Proximity among Distant Regulatory Elements at the β-Globin Locus Requires GATA-1 and FOG-1

ArticleinMolecular Cell 17(3):453-62 · March 2005with17 Reads
DOI: 10.1016/j.molcel.2004.12.028 · Source: PubMed
Abstract
Recent evidence suggests that long-range enhancers and gene promoters are in close proximity, which might reflect the formation of chromatin loops. Here, we examined the mechanism for DNA looping at the beta-globin locus. By using chromosome conformation capture (3C), we show that the hematopoietic transcription factor GATA-1 and its cofactor FOG-1 are required for the physical interaction between the beta-globin locus control region (LCR) and the beta-major globin promoter. Kinetic studies reveal that GATA-1-induced loop formation correlates with the onset of beta-globin transcription and occurs independently of new protein synthesis. GATA-1 occupies the beta-major globin promoter normally in fetal liver erythroblasts from mice lacking the LCR, suggesting that GATA-1 binding to the promoter and LCR are independent events that occur prior to loop formation. Together, these data demonstrate that GATA-1 and FOG-1 are essential anchors for a tissue-specific chromatin loop, providing general insights into long-range enhancer function.
    • "Genome-wide co-localization of marks that were originally thought to affect transcription antagonistically might reflect the additional functions of these marks that are unrelated to the regulation of gene expression. For example, H3K9me3 is not restricted to heterochromatin but is also found at active genes [33, 52], H3K9me3, H3K27me3 and H3K36me3 have been . CC-BY-NC-ND 4.0 International license not peer-reviewed) is the author/funder. "
    [Show abstract] [Hide abstract] ABSTRACT: Epigenetic modifications and other chromatin features partition the genome on multiple length scales to control its biological function. Some of them like DNA methylation target single bases, whereas others such as heterochromatic histone modifications span regions of several megabases. It has now become a routine task to map chromatin marks by deep sequencing. However, the quantitative assessment and comparison of the topology of chromatin domains and their spatial relationships across data sets without a priori assumptions remains challenging, especially if broad domains are involved. Here, we introduce multi-scale correlation evaluation (MCORE), which uses the fluctuation spectrum of mapped sequencing reads to quantify and compare spatial patterns on multiple length scales in a model-independent manner. We used MCORE to dissect the chromatin domain topology of embryonic stem cells and neural cells by integrating sequencing data from chromatin immunoprecipitation, RNA expression, DNA methylation and chromosome interaction experiments. Further, we constructed network models that reflect the relationships among these features on different genomic scales. We anticipate that MCORE will complement current sequencing evaluation schemes and aid in the design and validation of mechanistic models for chromatin signaling.
    Article · May 2016 · Genome biology
    • "In the absence of DRB, HS2 formed contacts with the active βglobin gene (βmaj) but not with the intervening inactive β-type globin genes (εy and βh1) (SupplementalFig. S1D), consistent with previous reports (Vakoc et al. 2005; Deng et al. 2012). While exposure of cells to DRB did not significantly diminish HS2–promoter interaction, there was a small but reproducible reduction in contacts between HS2 and the 3 ′ portion of the β-globin gene (Sup- plementalFig. "
    [Show abstract] [Hide abstract] ABSTRACT: Enhancers govern transcription through multiple mechanisms, including the regulation of elongation by RNA polymerase II (RNAPII). We characterized the dynamics of looped enhancer contacts during synchronous transcription elongation. We found that many distal enhancers form stable contacts with their target promoters during the entire interval of elongation. Notably, we detected additional dynamic enhancer contacts throughout the gene bodies that track with elongating RNAPII and the leading edge of RNA synthesis. These results support a model in which the gene body changes its position relative to a stable enhancer–promoter complex, which has broad ramifications for enhancer function and architectural models of transcriptional elongation.
    Article · Oct 2015
    • "Formation of tissue-specific enhancer-promoter loops depends on the association of tissue-specific transcription factors that often recruit ubiquitous factors such as mediator, cohesin, and cohesin cofactor Nipbl that might help establish chromatin loops [67, 89]. Several studies have shown that enhancer-promoter loops dissolve upon depletion of the associated tissue-specific transcription factors [90, 91] , which was also usually found to be accompanied by decreased transcription of the target gene. Of note, the inhibition of transcription itself has no impact on the maintenance of chromatin loops [92, 93]. "
    [Show abstract] [Hide abstract] ABSTRACT: The three-dimensional folding of the genome has emerged as an important regulatory layer of transcription and is regarded as being pivotal for the establishment and faithful maintenance of cellular identity. The hierarchical levels of genome compaction and folding exert transcriptional control by tuning the accessibility and proximity of genes and cognate regulatory elements. Despite the identification of many factors involved in genome topology, the mechanisms that underlie the establishment of three-dimensional genome architecture and its inheritance through successive cell divisions have remained largely unknown. Here, we review current insights into the chromatin components and associated trans-acting factors that enable the genome to flexibly adopt different functionally relevant conformations.
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