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Open accessJournal ArticleDOI: 10.1016/J.MOLCEL.2020.12.047

Temporal dissection of an enhancer cluster reveals distinct temporal and functional contributions of individual elements

04 Mar 2021-Molecular Cell (Cell Press)-Vol. 81, Iss: 5
Abstract: Many genes are regulated by multiple enhancers that often simultaneously activate their target gene. However, how individual enhancers collaborate to activate transcription is not well understood. Here, we dissect the functions and interdependencies of five enhancer elements that together activate Fgf5 expression during exit from naive murine pluripotency. Four intergenic elements form a super-enhancer, and most of the elements contribute to Fgf5 induction at distinct time points. A fifth, poised enhancer located in the first intron contributes to Fgf5 expression at every time point by amplifying overall Fgf5 expression levels. Despite low individual enhancer activity, together these elements strongly induce Fgf5 expression in a super-additive fashion that involves strong accumulation of RNA polymerase II at the intronic enhancer. Finally, we observe a strong anti-correlation between RNA polymerase II levels at enhancers and their distance to the closest promoter, and we identify candidate elements with properties similar to the intronic enhancer.

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Topics: Enhancer (62%), Super-enhancer (52%), Transcription (biology) (52%) ... show more

13 results found

Journal ArticleDOI: 10.1093/PLCELL/KOAB093
Fanli Meng1, Fanli Meng2, Hainan Zhao1, Bo Zhu3  +5 moreInstitutions (4)
19 Jul 2021-The Plant Cell
Abstract: Enhancers located in introns are abundant and play a major role in the regulation of gene expression in mammalian species. By contrast, the functions of intronic enhancers in plants have largely been unexplored and only a handful of plant intronic enhancers have been reported. We performed a genome-wide prediction of intronic enhancers in Arabidopsis thaliana using open chromatin signatures based on DNase I sequencing. We identified 941 candidate intronic enhancers associated with 806 genes in seedling tissue and 1,271 intronic enhancers associated with 1,069 genes in floral tissue. We validated the function of 15 of 21 (71%) of the predicted intronic enhancers in transgenic assays using a reporter gene. We also created deletion lines of three intronic enhancers associated with two different genes using CRISPR/Cas. Deletion of these enhancers, which span key transcription factor binding sites, did not abolish gene expression but caused varying levels of transcriptional repression of their cognate genes. Remarkably, the transcriptional repression of the deletion lines occurred at specific developmental stages and resulted in distinct phenotypic effects on plant morphology and development. Clearly, these three intronic enhancers are important in fine-tuning tissue- and development-specific expression of their cognate genes.

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Topics: Enhancer (57%), Tissue-Specific Gene Expression (54%), Gene (53%) ... show more

5 Citations

Open accessPosted ContentDOI: 10.1101/2021.06.21.449340
22 Jun 2021-bioRxiv
Abstract: Three-dimensional (3D) epigenome remodelling is emerging as an important mechanism of gene deregulation in cancer. However, its potential as a target to overcome cancer therapy resistance remains largely unaddressed. Here we show that treatment of endocrine-resistant estrogen receptor positive (ER+) breast cancer with an FDA-approved epigenetic therapy Decitabine (5-Aza-mC), results in genome-wide DNA hypomethylation and suppression of tumour growth in preclinical metastatic ER+ breast tumour xenograft models. Systematic integration of matched chromatin conformation capture (Hi-C), Promoter Capture Hi-C, RNA-seq and ER ChIP-seq data revealed widespread effects on epigenome deregulation, including de-compaction of higher order chromatin structure and loss of topologically associating domains (TAD) boundary insulation. Key enhancer ER binding sites were demethylated and re-activated after Decitabine treatment, resulting in new ER-mediated enhancer-promoter interactions and concordant activation of tumour-suppressive gene pathways. Importantly, we show that the activated ER target genes were also predictive of good outcome in multiple ER+ breast cancer clinical cohorts. Together our study reveals a previously undescribed mechanism of Decitabine in re-wiring DNA methylation-dependent 3D genome architecture resulting in suppression of tumour growth, and highlights the potential of epigenetic therapy in targeting ER+ endocrine-resistant breast cancer. One line summaryEpigenetic therapy suppresses tumour growth in metastatic ER+ breast cancer via DNA hypomethylation-induced rewiring of long-range ER-mediated enhancer-promoter chromatin interactions to activate ER target genes involved in repression of proliferation and the cell cycle.

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Topics: Epigenetic therapy (59%), Epigenome (57%), Cancer (55%) ... show more

2 Citations

Journal ArticleDOI: 10.1016/J.SBI.2021.06.005
Juhyun Kim1, Ann Dean1Institutions (1)
Abstract: The activity and selectivity of transcriptional enhancers determine gene expression patterns that enable a zygote to become a complex organism. How enhancers convey regulatory information is a central conundrum in biology. Here, we discuss recent progress provided by rapidly evolving technologies in understanding enhancer-promoter interactions in the context of overall nuclear genome organization.

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Topics: Genome (57%), Enhancer (54%), Context (language use) (52%) ... show more

2 Citations

Open accessJournal ArticleDOI: 10.1186/S13059-021-02485-X
Yan Kai1, Bin E. Li1, Ming Zhu2, Grace Y Li1  +9 moreInstitutions (4)
15 Sep 2021-Genome Biology
Abstract: Background Super-enhancers are clusters of enhancer elements that play critical roles in the maintenance of cell identity. Current investigations on super-enhancers are centered on the established ones in static cell types. How super-enhancers are established during cell differentiation remains obscure. Results Here, by developing an unbiased approach to systematically analyze the evolving landscape of super-enhancers during cell differentiation in multiple lineages, we discover a general trend where super-enhancers emerge through three distinct temporal patterns: conserved, temporally hierarchical, and de novo. The three types of super-enhancers differ further in association patterns in target gene expression, functional enrichment, and 3D chromatin organization, suggesting they may represent distinct structural and functional subtypes. Furthermore, we dissect the enhancer repertoire within temporally hierarchical super-enhancers, and find enhancers that emerge at early and late stages are enriched with distinct transcription factors, suggesting that the temporal order of establishment of elements within super-enhancers may be directed by underlying DNA sequence. CRISPR-mediated deletion of individual enhancers in differentiated cells shows that both the early- and late-emerged enhancers are indispensable for target gene expression, while in undifferentiated cells early enhancers are involved in the regulation of target genes. Conclusions In summary, our analysis highlights the heterogeneity of the super-enhancer population and provides new insights to enhancer functions within super-enhancers.

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Topics: Enhancer (57%), Cellular differentiation (54%), Population (51%)

2 Citations

Open accessJournal ArticleDOI: 10.1007/S00018-021-03903-W
Helen Ray-Jones, Mikhail Spivakov1Institutions (1)
Abstract: Transcriptional enhancers play a key role in the initiation and maintenance of gene expression programmes, particularly in metazoa. How these elements control their target genes in the right place and time is one of the most pertinent questions in functional genomics, with wide implications for most areas of biology. Here, we synthesise classic and recent evidence on the regulatory logic of enhancers, including the principles of enhancer organisation, factors that facilitate and delimit enhancer-promoter communication, and the joint effects of multiple enhancers. We show how modern approaches building on classic insights have begun to unravel the complexity of enhancer-promoter relationships, paving the way towards a quantitative understanding of gene control.

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Topics: Functional genomics (51%), Enhancer (51%)

1 Citations


70 results found

Open accessJournal Article
01 Jan 2014-MSOR connections
Abstract: Copyright (©) 1999–2012 R Foundation for Statistical Computing. Permission is granted to make and distribute verbatim copies of this manual provided the copyright notice and this permission notice are preserved on all copies. Permission is granted to copy and distribute modified versions of this manual under the conditions for verbatim copying, provided that the entire resulting derived work is distributed under the terms of a permission notice identical to this one. Permission is granted to copy and distribute translations of this manual into another language, under the above conditions for modified versions, except that this permission notice may be stated in a translation approved by the R Core Team.

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Topics: R Programming Language (78%)

229,202 Citations

Open accessJournal ArticleDOI: 10.1093/BIOINFORMATICS/BTP352
Heng Li1, Bob Handsaker2, Alec Wysoker2, T. J. Fennell2  +5 moreInstitutions (4)
01 Aug 2009-Bioinformatics
Abstract: Summary: The Sequence Alignment/Map (SAM) format is a generic alignment format for storing read alignments against reference sequences, supporting short and long reads (up to 128 Mbp) produced by different sequencing platforms. It is flexible in style, compact in size, efficient in random access and is the format in which alignments from the 1000 Genomes Project are released. SAMtools implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments. Availability: Contact: [email protected]

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Topics: Variant Call Format (62%), Stockholm format (61%), FASTQ format (56%) ... show more

35,747 Citations

Open accessJournal ArticleDOI: 10.1093/BIOINFORMATICS/BTP324
Heng Li1, Richard Durbin1Institutions (1)
01 Jul 2009-Bioinformatics
Abstract: Motivation: The enormous amount of short reads generated by the new DNA sequencing technologies call for the development of fast and accurate read alignment programs. A first generation of hash table-based methods has been developed, including MAQ, which is accurate, feature rich and fast enough to align short reads from a single individual. However, MAQ does not support gapped alignment for single-end reads, which makes it unsuitable for alignment of longer reads where indels may occur frequently. The speed of MAQ is also a concern when the alignment is scaled up to the resequencing of hundreds of individuals. Results: We implemented Burrows-Wheeler Alignment tool (BWA), a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps. BWA supports both base space reads, e.g. from Illumina sequencing machines, and color space reads from AB SOLiD machines. Evaluations on both simulated and real data suggest that BWA is ~10–20× faster than MAQ, while achieving similar accuracy. In addition, BWA outputs alignment in the new standard SAM (Sequence Alignment/Map) format. Variant calling and other downstream analyses after the alignment can be achieved with the open source SAMtools software package. Availability: Contact: [email protected]

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Topics: Hybrid genome assembly (54%), Sequence assembly (53%), 2 base encoding (52%) ... show more

35,234 Citations

Open accessJournal ArticleDOI: 10.1186/S13059-014-0550-8
05 Dec 2014-Genome Biology
Abstract: In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The DESeq2 package is available at .

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Topics: MRNA Sequencing (54%), Integrator complex (51%), Count data (50%) ... show more

29,675 Citations

Open accessJournal ArticleDOI: 10.1038/NMETH.1923
01 Apr 2012-Nature Methods
Abstract: As the rate of sequencing increases, greater throughput is demanded from read aligners. The full-text minute index is often used to make alignment very fast and memory-efficient, but the approach is ill-suited to finding longer, gapped alignments. Bowtie 2 combines the strengths of the full-text minute index with the flexibility and speed of hardware-accelerated dynamic programming algorithms to achieve a combination of high speed, sensitivity and accuracy.

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27,973 Citations

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