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Article: Genomic context sensitizes regulatory elements to genetic disruption.

Ordoñez, Raquel / Zhang, Weimin / Ellis, Gwen / Zhu, Yinan / Ashe, Hannah J / Ribeiro-Dos-Santos, André M / Brosh, Ran / Huang, Emily / Hogan, Megan S / Boeke, Jef D / Maurano, Matthew T

bioRxiv : the preprint server for biology

2024

Abstract: Enhancer function is frequently investigated piecemeal using truncated reporter assays or single deletion analysis. Thus it remains unclear to what extent enhancer function at native loci relies on surrounding genomic context. Using the Big-IN technology ...

Abstract	Enhancer function is frequently investigated piecemeal using truncated reporter assays or single deletion analysis. Thus it remains unclear to what extent enhancer function at native loci relies on surrounding genomic context. Using the Big-IN technology for targeted integration of large DNAs, we analyzed the regulatory architecture of the murine
Language	English
Publishing date	2024-03-12
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.07.02.547201
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Article ; Online: Genomic context sensitizes regulatory elements to genetic disruption.

Ordoñez, Raquel / Zhang, Weimin / Ellis, Gwen / Zhu, Yinan / Ashe, Hannah J / Ribeiro-Dos-Santos, André M / Brosh, Ran / Huang, Emily / Hogan, Megan S / Boeke, Jef D / Maurano, Matthew T

Molecular cell

2024 Volume 84, Issue 10, Page(s) 1842–1854.e7

Abstract: Genomic context critically modulates regulatory function but is difficult to manipulate systematically. The murine insulin-like growth factor 2 (Igf2)/H19 locus is a paradigmatic model of enhancer selectivity, whereby CTCF occupancy at an imprinting ... ...

Abstract	Genomic context critically modulates regulatory function but is difficult to manipulate systematically. The murine insulin-like growth factor 2 (Igf2)/H19 locus is a paradigmatic model of enhancer selectivity, whereby CTCF occupancy at an imprinting control region directs downstream enhancers to activate either H19 or Igf2. We used synthetic regulatory genomics to repeatedly replace the native locus with 157-kb payloads, and we systematically dissected its architecture. Enhancer deletion and ectopic delivery revealed previously uncharacterized long-range regulatory dependencies at the native locus. Exchanging the H19 enhancer cluster with the Sox2 locus control region (LCR) showed that the H19 enhancers relied on their native surroundings while the Sox2 LCR functioned autonomously. Analysis of regulatory DNA actuation across cell types revealed that these enhancer clusters typify broader classes of context sensitivity genome wide. These results show that unexpected dependencies influence even well-studied loci, and our approach permits large-scale manipulation of complete loci to investigate the relationship between regulatory architecture and function.
MeSH term(s)	Animals ; Mice ; Enhancer Elements, Genetic ; CCCTC-Binding Factor/metabolism ; CCCTC-Binding Factor/genetics ; Insulin-Like Growth Factor II/genetics ; Insulin-Like Growth Factor II/metabolism ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism ; SOXB1 Transcription Factors/genetics ; SOXB1 Transcription Factors/metabolism ; Locus Control Region/genetics ; Genomic Imprinting ; Genomics/methods
Chemical Substances	Ctcf protein, mouse ; H19 long non-coding RNA ; IGF2 protein, mouse ; Sox2 protein, mouse
Language	English
Publishing date	2024-05-14
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.2024.04.013
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Article: Correction: Ordoñez, et al.; DNA Methylation of Enhancer Elements in Myeloid Neoplasms: Think Outside the Promoters? Cancers 2019, 11, 1424.

Ordoñez, Raquel / Martínez-Calle, Nicolás / Agirre, Xabier / Prosper, Felipe

Cancers

2020 Volume 12, Issue 7

Abstract: The authors would like to make a correction to their published paper [ ... ]. ...

Abstract	The authors would like to make a correction to their published paper [...].
Language	English
Publishing date	2020-07-13
Publishing country	Switzerland
Document type	Published Erratum
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12071885
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Article ; Online: A new background subtraction method for Western blot densitometry band quantification through image analysis software.

Gallo-Oller, Gabriel / Ordoñez, Raquel / Dotor, Javier

Journal of immunological methods

2018 Volume 457, Page(s) 1–5

Abstract: Since its first description, Western blot has been widely used in molecular labs. It constitutes a multistep method that allows the detection and/or quantification of proteins from simple to complex protein mixtures. Western blot quantification method ... ...

Abstract	Since its first description, Western blot has been widely used in molecular labs. It constitutes a multistep method that allows the detection and/or quantification of proteins from simple to complex protein mixtures. Western blot quantification method constitutes a critical step in order to obtain accurate and reproducible results. Due to the technical knowledge required for densitometry analysis together with the resources availability, standard office scanners are often used for the imaging acquisition of developed Western blot films. Furthermore, the use of semi-quantitative software as ImageJ (Java-based image-processing and analysis software) is clearly increasing in different scientific fields. In this work, we describe the use of office scanner coupled with the ImageJ software together with a new image background subtraction method for accurate Western blot quantification. The proposed method represents an affordable, accurate and reproducible approximation that could be used in the presence of limited resources availability.
MeSH term(s)	Blotting, Western ; Densitometry ; Image Processing, Computer-Assisted/methods ; Proteins/analysis ; Reproducibility of Results ; Software
Chemical Substances	Proteins
Language	English
Publishing date	2018-03-06
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	120142-6
ISSN	1872-7905 ; 0022-1759
ISSN (online)	1872-7905
ISSN	0022-1759
DOI	10.1016/j.jim.2018.03.004
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Article: DNA Methylation of Enhancer Elements in Myeloid Neoplasms: Think Outside the Promoters?

Ordoñez, Raquel / Martínez-Calle, Nicolás / Agirre, Xabier / Prosper, Felipe

Cancers

2019 Volume 11, Issue 10

Abstract: Gene regulation through DNA methylation is a well described phenomenon that has a prominent role in physiological and pathological cell-states. This epigenetic modification is usually grouped in regions denominated CpG islands, which frequently co- ... ...

Abstract	Gene regulation through DNA methylation is a well described phenomenon that has a prominent role in physiological and pathological cell-states. This epigenetic modification is usually grouped in regions denominated CpG islands, which frequently co-localize with gene promoters, silencing the transcription of those genes. Recent genome-wide DNA methylation studies have challenged this paradigm, demonstrating that DNA methylation of regulatory regions outside promoters is able to influence cell-type specific gene expression programs under physiologic or pathologic conditions. Coupling genome-wide DNA methylation assays with histone mark annotation has allowed for the identification of specific epigenomic changes that affect enhancer regulatory regions, revealing an additional layer of complexity to the epigenetic regulation of gene expression. In this review, we summarize the novel evidence for the molecular and biological regulation of DNA methylation in enhancer regions and the dynamism of these changes contributing to the fine-tuning of gene expression. We also analyze the contribution of enhancer DNA methylation on the expression of relevant genes in acute myeloid leukemia and chronic myeloproliferative neoplasms. The characterization of the aberrant enhancer DNA methylation provides not only a novel pathogenic mechanism for different tumors but also highlights novel potential therapeutic targets for myeloid derived neoplasms.
Language	English
Publishing date	2019-09-24
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers11101424
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Article ; Online: Synthetic regulatory genomics uncovers enhancer context dependence at the Sox2 locus

Brosh, Ran / Coelho, Camila / Ribeiro-dos-Santos, André M. / Ellis, Gwen / Hogan, Megan S. / Ashe, Hannah J. / Somogyi, Nicolette / Ordoñez, Raquel / Luther, Raven D. / Huang, Emily / Boeke, Jef D. / Maurano, Matthew T.

Molecular Cell. 2023 Apr., v. 83, no. 7 p.1140-1152.e7

2023

Abstract: Sox2 expression in mouse embryonic stem cells (mESCs) depends on a distal cluster of DNase I hypersensitive sites (DHSs), but their individual contributions and degree of interdependence remain a mystery. We analyzed the endogenous Sox2 locus using Big- ... ...

Abstract	Sox2 expression in mouse embryonic stem cells (mESCs) depends on a distal cluster of DNase I hypersensitive sites (DHSs), but their individual contributions and degree of interdependence remain a mystery. We analyzed the endogenous Sox2 locus using Big-IN to scarlessly integrate large DNA payloads incorporating deletions, rearrangements, and inversions affecting single or multiple DHSs, as well as surgical alterations to transcription factor (TF) recognition sequences. Multiple mESC clones were derived for each payload, sequence-verified, and analyzed for Sox2 expression. We found that two DHSs comprising a handful of key TF recognition sequences were each sufficient for long-range activation of Sox2 expression. By contrast, three nearby DHSs were entirely context dependent, showing no activity alone but dramatically augmenting the activity of the autonomous DHSs. Our results highlight the role of context in modulating genomic regulatory element function, and our synthetic regulatory genomics approach provides a roadmap for the dissection of other genomic loci.
Keywords	DNA ; deoxyribonucleases ; dissection ; genomics ; loci ; mice ; transcription factors ; genome writing ; genetic engineering ; gene regulation ; synthetic regulatory genomics ; enhancers ; CTCF ; stem cells
Language	English
Dates of publication	2023-04
Size	p. 1140-1152.e7.
Publishing place	Elsevier Inc.
Document type	Article ; Online
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2023.02.027
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Article ; Online: Synthetic regulatory genomics uncovers enhancer context dependence at the Sox2 locus.

Brosh, Ran / Coelho, Camila / Ribeiro-Dos-Santos, André M / Ellis, Gwen / Hogan, Megan S / Ashe, Hannah J / Somogyi, Nicolette / Ordoñez, Raquel / Luther, Raven D / Huang, Emily / Boeke, Jef D / Maurano, Matthew T

Molecular cell

2023 Volume 83, Issue 7, Page(s) 1140–1152.e7

Abstract	Sox2 expression in mouse embryonic stem cells (mESCs) depends on a distal cluster of DNase I hypersensitive sites (DHSs), but their individual contributions and degree of interdependence remain a mystery. We analyzed the endogenous Sox2 locus using Big-IN to scarlessly integrate large DNA payloads incorporating deletions, rearrangements, and inversions affecting single or multiple DHSs, as well as surgical alterations to transcription factor (TF) recognition sequences. Multiple mESC clones were derived for each payload, sequence-verified, and analyzed for Sox2 expression. We found that two DHSs comprising a handful of key TF recognition sequences were each sufficient for long-range activation of Sox2 expression. By contrast, three nearby DHSs were entirely context dependent, showing no activity alone but dramatically augmenting the activity of the autonomous DHSs. Our results highlight the role of context in modulating genomic regulatory element function, and our synthetic regulatory genomics approach provides a roadmap for the dissection of other genomic loci.
MeSH term(s)	Animals ; Mice ; Enhancer Elements, Genetic ; Gene Expression Regulation ; Genomics ; Regulatory Sequences, Nucleic Acid/genetics ; Transcription Factors/genetics ; Transcription Factors/metabolism ; SOXB1 Transcription Factors/metabolism
Chemical Substances	di-n-hexyl sulfosuccinate (1CYC51DFL6) ; Transcription Factors ; SOXB1 Transcription Factors
Language	English
Publishing date	2023-03-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2023.02.027
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Article ; Online: Tissue context determines the penetrance of regulatory DNA variation.

Halow, Jessica M / Byron, Rachel / Hogan, Megan S / Ordoñez, Raquel / Groudine, Mark / Bender, M A / Stamatoyannopoulos, John A / Maurano, Matthew T

Nature communications

2021 Volume 12, Issue 1, Page(s) 2850

Abstract: Functional assessment of disease-associated sequence variation at non-coding regulatory elements is complicated by their high degree of context sensitivity to both the local chromatin and nuclear environments. Allelic profiling of DNA accessibility ... ...

Abstract	Functional assessment of disease-associated sequence variation at non-coding regulatory elements is complicated by their high degree of context sensitivity to both the local chromatin and nuclear environments. Allelic profiling of DNA accessibility across individuals has shown that only a select minority of sequence variation affects transcription factor (TF) occupancy, yet low sequence diversity in human populations means that no experimental assessment is available for the majority of disease-associated variants. Here we describe high-resolution in vivo maps of allelic DNA accessibility in liver, kidney, lung and B cells from 5 increasingly diverged strains of F1 hybrid mice. The high density of heterozygous sites in these hybrids enables precise quantification of effect size and cell-type specificity for hundreds of thousands of variants throughout the mouse genome. We show that chromatin-altering variants delineate characteristic sensitivity profiles for hundreds of TF motifs. We develop a compendium of TF-specific sensitivity profiles accounting for genomic context effects. Finally, we link maps of allelic accessibility to allelic transcript levels in the same samples. This work provides a foundation for quantitative prediction of cell-type specific effects of non-coding variation on TF activity, which will facilitate both fine-mapping and systems-level analyses of common disease-associated variation in human genomes.
MeSH term(s)	Alleles ; Animals ; Binding Sites/genetics ; Chromatin/genetics ; Chromatin/metabolism ; Chromosome Mapping ; DNA/genetics ; DNA/metabolism ; Female ; Gene Expression Regulation ; Genetic Variation ; Genome, Human ; Humans ; Hybridization, Genetic ; Male ; Mice ; Mice, 129 Strain ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Organ Specificity/genetics ; Penetrance ; Regulatory Sequences, Nucleic Acid ; Transcription Factors/metabolism
Chemical Substances	Chromatin ; Transcription Factors ; DNA (9007-49-2)
Language	English
Publishing date	2021-05-14
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-23139-3
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Article ; Online: Molecular characterization of autophagic and apoptotic signaling induced by sorafenib in liver cancer cells.

Rodríguez-Hernández, María A / González, Raúl / de la Rosa, Ángel J / Gallego, Paloma / Ordóñez, Raquel / Navarro-Villarán, Elena / Contreras, Laura / Rodríguez-Arribas, Mario / González-Gallego, Javier / Álamo-Martínez, José M / Marín-Gómez, Luís M / Del Campo, José A / Quiles, José L / Fuentes, José M / Cruz, Jesús de la / Mauriz, José L / Padillo, Francisco J / Muntané, Jordi

Journal of cellular physiology

2024 Volume 239, Issue 2, Page(s) e31206

Language	English
Publishing date	2024-02-04
Publishing country	United States
Document type	Published Erratum
ZDB-ID	3116-1
ISSN	1097-4652 ; 0021-9541
ISSN (online)	1097-4652
ISSN	0021-9541
DOI	10.1002/jcp.31206
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Article ; Online: A versatile platform for locus-scale genome rewriting and verification.

Brosh, Ran / Laurent, Jon M / Ordoñez, Raquel / Huang, Emily / Hogan, Megan S / Hitchcock, Angela M / Mitchell, Leslie A / Pinglay, Sudarshan / Cadley, John A / Luther, Raven D / Truong, David M / Boeke, Jef D / Maurano, Matthew T

Proceedings of the National Academy of Sciences of the United States of America

2021 Volume 118, Issue 10

Abstract: Routine rewriting of loci associated with human traits and diseases would facilitate their functional analysis. However, existing DNA integration approaches are limited in terms of scalability and portability across genomic loci and cellular contexts. We ...

Abstract	Routine rewriting of loci associated with human traits and diseases would facilitate their functional analysis. However, existing DNA integration approaches are limited in terms of scalability and portability across genomic loci and cellular contexts. We describe Big-IN, a versatile platform for targeted integration of large DNAs into mammalian cells. CRISPR/Cas9-mediated targeting of a landing pad enables subsequent recombinase-mediated delivery of variant payloads and efficient positive/negative selection for correct clones in mammalian stem cells. We demonstrate integration of constructs up to 143 kb, and an approach for one-step scarless delivery. We developed a staged pipeline combining PCR genotyping and targeted capture sequencing for economical and comprehensive verification of engineered stem cells. Our approach should enable combinatorial interrogation of genomic functional elements and systematic locus-scale analysis of genome function.
MeSH term(s)	Animals ; CRISPR-Cas Systems ; Cell Line ; Gene Editing ; Genetic Loci ; Genome, Human ; Human Embryonic Stem Cells ; Humans ; Mice ; Mouse Embryonic Stem Cells
Language	English
Publishing date	2021-02-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2023952118
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