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Article ; Online: Enhancers have more cofactor specificity than we think: A potential new way to classify enhancers based on their functional cofactor requirements.

Pijuan-Sala, Blanca / Furlong, Eileen E M

2022 Volume 82, Issue 16, Page(s) 2922–2924

Abstract: By systematically assessing the effects of depleting eight cofactors on enhancer activity, Neumayr et al. (2022) found that different enhancers have different requirements for some perceived universal cofactors. While some cofactors influence enhancer ... ...

Abstract	By systematically assessing the effects of depleting eight cofactors on enhancer activity, Neumayr et al. (2022) found that different enhancers have different requirements for some perceived universal cofactors. While some cofactors influence enhancer strength, others affect enhancer-promoter specificity.
MeSH term(s)	Enhancer Elements, Genetic ; Promoter Regions, Genetic
Language	English
Publishing date	2022-08-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2022.07.015
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Article ; Online: Regulating specificity in enhancer-promoter communication.

Galouzis, Charalampos Chrysovalantis / Furlong, Eileen E M

Current opinion in cell biology

2022 Volume 75, Page(s) 102065

Abstract: Enhancers are cis-regulatory elements that can activate transcription remotely to regulate a specific pattern of a gene's expression. Genes typically have many enhancers that are often intermingled in the loci of other genes. To regulate expression, ... ...

Abstract	Enhancers are cis-regulatory elements that can activate transcription remotely to regulate a specific pattern of a gene's expression. Genes typically have many enhancers that are often intermingled in the loci of other genes. To regulate expression, enhancers must therefore activate their correct promoter while ignoring others that may be in closer linear proximity. In this review, we discuss mechanisms by which enhancers engage with promoters, including recent findings on the role of cohesin and the Mediator complex, and how this specificity in enhancer-promoter communication is encoded. Genetic dissection of model loci, in addition to more recent findings using genome-wide approaches, highlight the core promoter sequence, its accessibility, cofactor-promoter preference, in addition to the surrounding genomic context, as key components.
MeSH term(s)	Cell Nucleus ; Communication ; Genomics ; Promoter Regions, Genetic
Language	English
Publishing date	2022-02-28
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1026381-0
ISSN	1879-0410 ; 0955-0674
ISSN (online)	1879-0410
ISSN	0955-0674
DOI	10.1016/j.ceb.2022.01.010
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Article ; Online: Enhancer-promoter interactions become more instructive in the transition from cell-fate specification to tissue differentiation.

Pollex, Tim / Rabinowitz, Adam / Gambetta, Maria Cristina / Marco-Ferreres, Raquel / Viales, Rebecca R / Jankowski, Aleksander / Schaub, Christoph / Furlong, Eileen E M

Nature genetics

2024 Volume 56, Issue 4, Page(s) 686–696

Abstract: To regulate expression, enhancers must come in proximity to their target gene. However, the relationship between the timing of enhancer-promoter (E-P) proximity and activity remains unclear, with examples of uncoupled, anticorrelated and correlated ... ...

Abstract	To regulate expression, enhancers must come in proximity to their target gene. However, the relationship between the timing of enhancer-promoter (E-P) proximity and activity remains unclear, with examples of uncoupled, anticorrelated and correlated interactions. To assess this, we selected 600 characterized enhancers or promoters with tissue-specific activity in Drosophila embryos and performed Capture-C in FACS-purified myogenic or neurogenic cells during specification and tissue differentiation. This enabled direct comparison between E-P proximity and activity transitioning from OFF-to-ON and ON-to-OFF states across developmental conditions. This showed remarkably similar E-P topologies between specified muscle and neuronal cells, which are uncoupled from activity. During tissue differentiation, many new distal interactions emerge where changes in E-P proximity reflect changes in activity. The mode of E-P regulation therefore appears to change as embryogenesis proceeds, from largely permissive topologies during cell-fate specification to more instructive regulation during terminal tissue differentiation, when E-P proximity is coupled to activation.
MeSH term(s)	Animals ; Enhancer Elements, Genetic/genetics ; Gene Expression Regulation, Developmental/genetics ; Promoter Regions, Genetic/genetics ; Drosophila/genetics ; Cell Differentiation/genetics
Language	English
Publishing date	2024-03-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-024-01678-x
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Article ; Online: Developmental enhancers and chromosome topology.

Furlong, Eileen E M / Levine, Michael

Science (New York, N.Y.)

2018 Volume 361, Issue 6409, Page(s) 1341–1345

Abstract: Developmental enhancers mediate on/off patterns of gene expression in specific cell types at particular stages during metazoan embryogenesis. They typically integrate multiple signals and regulatory determinants to achieve precise spatiotemporal ... ...

Abstract	Developmental enhancers mediate on/off patterns of gene expression in specific cell types at particular stages during metazoan embryogenesis. They typically integrate multiple signals and regulatory determinants to achieve precise spatiotemporal expression. Such enhancers can map quite far-one megabase or more-from the genes they regulate. How remote enhancers relay regulatory information to their target promoters is one of the central mysteries of genome organization and function. A variety of contrasting mechanisms have been proposed over the years, including enhancer tracking, linking, looping, and mobilization to transcription factories. We argue that extreme versions of these mechanisms cannot account for the transcriptional dynamics and precision seen in living cells, tissues, and embryos. We describe emerging evidence for dynamic three-dimensional hubs that combine different elements of the classical models.
MeSH term(s)	Animals ; Chromatin/chemistry ; Chromosomes/chemistry ; Chromosomes/ultrastructure ; Embryonic Development/genetics ; Enhancer Elements, Genetic ; Gene Expression Regulation, Developmental ; Humans ; Mice ; Promoter Regions, Genetic ; Protein Domains ; Transcription, Genetic
Chemical Substances	Chromatin
Language	English
Publishing date	2018-09-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.aau0320
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Article ; Online: scDALI: modeling allelic heterogeneity in single cells reveals context-specific genetic regulation.

Heinen, Tobias / Secchia, Stefano / Reddington, James P / Zhao, Bingqing / Furlong, Eileen E M / Stegle, Oliver

Genome biology

2022 Volume 23, Issue 1, Page(s) 8

Abstract: While it is established that the functional impact of genetic variation can vary across cell types and states, capturing this diversity remains challenging. Current studies using bulk sequencing either ignore this heterogeneity or use sorted cell ... ...

Abstract	While it is established that the functional impact of genetic variation can vary across cell types and states, capturing this diversity remains challenging. Current studies using bulk sequencing either ignore this heterogeneity or use sorted cell populations, reducing discovery and explanatory power. Here, we develop scDALI, a versatile computational framework that integrates information on cellular states with allelic quantifications of single-cell sequencing data to characterize cell-state-specific genetic effects. We apply scDALI to scATAC-seq profiles from developing F1 Drosophila embryos and scRNA-seq from differentiating human iPSCs, uncovering heterogeneous genetic effects in specific lineages, developmental stages, or cell types.
MeSH term(s)	Gene Expression Regulation ; Induced Pluripotent Stem Cells ; Single-Cell Analysis
Language	English
Publishing date	2022-01-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2040529-7
ISSN	1474-760X ; 1474-760X
ISSN (online)	1474-760X
ISSN	1474-760X
DOI	10.1186/s13059-021-02593-8
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Article ; Online: Simultaneous cellular and molecular phenotyping of embryonic mutants using single-cell regulatory trajectories.

Secchia, Stefano / Forneris, Mattia / Heinen, Tobias / Stegle, Oliver / Furlong, Eileen E M

Developmental cell

2022 Volume 57, Issue 4, Page(s) 496–511.e8

Abstract: Developmental progression and cellular diversity are largely driven by transcription factors (TFs); yet, characterizing their loss-of-function phenotypes remains challenging and often disconnected from their underlying molecular mechanisms. Here, we ... ...

Abstract	Developmental progression and cellular diversity are largely driven by transcription factors (TFs); yet, characterizing their loss-of-function phenotypes remains challenging and often disconnected from their underlying molecular mechanisms. Here, we combine single-cell regulatory genomics with loss-of-function mutants to jointly assess both cellular and molecular phenotypes. Performing sci-ATAC-seq at eight overlapping time points during Drosophila mesoderm development could reconstruct the developmental trajectories of all major muscle types and reveal the TFs and enhancers involved. To systematically assess mutant phenotypes, we developed a single-nucleus genotyping strategy to process embryo pools of mixed genotypes. Applying this to four TF mutants could identify and quantify their characterized phenotypes de novo and discover new ones, while simultaneously revealing their regulatory input and mode of action. Our approach is a general framework to dissect the functional input of TFs in a systematic, unbiased manner, identifying both cellular and molecular phenotypes at a scale and resolution that has not been feasible before.
MeSH term(s)	Animals ; Chromatin/metabolism ; Drosophila/metabolism ; Enhancer Elements, Genetic/genetics ; Gene Expression Regulation, Developmental/genetics ; Gene Regulatory Networks/genetics ; Genomics ; Phenotype ; Transcription Factors/metabolism
Chemical Substances	Chromatin ; Transcription Factors
Language	English
Publishing date	2022-02-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2054967-2
ISSN	1878-1551 ; 1534-5807
ISSN (online)	1878-1551
ISSN	1534-5807
DOI	10.1016/j.devcel.2022.01.016
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Article ; Online: Targeted design of synthetic enhancers for selected tissues in the Drosophila embryo.

de Almeida, Bernardo P / Schaub, Christoph / Pagani, Michaela / Secchia, Stefano / Furlong, Eileen E M / Stark, Alexander

Nature

2023 Volume 626, Issue 7997, Page(s) 207–211

Abstract: Enhancers control gene expression and have crucial roles in development and ... ...

Abstract	Enhancers control gene expression and have crucial roles in development and homeostasis
MeSH term(s)	Animals ; Chromatin/genetics ; Chromatin/metabolism ; Datasets as Topic ; Deep Learning ; Drosophila melanogaster/embryology ; Drosophila melanogaster/genetics ; Embryo, Nonmammalian/embryology ; Embryo, Nonmammalian/metabolism ; Enhancer Elements, Genetic/genetics ; Neural Networks, Computer ; Organ Specificity/genetics ; Reproducibility of Results ; Single-Cell Analysis ; Transposases/metabolism ; Synthetic Biology/methods
Chemical Substances	Chromatin ; Transposases (EC 2.7.7.-)
Language	English
Publishing date	2023-12-12
Publishing country	England
Document type	Journal Article
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-023-06905-9
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Article ; Online: Correlation Does Not Imply Causation: Histone Methyltransferases, but Not Histone Methylation, SET the Stage for Enhancer Activation.

Pollex, Tim / Furlong, Eileen E M

Molecular cell

2017 Volume 66, Issue 4, Page(s) 439–441

Abstract: Although H3K4me1 is a pervasive "mark" of enhancers, its functional requirement for enhancer activity remains unclear. In this issue of Molecular Cell, Dorighi et al. (2017) show that in some contexts, the methyltransferase complex, rather than the ... ...

Abstract	Although H3K4me1 is a pervasive "mark" of enhancers, its functional requirement for enhancer activity remains unclear. In this issue of Molecular Cell, Dorighi et al. (2017) show that in some contexts, the methyltransferase complex, rather than the H3K4me1 mark, is required for gene expression.
MeSH term(s)	Enhancer Elements, Genetic ; Histone-Lysine N-Methyltransferase/genetics ; Histones/genetics ; Humans ; Methylation
Chemical Substances	Histones ; histone methyltransferase (EC 2.1.1.-) ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43)
Language	English
Publishing date	2017-05-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2017.05.005
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Article: scDALI: modeling allelic heterogeneity in single cells reveals context-specific genetic regulation

Heinen, Tobias / Secchia, Stefano / Reddington, James P. / Zhao, Bingqing / Furlong, Eileen E. M. / Stegle, Oliver

Genome biology. 2022 Dec., v. 23, no. 1

2022

Abstract	While it is established that the functional impact of genetic variation can vary across cell types and states, capturing this diversity remains challenging. Current studies using bulk sequencing either ignore this heterogeneity or use sorted cell populations, reducing discovery and explanatory power. Here, we develop scDALI, a versatile computational framework that integrates information on cellular states with allelic quantifications of single-cell sequencing data to characterize cell-state-specific genetic effects. We apply scDALI to scATAC-seq profiles from developing F1 Drosophila embryos and scRNA-seq from differentiating human iPSCs, uncovering heterogeneous genetic effects in specific lineages, developmental stages, or cell types.
Keywords	Drosophila ; genetic variation ; genome ; humans
Language	English
Dates of publication	2022-12
Size	p. 8.
Publishing place	BioMed Central
Document type	Article
ZDB-ID	2040529-7
ISSN	1474-760X
ISSN	1474-760X
DOI	10.1186/s13059-021-02593-8
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: The role of transcription in shaping the spatial organization of the genome.

van Steensel, Bas / Furlong, Eileen E M

Nature reviews. Molecular cell biology

2019 Volume 20, Issue 6, Page(s) 327–337

Abstract: The spatial organization of the genome into compartments and topologically associated domains can have an important role in the regulation of gene expression. But could gene expression conversely regulate genome organization? Here, we review recent ... ...

Abstract	The spatial organization of the genome into compartments and topologically associated domains can have an important role in the regulation of gene expression. But could gene expression conversely regulate genome organization? Here, we review recent studies that assessed the requirement of transcription and/or the transcription machinery for the establishment or maintenance of genome topology. The results reveal different requirements at different genomic scales. Transcription is generally not required for higher-level genome compartmentalization, has only moderate effects on domain organization and is not sufficient to create new domain boundaries. However, on a finer scale, transcripts or transcription does seem to have a role in the formation of subcompartments and subdomains and in stabilizing enhancer-promoter interactions. Recent evidence suggests a dynamic, reciprocal interplay between fine-scale genome organization and transcription, in which each is able to modulate or reinforce the activity of the other.
MeSH term(s)	Animals ; Chromatin/genetics ; Chromatin/metabolism ; Enhancer Elements, Genetic ; Genome, Human ; Humans ; Promoter Regions, Genetic ; Transcription, Genetic
Chemical Substances	Chromatin
Language	English
Publishing date	2019-03-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2031313-5
ISSN	1471-0080 ; 1471-0072
ISSN (online)	1471-0080
ISSN	1471-0072
DOI	10.1038/s41580-019-0114-6
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