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A dynamic folded hairpin conformation is associated with -globin activation in erythroid cells

ABSTRACT: We investigate the three-dimensional conformations of the -globin locus at the single-allele level in murine ES and erythroid cells, combining polymer physics models and high-resolution Capture-C data. Model predictions are validated against independent FISH data measuring pairwise distances, and Tri-C data identifying three-way contacts. The architecture is rearranged during the transition from ES cells to erythroid cells, associated with the activation of the globin genes. We find that in ES cells, the spatial organization conforms to a highly intermingled 3D structure involving non-specific contacts, while in erythroid cells the -globin genes and their enhancers form a self-contained domain, arranged in a folded hairpin conformation, separated from intermingling flanking regions by a thermodynamic mechanism of micro-phase separation. The flanking regions are rich in convergent CTCF sites, which only marginally participate in the erythroid-specific gene-enhancer contacts, suggesting that beyond the interaction of CTCF sites multiple molecular mechanisms cooperate to form an interacting domain.

ORGANISM(S): Mus musculus

PROVIDER: GSE107937 | GEO | 2020/02/10

REPOSITORIES: GEO

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A dynamic folded hairpin conformation is associated with -globin activation in erythroid cells

Project description:We investigate the three-dimensional conformations of the -globin locus at the single-allele level in murine ES and erythroid cells, combining polymer physics models and high-resolution Capture-C data. Model predictions are validated against independent FISH data measuring pairwise distances, and Tri-C data identifying three-way contacts. The architecture is rearranged during the transition from ES cells to erythroid cells, associated with the activation of the globin genes. We find that in ES cells, the spatial organization conforms to a highly intermingled 3D structure involving non-specific contacts, while in erythroid cells the -globin genes and their enhancers form a self-contained domain, arranged in a folded hairpin conformation, separated from intermingling flanking regions by a thermodynamic mechanism of micro-phase separation. The flanking regions are rich in convergent CTCF sites, which only marginally participate in the erythroid-specific gene-enhancer contacts, suggesting that beyond the interaction of CTCF sites multiple molecular mechanisms cooperate to form an interacting domain.

2020-02-10 | GSE107938 | GEO

Cell type specificity of chromatin organization mediated by CTCF and cohesin

Project description:CTCF sites are abundant in the genomes of diverse species but their function is enigmatic. We used chromosome conformation capture to determine long-range interactions among CTCF/cohesin sites over 2 Mb on human chromosome 11 encompassing the β-globin locus and flanking olfactory receptor genes. Although CTCF occupies these sites in both erythroid K562 cells and fibroblast 293T cells, the long-range interaction frequencies among the sites are highly cell type specific, revealing a more densely clustered organization in the absence of globin gene activity. Both CTCF and cohesins are required for the cell-type-specific chromatin conformation. Furthermore, loss of the organizational loops in K562 cells through reduction of CTCF with shRNA results in acquisition of repressive histone marks in the globin locus and reduces globin gene expression, whereas silent flanking olfactory receptor genes are unaffected. These results support a genome-wide role for CTCF/cohesin sites through loop formation that both influences transcription and contributes to cell-type-specific chromatin organization and function. Comparison of CTCF binding in K562 and 293T cells using ChIP-chip. 3 replicates each cell type, ChIP and input DNA for each replicate.

2011-01-13 | E-GEOD-26507 | biostudies-arrayexpress

Cell type specificity of chromatin organization mediated by CTCF and cohesin

2011-01-13 | GSE26507 | GEO

Activation of the alpha-globin gene expression correlates with dramatic upregulation of nearby non-globin genes and changes of local and large-scale chromatin spatial structure

Project description:We have analyzed the total transcription output, the overall chromatin contact profile, and CTCF binding within the 2.7 Mb segment of chicken chromosome 14 harboring the alpha-globin gene cluster in cultured lymphoid cells and cultured erythroid cells before and after induction of terminal erythroid differentiation. We found that, similarly to mammalian genome, the chicken genome is organized in TADs and compartments. Full activation of the alpha-globin gene transcription in differentiated erythroid cells is correlated with upregulation of several adjacent housekeeping genes and the emergence of abundant intergenic transcription. An extended chromosome region encompassing the alpha-globin cluster becomes significantly decompacted in differentiated erythroid cells, and depleted in CTCF binding and CTCF-anchored chromatin loops, while the sub-TAD harboring alpha-globin gene cluster and the upstream regulatory element (MRE) becomes highly enriched with chromatin interactions as compared to lymphoid and proliferating erythroid cells. The alpha-globin gene domain and the neighboring loci reside within the A-like chromatin compartment in both lymphoid and erythroid cells and become further segregated from the upstream gene desert upon terminal erythroid differentiation.

2017-07-12 | GSE76573 | GEO

Tissue-specific CTCF/Cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo (RNA-Seq)

Project description:The genome is organized via CTCF/cohesin binding sites, which partition chromosomes into 1-5Mb topologically associated domains (TADs), and further into smaller contact sub-domains within TADs (sub-TADs; 40-1000kb). Here we examined in vivo an ~80kb sub-TAD, containing the mouse α-globin gene cluster, lying within a ~1Mb TAD. We find that the sub-TAD is flanked by predominantly convergent CTCF/cohesin sites which are ubiquitously bound by CTCF but only interact during erythropoiesis, defining a self-interacting erythroid compartment. Whereas the α-globin regulatory elements normally act solely on promoters downstream of the enhancers, removal of a conserved upstream CTCF/cohesin boundary extends the sub-TAD to the adjacent upstream CTCF/cohesin binding site. The α-globin enhancers now interact with the flanking chromatin, upregulating expression of genes within this extended sub-TAD. Rather than acting solely as a barrier to chromatin modification, CTCF/cohesin boundaries in this sub-TAD regulate both directionality and specificity of enhancer interactions with surrounding promoters.

2017-06-14 | GSE97870 | GEO

Tissue-specific CTCF/Cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo (ChIP-Seq)

2017-06-14 | GSE97869 | GEO

Tissue-specific CTCF/Cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo (Capture-C"

2017-06-14 | GSE97867 | GEO

Tissue-specific CTCF/Cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo (ATAC-Seq)

2017-06-14 | GSE97866 | GEO

Clustering of CpG islands constitutes an important determinant of the interphase chromosome 3D organization [ChIP-Seq]

Project description:Using 4C-Seq experimental procedure we have characterized, in cultured chicken lymphoid and erythroid cells, genome-wide patterns of spatial contacts of several CpG islands scattered along the chromosome 14. A clear tendency for interaction of CpG islands present within the same and different chromosomes has been observed. Accordingly, preferential spatial contacts between Sp1 binding motifs, and other GC-rich genomic elements including DNA sequence motifs capable to form G-quadruplexes were demonstrated. On the other hand, an anchor placed in gene/CpG islands-poor area was found to form spatial contacts with other gene/CpG islands-poor areas within chromosome 14 and other chromosomes. These results corroborate the two compartments model of interphase chromosome spatial organization and suggest that clustering of CpG islands harboring promoters and origins of DNA replication constitutes an important determinant of the 3D organization of eukaryotic genome in the cell nucleus. Using ChIP-Seq experimental procedure we have mapped genome-wide the CTCF deposition sites in chicken lymphoid and erythroid cells subjected to the 4C analysis. A good correlation between the density of these sites and the level of 4C signals was observed for the anchors located in CpG islands. It is thus possible that CTCF contributes to the clustering of CpG islands revealed in our experiments. Using ChIP-Seq experimental procedure we have mapped genome-wide the CTCF deposition sites in chicken lymphoid and erythroid cells subjected to the 4C analysis. CTCF deposition sites in chicken lymphoid and erythroid (induced and non-induced) cells.

2014-03-01 | E-GEOD-51846 | biostudies-arrayexpress

Forced enhancer-promoter rewiring to alter gene expression in animal models

Project description:Transcriptional enhancers can be in physical proximity with their target genes via chromatin looping. The enhancer at the beta-globin locus (LCR) contacts the fetal (HBG) and adult (HBB) type beta-globin genes during corresponding developmental stages. We previously demonstrated that forcing proximity between the LCR and HBG genes in cultured adult-stage erythroid cells can activate HBG transcription. Activation of HBG expression in erythroid cells is of benefit to patients with sickle cell disease. Here, using the beta-globin locus as a model we provide proof-of-concept at the organismal level that forced enhancer re-wiring might present a strategy to alter gene expression for therapeutic purposes. Hematopoietic stem and progenitor cells (HSPC) from mice bearing human beta-globin genes were transduced with lentiviral vectors expressing a synthetic transcription factor (ZF-Ldb1) that fosters LCR-HBG contacts. When engrafted into host animals, HSPCs gave rise to adult-type erythroid cells with elevated HBG expression. Vectors containing ZF-Ldb1 were optimized for activity in cultured human and rhesus erythroid cells. Upon transplantation into rhesus macaques, erythroid cells from HSPCs expressing ZF-Ldb1 displayed elevated HBG production. These findings in two animal models suggest that forced redirection of gene regulatory elements may be used to alter gene expression to treat disease.

2023-02-08 | GSE221182 | GEO

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