Characterization of Enhancer Function from Genome-Wide Analyses

Maston, Glenn A.; Landt, Stephen G.; Snyder, M; Green, Michael R.

doi:10.1146/annurev-genom-090711-163723

Cited by 91 publications

(81 citation statements)

References 184 publications

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“…The enrichment of several genomic features has been proposed to be marks of active enhancers, including H3K4me1, H3K27ac, EP300/CREBBP, RNA Pol II, and an open chromatin architecture (for review, see Maston et al 2012;Natoli and Andrau 2012). Our results indicate that the production of eRNAs at ERBSs strongly correlates with the enrichment of these features and, in fact, may be a good indicator of active enhancers.…”

Section: Relation Of Erna Production To Features Of Active Enhancerssupporting

confidence: 51%

Enhancer transcripts mark active estrogen receptor binding sites

et al. 2013

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We have integrated and analyzed a large number of data sets from a variety of genomic assays using a novel computational pipeline to provide a global view of estrogen receptor 1 (ESR1; a.k.a. ERα) enhancers in MCF-7 human breast cancer cells. Using this approach, we have defined a class of primary transcripts (eRNAs) that are transcribed uni- or bidirectionally from estrogen receptor binding sites (ERBSs) with an average transcription unit length of ∼3–5 kb. The majority are up-regulated by short treatments with estradiol (i.e., 10, 25, or 40 min) with kinetics that precede or match the induction of the target genes. The production of eRNAs at ERBSs is strongly correlated with the enrichment of a number of genomic features that are associated with enhancers (e.g., H3K4me1, H3K27ac, EP300/CREBBP, RNA polymerase II, open chromatin architecture), as well as enhancer looping to target gene promoters. In the absence of eRNA production, strong enrichment of these features is not observed, even though ESR1 binding is evident. We find that flavopiridol, a CDK9 inhibitor that blocks transcription elongation, inhibits eRNA production but does not affect other molecular indicators of enhancer activity, suggesting that eRNA production occurs after the assembly of active enhancers. Finally, we show that an enhancer transcription “signature” based on GRO-seq data can be used for de novo enhancer prediction across cell types. Together, our studies shed new light on the activity of ESR1 at its enhancer sites and provide new insights about enhancer function.

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Section: Relation Of Erna Production To Features Of Active Enhancerssupporting

confidence: 51%

Enhancer transcripts mark active estrogen receptor binding sites

et al. 2013

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“…The current paradigm of how transcription factors discriminate between functional and nonfunctional locations is based on the combinatorial action of transcription factors. Here, binding specificity is achieved through clusters of binding motifs co-occurring within an enhancer (Panne 2008;Maston et al 2012;Lee and Young 2013;Shlyueva et al 2014;Stampfel et al 2015) or by generating new recognition sequences for pairs of TFs (Jolma et al 2015). Such enhancers are generally classified under the enhanceosome or billboard models, depending on whether or not the order and spacing of motifs is important (Arnosti and Kulkarni 2005).…”

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confidence: 99%

Multiplex enhancer-reporter assays uncover unsophisticated TP53 enhancer logic

et al. 2016

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Transcription factors regulate their target genes by binding to regulatory regions in the genome. Although the binding preferences of TP53 are known, it remains unclear what distinguishes functional enhancers from nonfunctional binding. In addition, the genome is scattered with recognition sequences that remain unoccupied. Using two complementary techniques of multiplex enhancer-reporter assays, we discovered that functional enhancers could be discriminated from nonfunctional binding events by the occurrence of a single TP53 canonical motif. By combining machine learning with a meta-analysis of TP53 ChIP-seq data sets, we identified a core set of more than 1000 responsive enhancers in the human genome. This TP53 cistrome is invariably used between cell types and experimental conditions, whereas differences among experiments can be attributed to indirect nonfunctional binding events. Our data suggest that TP53 enhancers represent a class of unsophisticated cell-autonomous enhancers containing a single TP53 binding site, distinct from complex developmental enhancers that integrate signals from multiple transcription factors.

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“…chromatin | genomics | proteomics T here are more than 1,000 transcription factors, cofactors, and chromatin regulators encoded in the mammalian genome, but we have limited understanding of the genomic occupancy and function of most of these (1)(2)(3)(4). Understanding how these proteins interact with specific active and repressed portions of the genome would provide clues to their functions in global gene control, but limitations inherent in widely used genomic and proteomic technologies make acquiring this information laborious and expensive.…”

mentioning

confidence: 99%

Chromatin proteomic profiling reveals novel proteins associated with histone-marked genomic regions

Xiong

Dadon

Abraham

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

120

112

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More than a thousand proteins are thought to contribute to mammalian chromatin and its regulation, but our understanding of the genomic occupancy and function of most of these proteins is limited. Here we describe an approach, which we call "chromatin proteomic profiling," to identify proteins associated with genomic regions marked by specifically modified histones. We used ChIP-MS to identify proteins associated with genomic regions marked by histones modified at specific lysine residues, including H3K27ac, H3K4me3, H3K79me2, H3K36me3, H3K9me3, and H4K20me3, in ES cells. We identified 332 known and 114 novel proteins associated with these histone-marked genomic segments. Many of the novel candidates have been implicated in various diseases, and their chromatin association may provide clues to disease mechanisms. More than 100 histone modifications have been described, so similar chromatin proteomic profiling studies should prove to be valuable for identifying many additional chromatin-associated proteins in a broad spectrum of cell types.chromatin | genomics | proteomics T here are more than 1,000 transcription factors, cofactors, and chromatin regulators encoded in the mammalian genome, but we have limited understanding of the genomic occupancy and function of most of these (1-4). Understanding how these proteins interact with specific active and repressed portions of the genome would provide clues to their functions in global gene control, but limitations inherent in widely used genomic and proteomic technologies make acquiring this information laborious and expensive. Chromatin immunoprecipitation coupled to sequencing (ChIP-seq) can reveal the sites that a specific protein occupies in the genome (5-7) but is laborious and is limited by the availability of antibodies specific to candidate genome-binding proteins. Mass spectrometry (MS) can identify large populations of proteins present in specific preparations (8-10) but does not reveal how these proteins occupy specific portions of the genome. A recently developed approach combined ChIP with MS (ChIP-MS) to identify protein complexes that are associated with other proteins known to occupy sites in the genome (11-13). Here we adapt this approach to profile the proteins associated with chromatin containing specific histone modifications across the genome of mouse embryonic stem cells (mESCs). These chromatin modifications mark regions of the genome where specific transcriptional activities occur, thus implicating the associated proteins in these activities.

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Characterization of Enhancer Function from Genome-Wide Analyses

Cited by 91 publications

References 184 publications

Enhancer transcripts mark active estrogen receptor binding sites

Enhancer transcripts mark active estrogen receptor binding sites

Multiplex enhancer-reporter assays uncover unsophisticated TP53 enhancer logic

Chromatin proteomic profiling reveals novel proteins associated with histone-marked genomic regions

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