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  1. Article ; Online: Synthetic reversed sequences reveal default genomic states.

    Camellato, Brendan R / Brosh, Ran / Ashe, Hannah J / Maurano, Matthew T / Boeke, Jef D

    Nature

    2024  Volume 628, Issue 8007, Page(s) 373–380

    Abstract: Pervasive transcriptional activity is observed across diverse species. The genomes of extant organisms have undergone billions of years of evolution, making it unclear whether these genomic activities represent effects of selection or 'noise' ...

    Abstract Pervasive transcriptional activity is observed across diverse species. The genomes of extant organisms have undergone billions of years of evolution, making it unclear whether these genomic activities represent effects of selection or 'noise'
    MeSH term(s) Animals ; Humans ; Mice ; Chromatin/genetics ; CpG Islands ; Genes, Synthetic/genetics ; Genome/genetics ; Mouse Embryonic Stem Cells/metabolism ; Promoter Regions, Genetic/genetics ; Saccharomyces cerevisiae/genetics ; Transcription, Genetic ; Hypoxanthine Phosphoribosyltransferase/genetics ; Evolution, Molecular
    Chemical Substances Chromatin ; Hypoxanthine Phosphoribosyltransferase (EC 2.4.2.8)
    Language English
    Publishing date 2024-03-06
    Publishing country England
    Document type Comparative Study ; Journal Article
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-024-07128-2
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  2. Article ; Online: Genomic context sensitivity of insulator function.

    Ribeiro-Dos-Santos, André M / Hogan, Megan S / Luther, Raven D / Brosh, Ran / Maurano, Matthew T

    Genome research

    2022  Volume 32, Issue 3, Page(s) 425–436

    Abstract: The specificity of interactions between genomic regulatory elements and potential target genes is influenced by the binding of insulator proteins such as CTCF, which can act as potent enhancer blockers when interposed between an enhancer and a promoter ... ...

    Abstract The specificity of interactions between genomic regulatory elements and potential target genes is influenced by the binding of insulator proteins such as CTCF, which can act as potent enhancer blockers when interposed between an enhancer and a promoter in a reporter assay. But not all CTCF sites genome-wide function as insulator elements, depending on cellular and genomic context. To dissect the influence of genomic context on enhancer blocker activity, we integrated reporter constructs with promoter-only, promoter and enhancer, and enhancer blocker configurations at hundreds of thousands of genomic sites using the
    MeSH term(s) CCCTC-Binding Factor/genetics ; CCCTC-Binding Factor/metabolism ; Enhancer Elements, Genetic ; Genomics ; Insulator Elements ; Promoter Regions, Genetic
    Chemical Substances CCCTC-Binding Factor
    Language English
    Publishing date 2022-01-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1284872-4
    ISSN 1549-5469 ; 1088-9051 ; 1054-9803
    ISSN (online) 1549-5469
    ISSN 1088-9051 ; 1054-9803
    DOI 10.1101/gr.276449.121
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. 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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  4. Article: Taking Stock of Regulatory Variation.

    Maurano, Matthew T / Stamatoyannopoulos, John A

    Cell systems

    2015  Volume 1, Issue 1, Page(s) 18–21

    Abstract: Three recent studies measure individual variation in regulatory DNA accessibility. What do they tell us about the prospects of assessing variation in single cells and across populations? ...

    Abstract Three recent studies measure individual variation in regulatory DNA accessibility. What do they tell us about the prospects of assessing variation in single cells and across populations?
    Language English
    Publishing date 2015-07-29
    Publishing country United States
    Document type Journal Article
    ISSN 2405-4712
    ISSN 2405-4712
    DOI 10.1016/j.cels.2015.07.011
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. 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- ... ...

    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
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. 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
    Database NAL-Catalogue (AGRICOLA)

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  7. 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
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Big DNA as a tool to dissect an age-related macular degeneration-associated haplotype.

    Laurent, Jon M / Fu, Xin / German, Sergei / Maurano, Matthew T / Zhang, Kang / Boeke, Jef D

    Precision clinical medicine

    2019  Volume 2, Issue 1, Page(s) 1–7

    Abstract: Age-related Macular Degeneration (AMD) is a leading cause of blindness in the developed world, especially in aging populations, and is therefore an important target for new therapeutic development. Recently, there have been several studies demonstrating ... ...

    Abstract Age-related Macular Degeneration (AMD) is a leading cause of blindness in the developed world, especially in aging populations, and is therefore an important target for new therapeutic development. Recently, there have been several studies demonstrating strong associations between AMD and sites of heritable genetic variation at multiple loci, including a highly significant association at 10q26. The 10q26 risk region contains two genes,
    Language English
    Publishing date 2019-01-22
    Publishing country England
    Document type Journal Article
    ZDB-ID 2948341-4
    ISSN 2516-1571 ; 2096-5303
    ISSN (online) 2516-1571
    ISSN 2096-5303
    DOI 10.1093/pcmedi/pby019
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  9. Article ; Online: On the genetic basis of tail-loss evolution in humans and apes.

    Xia, Bo / Zhang, Weimin / Zhao, Guisheng / Zhang, Xinru / Bai, Jiangshan / Brosh, Ran / Wudzinska, Aleksandra / Huang, Emily / Ashe, Hannah / Ellis, Gwen / Pour, Maayan / Zhao, Yu / Coelho, Camila / Zhu, Yinan / Miller, Alexander / Dasen, Jeremy S / Maurano, Matthew T / Kim, Sang Y / Boeke, Jef D /
    Yanai, Itai

    Nature

    2024  Volume 626, Issue 8001, Page(s) 1042–1048

    Abstract: The loss of the tail is among the most notable anatomical changes to have occurred along the evolutionary lineage leading to humans and to the 'anthropomorphous apes' ...

    Abstract The loss of the tail is among the most notable anatomical changes to have occurred along the evolutionary lineage leading to humans and to the 'anthropomorphous apes'
    MeSH term(s) Animals ; Humans ; Mice ; Alternative Splicing/genetics ; Alu Elements/genetics ; Disease Models, Animal ; Evolution, Molecular ; Genome/genetics ; Hominidae/anatomy & histology ; Hominidae/genetics ; Introns/genetics ; Neural Tube Defects/genetics ; Neural Tube Defects/metabolism ; Phenotype ; Protein Isoforms/deficiency ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; T-Box Domain Proteins/deficiency ; T-Box Domain Proteins/genetics ; T-Box Domain Proteins/metabolism ; Tail/anatomy & histology ; Tail/embryology ; Exons/genetics
    Chemical Substances Protein Isoforms ; T-Box Domain Proteins ; TBXT protein, human
    Language English
    Publishing date 2024-02-28
    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/s41586-024-07095-8
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  10. Article ; Online: A conditional counterselectable

    Zhang, Weimin / Brosh, Ran / McCulloch, Laura H / Zhu, Yinan / Ashe, Hannah / Ellis, Gwen / Camellato, Brendan R / Kim, Sang Yong / Maurano, Matthew T / Boeke, Jef D

    iScience

    2022  Volume 25, Issue 6, Page(s) 104438

    Abstract: Overwriting counterselectable markers is an efficient strategy for removing wild-type DNA or replacing it with payload DNA of interest. Currently, one bottleneck of efficient genome engineering in mammals is the shortage of counterselectable (negative ... ...

    Abstract Overwriting counterselectable markers is an efficient strategy for removing wild-type DNA or replacing it with payload DNA of interest. Currently, one bottleneck of efficient genome engineering in mammals is the shortage of counterselectable (negative selection) markers that work robustly without affecting organismal developmental potential. Here, we report a conditional
    Language English
    Publishing date 2022-05-23
    Publishing country United States
    Document type Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2022.104438
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