Functional conservation of a developmental switch in mammals since the Jurassic age
Program in Systems Biology; Program in Molecular Medicine
Cell and Developmental Biology | Ecology and Evolutionary Biology | Genetic Phenomena | Genetics and Genomics | Molecular Biology | Systems Biology
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.
DOI of Published Version
Mol Biol Evol. 2018 Oct 8. pii: 5123519. doi: 10.1093/molbev/msy191. [Epub ahead of print] Link to article on publisher's site
Molecular biology and evolution
Mookerjee-Basu J, Hua X, Ge L, Nicolas E, Li Q, Czyzewicz P, Zhongping D, Peri S, Fuxman Bass J, Walhout AJ, Kappes DJ. (2018). Functional conservation of a developmental switch in mammals since the Jurassic age. Program in Systems Biology Publications and Presentations. https://doi.org/10.1093/molbev/msy191. Retrieved from https://escholarship.umassmed.edu/sysbio_pubs/150