Integration of Hi-C and ChIP-seq data reveals distinct types of chromatin linkages

Lan, Xun; Witt, Heather; Katsumura, Koichi R.; Ye, Zhenqing; Wang, Qianben; Bresnick, Emery H.; Farnham, Peggy J.; Jin, Victor X.

doi:10.1093/nar/gks501

Cited by 95 publications

(97 citation statements)

References 54 publications

(78 reference statements)

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“…Our analysis of the H3K4me1 epigenetic mark in infected cells, coupled with the combined ChIP-seq studies of H3K27Ac by the ENCODE project (50), strongly suggested that the immediate upstream region of the relatively compact IL23A locus encompasses transcriptional enhancer(s). In humans, we found that this region contains three consensus or near-consensus AHREs, all of which were engaged at elevated levels by AHR and its heterodimeric partners in infected cells.…”

Section: Discussionmentioning

confidence: 83%

Engagement of the Aryl Hydrocarbon Receptor in Mycobacterium tuberculosis–Infected Macrophages Has Pleiotropic Effects on Innate Immune Signaling

Memari

Bouttier

Dimitrov

et al. 2015

The Journal of Immunology

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Understanding the mechanisms of host macrophage responses to Mycobacterium tuberculosis is essential for uncovering potential avenues of intervention to boost host resistance to infection. Macrophage transcriptome profiling revealed that M. tuberculosis infection strongly induced the expression of several enzymes controlling tryptophan catabolism. These included IDO1 and tryptophan 2,3-dioxygenase, which catalyze the rate-limiting step in the kynurenine pathway, producing ligands for the aryl hydrocarbon receptor (AHR). The AHR and heterodimeric partners AHR nuclear translocator and RELB are robustly expressed, and AHR and RELB levels increased further during infection. Infection enhanced AHR/AHR nuclear translocator and AHR/RELB DNA binding and stimulated the expression of AHR target genes, including that encoding the inflammatory cytokine IL-1β. AHR target gene expression was further enhanced by exogenous kynurenine, and exogenous tryptophan, kynurenine, or synthetic agonist indirubin reduced mycobacterial viability. Comparative expression profiling revealed that AHR ablation diminished the expression of numerous genes implicated in innate immune responses, including several cytokines. Notably, AHR depletion reduced the expression of IL23A and IL12B transcripts, which encode subunits of IL-23, a macrophage cytokine that stimulates production of IL-22 by innate lymphoid cells. AHR directly induced IL23A transcription in human and mouse macrophages through near-upstream enhancer regions. Taken together, these findings show that AHR signaling is strongly engaged in M. tuberculosis–infected macrophages and has widespread effects on innate immune responses. Moreover, they reveal a cascade of AHR-driven innate immune signaling, because IL-1β and IL-23 stimulate T cell subsets producing IL-22, another direct target of AHR transactivation.

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Section: Discussionmentioning

confidence: 83%

Engagement of the Aryl Hydrocarbon Receptor in Mycobacterium tuberculosis–Infected Macrophages Has Pleiotropic Effects on Innate Immune Signaling

Memari

Bouttier

Dimitrov

et al. 2015

The Journal of Immunology

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“…SMARCA4 binds to poised developmental enhancers in embryonic stem cells (Hu et al 2011;RadaIglesias et al 2011) and B-cells (Bossen et al 2015) and colocalizes with pluripotency factors (Ho et al 2009), suggesting important roles in enhancer function. Furthermore, previous work classifying genome-wide interactions according to their histone modifications and transcription factor binding revealed SMARCA4 enrichment at open chromatin regions, indicating a possible structural role for SMARCA4 (Lan et al 2012). In addition, SMARCA4 knockdown affects nuclear size (Hill et al 2004) and the integrity of nuclear shape via a mechanism independent of cytoskeletal connections (Imbalzano et al 2013b).…”

mentioning

confidence: 86%

SMARCA4 regulates gene expression and higher-order chromatin structure in proliferating mammary epithelial cells

et al. 2016

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The packaging of DNA into chromatin plays an important role in transcriptional regulation and nuclear processes. Brahmarelated gene-1 SMARCA4 (also known as BRG1), the essential ATPase subunit of the mammalian SWI/SNF chromatin remodeling complex, uses the energy from ATP hydrolysis to disrupt nucleosomes at target regions. Although the transcriptional role of SMARCA4 at gene promoters is well-studied, less is known about its role in higher-order genome organization. SMARCA4 knockdown in human mammary epithelial MCF-10A cells resulted in 176 up-regulated genes, including many related to lipid and calcium metabolism, and 1292 down-regulated genes, some of which encode extracellular matrix (ECM) components that can exert mechanical forces and affect nuclear structure. ChIP-seq analysis of SMARCA4 localization and SMARCA4-bound super-enhancers demonstrated extensive binding at intergenic regions. Furthermore, Hi-C analysis showed extensive SMARCA4-mediated alterations in higher-order genome organization at multiple resolutions. First, SMARCA4 knockdown resulted in clustering of intra-and inter-subtelomeric regions, demonstrating a novel role for SMARCA4 in telomere organization. SMARCA4 binding was enriched at topologically associating domain (TAD) boundaries, and SMARCA4 knockdown resulted in weakening of TAD boundary strength. Taken together, these findings provide a dynamic view of SMARCA4-dependent changes in higher-order chromatin organization and gene expression, identifying SMARCA4 as a novel component of chromatin organization.

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“…Here to CTCF appears to play a role, probably to accomodate developmental changes in gene expression [80,81].…”

Section: Genome-wide Chromatin Loops Mediated By Ctcfmentioning

confidence: 99%

CTCF: the protein, the binding partners, the binding sites and their chromatin loops

Holwerda

Laat

2013

Phil. Trans. R. Soc. B

192

167

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CTCF has it all. The transcription factor binds to tens of thousands of genomic sites, some tissue-specific, others ultra-conserved. It can act as a transcriptional activator, repressor and insulator, and it can pause transcription. CTCF binds at chromatin domain boundaries, at enhancers and gene promoters, and inside gene bodies. It can attract many other transcription factors to chromatin, including tissue-specific transcriptional activators, repressors, cohesin and RNA polymerase II, and it forms chromatin loops. Yet, or perhaps therefore, CTCF's exact function at a given genomic site is unpredictable. It appears to be determined by the associated transcription factors, by the location of the binding site relative to the transcriptional start site of a gene, and by the site's engagement in chromatin loops with other CTCF-binding sites, enhancers or gene promoters. Here, we will discuss genome-wide features of CTCF binding events, as well as locus-specific functions of this remarkable transcription factor.

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Integration of Hi-C and ChIP-seq data reveals distinct types of chromatin linkages

Cited by 95 publications

References 54 publications

Engagement of the Aryl Hydrocarbon Receptor in Mycobacterium tuberculosis–Infected Macrophages Has Pleiotropic Effects on Innate Immune Signaling

Engagement of the Aryl Hydrocarbon Receptor in Mycobacterium tuberculosis–Infected Macrophages Has Pleiotropic Effects on Innate Immune Signaling

SMARCA4 regulates gene expression and higher-order chromatin structure in proliferating mammary epithelial cells

CTCF: the protein, the binding partners, the binding sites and their chromatin loops

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