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    Functional conservation of a developmental switch in mammals since the Jurassic age

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    Authors
    Mookerjee-Basu, Jayati
    Hua, Xiang
    Ge, Lu
    Nicolas, Emmanuelle
    Li, Qin
    Czyzewicz, Philip
    Zhongping, Dai
    Peri, Suraj
    Fuxman Bass, Juan
    Walhout, Albertha J. M.
    Kappes, Dietmar J.
    Show allShow less
    UMass Chan Affiliations
    Program in Molecular Medicine
    Program in Systems Biology
    Document Type
    Journal Article
    Publication Date
    2018-10-08
    Keywords
    Cell and Developmental Biology
    Ecology and Evolutionary Biology
    Genetic Phenomena
    Genetics and Genomics
    Molecular Biology
    Systems Biology
    
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    Link to Full Text
    https://doi.org/10.1093/molbev/msy191
    Abstract
    ThPOK is a "master regulator" of T lymphocyte lineage choice, whose presence or absence is sufficient to dictate development to the CD4 or CD8 lineages, respectively. Induction of ThPOK is critically regulated at the transcriptional level, via a lineage-specific silencer element, SilThPOK. Here, we take advantage of the available genome sequence data as well as site-specific gene targeting technology, to evaluate the functional conservation of ThPOK regulation across mammalian evolution, and assess the importance of motif grammar (order and orientation of TF binding sites) on SilThPOK function in vivo. We make 3 important points: First, the SilThPOK is present in marsupial and placental mammals, but is not found in available genome assemblies of non-mammalian vertebrates, indicating that it arose after divergence of mammals from other vertebrates. Secondly, by replacing the murine SilThPOK in situ with its marsupial equivalent using a knockin approach, we demonstrate that the marsupial SilThPOK supports correct CD4 T lymphocyte lineage-specification in mice. To our knowledge, this is the first in vivo demonstration of functional equivalency for a silencer element between marsupial and placental mammals using a definitive knockin approach. Finally, we show that alteration of the position/orientation of a highly conserved region within the murine SilThPOK is sufficient to destroy silencer activity in vivo, demonstrating that motif grammar of this "solid" synteny block is critical for silencer function. Dependence of SilThPOK function on motif grammar conserved since the mid-Jurassic age, 165 million years ago, suggests that the SilThPOK operates as a silenceosome, by analogy with the previously proposed enhanceosome model.
    Source

    Mol Biol Evol. 2018 Oct 8. pii: 5123519. doi: 10.1093/molbev/msy191. [Epub ahead of print] Link to article on publisher's site

    DOI
    10.1093/molbev/msy191
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/49879
    PubMed ID
    30295892
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    Link to Article in PubMed

    ae974a485f413a2113503eed53cd6c53
    10.1093/molbev/msy191
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