomes in multi-nucleosome arrays. This effect was consistent among several methylation datasets generated independently using two unrelated methylation assays. Linker-associated methylation was most prominent within long Partially Methylated Domains (PMDs) and the positioned nucleosomes that flank CTCF binding sites. CTCF adjacent nucleosomes retained the correct positioning in regions completely devoid of CpG dinucleotides, suggesting that DNA methylation is not required for proper nucleosomes positioning. Conclusions: The biological mechanisms responsible for DNA methylation patterns outside of gene promoters remain poorly understood. We identified a significant genome-wide relationship between nucleosome organization and DNA methylation, which can be used to more accurately analyze and understand the epigenetic changes that accompany cancer and other diseases.

Sign in / Sign up

Export Citation Format

Share Document