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  1. Article ; Online: Embryonic development across space and time.

    Waymack, Rachel / Wunderlich, Zeba

    Nature computational science

    2021  Volume 1, Issue 8, Page(s) 507–508

    Language English
    Publishing date 2021-08-20
    Publishing country United States
    Document type Journal Article
    ISSN 2662-8457
    ISSN (online) 2662-8457
    DOI 10.1038/s43588-021-00117-9
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  2. Article ; Online: Shadow enhancers mediate trade-offs between transcriptional noise and fidelity.

    Fletcher, Alvaro / Wunderlich, Zeba / Enciso, German

    PLoS computational biology

    2023  Volume 19, Issue 5, Page(s) e1011071

    Abstract: Enhancers are stretches of regulatory DNA that bind transcription factors (TFs) and regulate the expression of a target gene. Shadow enhancers are two or more enhancers that regulate the same target gene in space and time and are associated with most ... ...

    Abstract Enhancers are stretches of regulatory DNA that bind transcription factors (TFs) and regulate the expression of a target gene. Shadow enhancers are two or more enhancers that regulate the same target gene in space and time and are associated with most animal developmental genes. These multi-enhancer systems can drive more consistent transcription than single enhancer systems. Nevertheless, it remains unclear why shadow enhancer TF binding sites are distributed across multiple enhancers rather than within a single large enhancer. Here, we use a computational approach to study systems with varying numbers of TF binding sites and enhancers. We employ chemical reaction networks with stochastic dynamics to determine the trends in transcriptional noise and fidelity, two key performance objectives of enhancers. This reveals that while additive shadow enhancers do not differ in noise and fidelity from their single enhancer counterparts, sub- and superadditive shadow enhancers have noise and fidelity trade-offs not available to single enhancers. We also use our computational approach to compare the duplication and splitting of a single enhancer as mechanisms for the generation of shadow enhancers and find that the duplication of enhancers can decrease noise and increase fidelity, although at the metabolic cost of increased RNA production. A saturation mechanism for enhancer interactions similarly improves on both of these metrics. Taken together, this work highlights that shadow enhancer systems may exist for several reasons: genetic drift or the tuning of key functions of enhancers, including transcription fidelity, noise and output.
    MeSH term(s) Animals ; Enhancer Elements, Genetic/genetics ; Transcription Factors/genetics ; Transcription Factors/metabolism
    Chemical Substances Transcription Factors
    Language English
    Publishing date 2023-05-19
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2193340-6
    ISSN 1553-7358 ; 1553-734X
    ISSN (online) 1553-7358
    ISSN 1553-734X
    DOI 10.1371/journal.pcbi.1011071
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  3. Article ; Online: Shadow enhancers mediate trade-offs between transcriptional noise and fidelity.

    Alvaro Fletcher / Zeba Wunderlich / German Enciso

    PLoS Computational Biology, Vol 19, Iss 5, p e

    2023  Volume 1011071

    Abstract: Enhancers are stretches of regulatory DNA that bind transcription factors (TFs) and regulate the expression of a target gene. Shadow enhancers are two or more enhancers that regulate the same target gene in space and time and are associated with most ... ...

    Abstract Enhancers are stretches of regulatory DNA that bind transcription factors (TFs) and regulate the expression of a target gene. Shadow enhancers are two or more enhancers that regulate the same target gene in space and time and are associated with most animal developmental genes. These multi-enhancer systems can drive more consistent transcription than single enhancer systems. Nevertheless, it remains unclear why shadow enhancer TF binding sites are distributed across multiple enhancers rather than within a single large enhancer. Here, we use a computational approach to study systems with varying numbers of TF binding sites and enhancers. We employ chemical reaction networks with stochastic dynamics to determine the trends in transcriptional noise and fidelity, two key performance objectives of enhancers. This reveals that while additive shadow enhancers do not differ in noise and fidelity from their single enhancer counterparts, sub- and superadditive shadow enhancers have noise and fidelity trade-offs not available to single enhancers. We also use our computational approach to compare the duplication and splitting of a single enhancer as mechanisms for the generation of shadow enhancers and find that the duplication of enhancers can decrease noise and increase fidelity, although at the metabolic cost of increased RNA production. A saturation mechanism for enhancer interactions similarly improves on both of these metrics. Taken together, this work highlights that shadow enhancer systems may exist for several reasons: genetic drift or the tuning of key functions of enhancers, including transcription fidelity, noise and output.
    Keywords Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2023-05-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Molecular competition can shape enhancer activity in the

    Waymack, Rachel / Gad, Mario / Wunderlich, Zeba

    iScience

    2021  Volume 24, Issue 9, Page(s) 103034

    Abstract: Transgenic reporters allow the measurement of regulatory DNA ... ...

    Abstract Transgenic reporters allow the measurement of regulatory DNA activity
    Language English
    Publishing date 2021-08-25
    Publishing country United States
    Document type Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2021.103034
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  5. Article ; Online: Longitudinal monitoring of individual infection progression in

    Ramirez-Corona, Bryan A / Love, Anna C / Chandrasekaran, Srikiran / Prescher, Jennifer A / Wunderlich, Zeba

    iScience

    2022  Volume 25, Issue 11, Page(s) 105378

    Abstract: The innate immune system is critical for infection survival. ...

    Abstract The innate immune system is critical for infection survival.
    Language English
    Publishing date 2022-10-17
    Publishing country United States
    Document type Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2022.105378
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Author Correction: Enhancer redundancy in development and disease.

    Kvon, Evgeny Z / Waymack, Rachel / Gad, Mario / Wunderlich, Zeba

    Nature reviews. Genetics

    2021  Volume 22, Issue 5, Page(s) 337

    Language English
    Publishing date 2021-04-13
    Publishing country England
    Document type Published Erratum
    ZDB-ID 2035157-4
    ISSN 1471-0064 ; 1471-0056
    ISSN (online) 1471-0064
    ISSN 1471-0056
    DOI 10.1038/s41576-021-00361-9
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  7. Article ; Online: Drosophila immune priming to Enterococcus faecalis relies on immune tolerance rather than resistance.

    Cabrera, Kevin / Hoard, Duncan S / Gibson, Olivia / Martinez, Daniel I / Wunderlich, Zeba

    PLoS pathogens

    2023  Volume 19, Issue 8, Page(s) e1011567

    Abstract: Innate immune priming increases an organism's survival of a second infection after an initial, non-lethal infection. We used Drosophila melanogaster and an insect-derived strain of Enterococcus faecalis to study transcriptional control of priming. In ... ...

    Abstract Innate immune priming increases an organism's survival of a second infection after an initial, non-lethal infection. We used Drosophila melanogaster and an insect-derived strain of Enterococcus faecalis to study transcriptional control of priming. In contrast to other pathogens, the enhanced survival in primed animals does not correlate with decreased E. faecalis load. Further analysis shows that primed organisms tolerate, rather than resist infection. Using RNA-seq of immune tissues, we found many genes were upregulated in only primed flies, suggesting a distinct transcriptional program in response to initial and secondary infections. In contrast, few genes continuously express throughout the experiment or more efficiently re-activate upon reinfection. Priming experiments in immune deficient mutants revealed Imd is largely dispensable for responding to a single infection but needed to fully prime. Together, this indicates the fly's innate immune response is plastic-differing in immune strategy, transcriptional program, and pathway use depending on infection history.
    MeSH term(s) Animals ; Drosophila melanogaster ; Drosophila/metabolism ; Drosophila Proteins/metabolism ; Enterococcus faecalis/genetics ; Enterococcus faecalis/metabolism ; Immunity, Innate ; Immune Tolerance
    Chemical Substances Drosophila Proteins
    Language English
    Publishing date 2023-08-11
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7374
    ISSN (online) 1553-7374
    ISSN 1553-7374
    DOI 10.1371/journal.ppat.1011567
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  8. Article ; Online: Mechanistic gene networks inferred from single-cell data with an outlier-insensitive method.

    Han, Jungmin / Perera, Sudheesha / Wunderlich, Zeba / Periwal, Vipul

    Mathematical biosciences

    2021  Volume 342, Page(s) 108722

    Abstract: With advances in single-cell techniques, measuring gene dynamics at cellular resolution has become practicable. In contrast, the increased complexity of data has made it more challenging computationally to unravel underlying biological mechanisms. Thus, ... ...

    Abstract With advances in single-cell techniques, measuring gene dynamics at cellular resolution has become practicable. In contrast, the increased complexity of data has made it more challenging computationally to unravel underlying biological mechanisms. Thus, it is critical to develop novel computational methods capable of dealing with such complexity and of providing predictive deductions from such data. Many methods have been developed to address such challenges, each with its own advantages and limitations. We present an iterative regression algorithm for inferring a mechanistic gene network from single-cell data, especially suited to overcoming problems posed by measurement outliers. Using this regression, we infer a developmental model for the gene dynamics in Drosophila melanogaster blastoderm embryo. Our results show that the predictive power of the inferred model is higher than that of other models inferred with least squares and ridge regressions. As a baseline for how well a mechanistic model should be expected to perform, we find that model predictions of the gene dynamics are more accurate than predictions made with neural networks of varying architectures and complexity. This holds true even in the limit of small sample sizes. We compare predictions for various gene knockouts with published experimental results, finding substantial qualitative agreement. We also make predictions for gene dynamics under various gene network perturbations, impossible in non-mechanistic models.
    MeSH term(s) Algorithms ; Animals ; Computational Biology/methods ; Drosophila melanogaster/genetics ; Gene Regulatory Networks ; Neural Networks, Computer
    Language English
    Publishing date 2021-10-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
    ZDB-ID 1126-5
    ISSN 1879-3134 ; 0025-5564
    ISSN (online) 1879-3134
    ISSN 0025-5564
    DOI 10.1016/j.mbs.2021.108722
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    Zs.A 1534: Show issues Location:
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  9. Article ; Online: Two promoters integrate multiple enhancer inputs to drive wild-type knirps expression in the Drosophila melanogaster embryo.

    Li, Lily / Waymack, Rachel / Gad, Mario / Wunderlich, Zeba

    Genetics

    2021  Volume 219, Issue 4

    Abstract: Proper development depends on precise spatiotemporal gene expression patterns. Most developmental genes are regulated by multiple enhancers and often by multiple core promoters that generate similar transcripts. We hypothesize that multiple promoters may ...

    Abstract Proper development depends on precise spatiotemporal gene expression patterns. Most developmental genes are regulated by multiple enhancers and often by multiple core promoters that generate similar transcripts. We hypothesize that multiple promoters may be required either because enhancers prefer a specific promoter or because multiple promoters serve as a redundancy mechanism. To test these hypotheses, we studied the expression of the knirps locus in the early Drosophila melanogaster embryo, which is mediated by multiple enhancers and core promoters. We found that one of these promoters resembles a typical "sharp" developmental promoter, while the other resembles a "broad" promoter usually associated with housekeeping genes. Using synthetic reporter constructs, we found that some, but not all, enhancers in the locus show a preference for one promoter, indicating that promoters provide both redundancy and specificity. By analyzing the reporter dynamics, we identified specific burst properties during the transcription process, namely burst size and frequency, that are most strongly tuned by the combination of promoter and enhancer. Using locus-sized reporters, we discovered that enhancers with no promoter preference in a synthetic setting have a preference in the locus context. Our results suggest that the presence of multiple promoters in a locus is due both to enhancer preference and a need for redundancy and that "broad" promoters with dispersed transcription start sites are common among developmental genes. They also imply that it can be difficult to extrapolate expression measurements from synthetic reporters to the locus context, where other variables shape a gene's overall expression pattern.
    MeSH term(s) Animals ; Drosophila Proteins/genetics ; Drosophila melanogaster/embryology ; Drosophila melanogaster/genetics ; Enhancer Elements, Genetic ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Genes, Essential ; Promoter Regions, Genetic ; Repressor Proteins/genetics
    Chemical Substances Drosophila Proteins ; Repressor Proteins ; kni protein, Drosophila
    Language English
    Publishing date 2021-12-05
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2167-2
    ISSN 1943-2631 ; 0016-6731
    ISSN (online) 1943-2631
    ISSN 0016-6731
    DOI 10.1093/genetics/iyab154
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    Zs.B 767: Show issues Location:
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  10. Article ; Online: The mode of expression divergence in

    Ramirez-Corona, Bryan A / Fruth, Stephanie / Ofoegbu, Oluchi / Wunderlich, Zeba

    Genome research

    2021  Volume 31, Issue 6, Page(s) 1024–1034

    Abstract: Transcription is controlled by interactions ... ...

    Abstract Transcription is controlled by interactions of
    MeSH term(s) Animals ; Bacterial Infections/genetics ; Biological Evolution ; Drosophila/genetics ; Drosophila Proteins/genetics ; Drosophila melanogaster/genetics ; Fat Body/immunology ; Fat Body/metabolism ; Gene Expression ; Regulatory Sequences, Nucleic Acid
    Chemical Substances Drosophila Proteins
    Language English
    Publishing date 2021-04-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1284872-4
    ISSN 1549-5469 ; 1088-9051 ; 1054-9803
    ISSN (online) 1549-5469
    ISSN 1088-9051 ; 1054-9803
    DOI 10.1101/gr.269597.120
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