Genomic Analysis Reveals a Novel Nuclear Factor-κB (NF-κB)-binding Site in Alu-repetitive Elements

Antonaki, Athina; Demetriades, Constantinos; Polyzos, Alexander; Banos, Aggelos; Vatsellas, Giannis; Lavigne, Matthieu D.; Apostolou, Effie; Mantouvalou, Eva; Papadopoulou, Deppie; Mosialos, George; Thanos, Dimitris

doi:10.1074/jbc.m111.234161

Cited by 58 publications

(56 citation statements)

References 48 publications

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“…Gene Expression Analysis DNA microarray analyses were performed as previously described (Antonaki et al, 2011) with three biological replicates on Affymetrix HG133plus2.0 chips. FC R 1.5 and p < 0.05 were used for DE calling, except for shmH2A1, where FC R 1.3 and p < 0.1 were used to detect more subtle changes.…”

Section: Chip-seqmentioning

confidence: 99%

Composite macroH2A/NRF-1 Nucleosomes Suppress Noise and Generate Robustness in Gene Expression

et al. 2015

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The histone variant macroH2A (mH2A) has been implicated in transcriptional repression, but the molecular mechanisms that contribute to global mH2A-dependent genome regulation remain elusive. Using chromatin immunoprecipitation sequencing (ChIP-seq) coupled with transcriptional profiling in mH2A knockdown cells, we demonstrate that singular mH2A nucleosomes occupy transcription start sites of subsets of both expressed and repressed genes, with opposing regulatory consequences. Specifically, mH2A nucleosomes mask repressor binding sites in expressed genes but activator binding sites in repressed genes, thus generating distinct chromatin landscapes that limit genetic or extracellular inductive signals. We show that composite nucleosomes containing mH2A and NRF-1 are stably positioned on gene regulatory regions and can buffer transcriptional noise associated with antiviral responses. In contrast, mH2A nucleosomes without NRF-1 bind promoters weakly and mark genes with noisier gene expression patterns. Thus, the strategic position and stabilization of mH2A nucleosomes in human promoters defines robust gene expression patterns.

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Section: Chip-seqmentioning

confidence: 99%

Composite macroH2A/NRF-1 Nucleosomes Suppress Noise and Generate Robustness in Gene Expression

et al. 2015

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“…There is ample evidence that Alu transposition, recombination, and expansion have contributed to genome evolution and changes to gene regulation (11,12). Alu repeats contain motifs recognized by several transcription factors (TFs) including SP1, p53, c-MYC, ANRIL, NF-κB (13), and previous work has suggested that they can function as enhancers (14). …”

Section: Introductionmentioning

confidence: 99%

Alu repeats as transcriptional regulatory platforms in macrophage responses toM. tuberculosisinfection

et al. 2016

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To understand the epigenetic regulation of transcriptional response of macrophages during early-stage M. tuberculosis (Mtb) infection, we performed ChIPseq analysis of H3K4 monomethylation (H3K4me1), a marker of poised or active enhancers. De novo H3K4me1 peaks in infected cells were associated with genes implicated in host defenses and apoptosis. Our analysis revealed that 40% of de novo regions contained human/primate-specific Alu transposable elements, enriched in the AluJ and S subtypes. These contained several transcription factor binding sites, including those for members of the MEF2 and ATF families, and LXR and RAR nuclear receptors, all of which have been implicated in macrophage differentiation, survival, and responses to stress and infection. Combining bioinformatics, molecular genetics, and biochemical approaches, we linked genes adjacent to H3K4me1-associated Alu repeats to macrophage metabolic responses against Mtb infection. In particular, we show that LXRα signaling, which reduced Mtb viability 18-fold by altering cholesterol metabolism and enhancing macrophage apoptosis, can be initiated at response elements present in Alu repeats. These studies decipher the mechanism of early macrophage transcriptional responses to Mtb, highlighting the role of Alu element transposition in shaping human transcription programs during innate immunity.

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“…Yet, the repertoire of active cis-elements per cell type is not constant, and introduction of a new transcription factor (TF) upon signaling also activates hitherto inactive enhancers (Kaikkonen et al 2013;Ostuni et al 2013;Brown et al 2014). Notably, high-throughput studies of the binding preferences of various NF-κB dimers in vitro (Wong et al 2011;Siggers et al 2012) and in vivo (Antonaki et al 2011;Zhao et al 2014) showed that binding to nonconsensus motifs is permissible. Still, how binding to noncanonical sites underlies the different NF-κB functions remains unknown.…”

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confidence: 99%

Binding of nuclear factor κB to noncanonical consensus sites reveals its multimodal role during the early inflammatory response

et al. 2016

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Mammalian cells have developed intricate mechanisms to interpret, integrate, and respond to extracellular stimuli. For example, tumor necrosis factor (TNF) rapidly activates proinflammatory genes, but our understanding of how this occurs against the ongoing transcriptional program of the cell is far from complete. Here, we monitor the early phase of this cascade at high spatiotemporal resolution in TNF-stimulated human endothelial cells. NF-κB, the transcription factor complex driving the response, interferes with the regulatory machinery by binding active enhancers already in interaction with gene promoters. Notably, >50% of these enhancers do not encode canonical NF-κB binding motifs. Using a combination of genomics tools, we find that binding site selection plays a key role in NF-κΒ-mediated transcriptional activation and repression. We demonstrate the latter by describing the synergy between NF-κΒ and the corepressor JDP2. Finally, detailed analysis of a 2.8-Mbp locus using sub-kbp-resolution targeted chromatin conformation capture and genome editing uncovers how NF-κΒ that has just entered the nucleus exploits pre-existing chromatin looping to exert its multimodal role. This work highlights the involvement of topology in cis-regulatory element function during acute transcriptional responses, where primary DNA sequence and its higher-order structure constitute a regulatory context leading to either gene activation or repression.[Supplemental material is available for this article.]Mammalian cells, embedded in a multicellular environment, require intricate mechanisms in order to interpret, integrate, and ultimately respond to extracellular stimuli. Inflammatory signaling constitutes a well-studied example (Bhatt and Ghosh 2014; Smale and Natoli 2014); tumor necrosis factor (TNF) rapidly remodels gene expression programs through its main effector, nuclear factor κB (NF-κB) (Hayden and Ghosh 2008;Bhatt et al. 2012). TNF activates the same genes across cell types (Moynagh 2005), but the cascade needs to unfold against the ongoing transcriptional program of the stimulated cell. Along these lines, recent work in adipocytes showed that NF-κB is involved in gene repression via redistribution of prebound factors . This is tightly linked to the choice of NF-κB binding in vivo, but the specific principles that guide this choice in three-dimensional (3D) nuclear space and over time are still not well understood, despite the wealth of data on the different phases of the inflammatory response. For example, we now know that signaling directs binding of its downstream effectors to already-active cis-regulatory ele-

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Genomic Analysis Reveals a Novel Nuclear Factor-κB (NF-κB)-binding Site in Alu-repetitive Elements

Cited by 58 publications

References 48 publications

Composite macroH2A/NRF-1 Nucleosomes Suppress Noise and Generate Robustness in Gene Expression

Composite macroH2A/NRF-1 Nucleosomes Suppress Noise and Generate Robustness in Gene Expression

Alu repeats as transcriptional regulatory platforms in macrophage responses toM. tuberculosisinfection

Binding of nuclear factor κB to noncanonical consensus sites reveals its multimodal role during the early inflammatory response

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