A Unifying Model for the Selective Regulation of Inducible Transcription by CpG Islands and Nucleosome Remodeling

Ramirez-Carrozzi, Vladimir; Braas, Daniel; Bhatt, Dev; Cheng, Christine S.; Hong, Christine; Doty, Kevin R.; Black, Joshua C.; Hoffmann, Ary A.; Carey, Michael P.; Smale, Stephen T.

doi:10.1016/s9999-9994(09)20361-8

Cited by 37 publications

(73 citation statements)

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“…When compared to a control group consisting of all the RefSeq genes mappable to probes in the microarray, the set of genes associated with inducible p300 binding was enriched for LPSstimulated transcripts at high statistical significance (p < 10 À16 in a chi-square test) ( Figure 1C), thus providing initial correlative evidence that inducible binding of p300 marks regulatory regions associated with LPS-stimulated genes. Importantly, genes associated with enhancers bound by p300 in an LPSinducible manner belonged to several classes of LPS-responsive genes (primary, secondary, promiscuously, and selectively activated genes) (Ramirez-Carrozzi et al, 2009), without any obvious specificity. Some representative regions are shown in Figure 1D, including the Sod2 intronic enhancer, an intergenic region upstream of the genic cluster containing the tumor necrosis factor alpha (Tnfa) and the lymphotoxin alpha (Lta) genes, and the genomic region including the housekeeping beta-actin (Actb) gene, which contains only noninducible p300 peaks.…”

Section: Resultsmentioning

confidence: 99%

Identification and Characterization of Enhancers Controlling the Inflammatory Gene Expression Program in Macrophages

et al. 2010

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Enhancers determine tissue-specific gene expression programs. Enhancers are marked by high histone H3 lysine 4 mono-methylation (H3K4me1) and by the acetyl-transferase p300, which has allowed genome-wide enhancer identification. However, the regulatory principles by which subsets of enhancers become active in specific developmental and/or environmental contexts are unknown. We exploited inducible p300 binding to chromatin to identify, and then mechanistically dissect, enhancers controlling endotoxin-stimulated gene expression in macrophages. In these enhancers, binding sites for the lineage-restricted and constitutive Ets protein PU.1 coexisted with those for ubiquitous stress-inducible transcription factors such as NF-kappaB, IRF, and AP-1. PU.1 was required for maintaining H3K4me1 at macrophage-specific enhancers. Reciprocally, ectopic expression of PU.1 reactivated these enhancers in fibroblasts. Thus, the combinatorial assembly of tissue- and signal-specific transcription factors determines the activity of a distinct group of enhancers. We suggest that this may represent a general paradigm in tissue-restricted and stimulus-responsive gene regulation.

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Section: Resultsmentioning

confidence: 99%

Identification and Characterization of Enhancers Controlling the Inflammatory Gene Expression Program in Macrophages

et al. 2010

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“…However, the mechanism by which DNA methylation perturbs chromatin state and regulatory elements in a site-specific fashion remains obscure (Deaton and Bird, 2011). Various possibilities have been suggested including direct potentiation of repressive chromatin features (Collings et al, 2013;Ramirez-Carrozzi et al, 2009), recruitment of methylcytosine-specific repressive factors (Baubec et al, 2013;Lewis et al, 1992;Tate and Bird, 1993), and physical obstruction of the transcription factor (TF) DNA interface (Hu et al, 2013;Tate and Bird, 1993). Consistent with the latter hypothesis, DNA methylation is specifically depleted at occupied TF-binding sites in vivo (Groudine and Conkin, 1985;Lister et al, 2009;Neph et al, 2012b;Thurman et al, 2012).…”

Section: Accession Numbers Gse30263 Gse50610mentioning

confidence: 98%

Role of DNA Methylation in Modulating Transcription Factor Occupancy

et al. 2015

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Although DNA methylation is commonly invoked as a mechanism for transcriptional repression, the extent to which it actively silences transcription factor (TF) occupancy sites in vivo is unknown. To study the role of DNA methylation in the active modulation of TF binding, we quantified the effect of DNA methylation depletion on the genomic occupancy patterns of CTCF, an abundant TF with known methylation sensitivity that is capable of autonomous binding to its target sites in chromatin. Here, we show that the vast majority (>98.5%) of the tens of thousands of unoccupied, methylated CTCF recognition sequences remain unbound upon abrogation of DNA methylation. The small fraction of sites that show methylation-dependent binding in vivo are in turn characterized by highly variable CTCF occupancy across cell types. Our results suggest that DNA methylation is not a primary groundskeeper of genomic TF landscapes, but rather a specialized mechanism for stabilizing intrinsically labile sites.

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“…On a genome-wide scale, and judging from the H3K4me3 mark, promoters seem to be more similar across cell types than enhancers (Heintzman et al, 2009). However, this observation must be taken cautiously, because it reflects the prevalence in the genome of CpG island-containing promoters (including housekeeping genes and tissue-specific genes with a CpG island) (Ramirez-Carrozzi et al, 2009), which are constitutively methylated at H3K4me3 (see below). Moreover, this observation does not imply at all that chromatin marks at promoters are not under active and dynamic control.…”

Section: Cell Type Specificity In Promoter Selectionmentioning

confidence: 99%

“…Moreover, this observation does not imply at all that chromatin marks at promoters are not under active and dynamic control. In fact, H3K4me3 is a highly reactive modification that is completely absent from the TSSs of inactive genes lacking a CpG island, and is strongly upregulated upon activation, as shown at many inducible genes in macrophages (De Santa et al, 2009;Foster et al, 2007;Hargreaves et al, 2009;Ramirez-Carrozzi et al, 2009). More importantly, the homogeneity across cell types of H3K4me3 profiles at TSSs and promoters of CpG island-containing genes does not necessarily argue against the notion that also TSSs may be subjected to regulation by cell type-specific cues.…”

Section: Cell Type Specificity In Promoter Selectionmentioning

confidence: 99%

Maintaining Cell Identity through Global Control of Genomic Organization

2010

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Cell differentiation entails early lineage choices leading to the activation, and the subsequent maintenance, of the gene expression program characteristic of each cell type. Alternative lineage choices involve the activation of different regulatory and coding regions of the genome, a process instructed by lineage-determining transcription factors, and at least in part mediated by the deposition of chromatin marks that modify functionality and accessibility of the underlying genome. According to classic epigenetics, subsequent maintenance of chromatin marks across mitoses and in spite of environmental perturbations occurs largely through autonomous and unsupervised mechanisms. However, paradigmatic genetic and biochemical studies in immune system and hematopoietic cells strongly point to the concept that both induction and maintenance of the differentiated state require constant supervision by lineage-determining transcription factors, which may act to globally organize the genome in both the one- and the three-dimensional space.

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A Unifying Model for the Selective Regulation of Inducible Transcription by CpG Islands and Nucleosome Remodeling

Cited by 37 publications

References 0 publications

Identification and Characterization of Enhancers Controlling the Inflammatory Gene Expression Program in Macrophages

Identification and Characterization of Enhancers Controlling the Inflammatory Gene Expression Program in Macrophages

Role of DNA Methylation in Modulating Transcription Factor Occupancy

Maintaining Cell Identity through Global Control of Genomic Organization

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