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Our lab is interested in the systems biology and evolution of epigenetic switches (bistability) and clocks (oscillators) in gene regulatory networks. We use experiment and theory, biology and physics, systems and synthetic biology to study the cell cycle, metabolic rhythms, and circadian clocks. How do oscillators with different frequencies co-exist in the same cell? Are there mechanisms and regulatory principles that ensure functional harmony between oscillators?

Gene duplication and co-evolution of G1/S transcription factor specificity

screen-shot-2017-05-23-at-3-41-41-pmRead our latest work that builds upon our growing expertise in cell cycle genomics and the evolution of the G1/S regulatory network in Fungi. This manuscript studied the evolution of duplicated G1/S transcription factors (SBF and MBF) in the budding yeast S. cerevisiae by examining 16 different chimeric transcription factor complexes containing the DNA binding domains from different fungi species. Our data shows that while SBF is the likely ancestral regulatory complex, the ancestral DNA binding element is more MCB-like. G1/S network expansion after gene duplication took place by both cis– and trans– co-evolutionary changes in closely related but distinct regulatory sequences. This was a fun collaboration with Amir Aharoni (Ben Gurion University) and Rob de Bruin (University College London)

Hendler A, Medina EM, Kishkevich A, Abu-Qarn M, Klier S, Buchler NE, de Bruin RAM, Aharoni A. Gene duplication and co-evolution of G1/S transcription factor specificity in fungi are essential for optimizing fitness.  PLoS Genetics 13: e1006778 (2017)

Evolution of new Rb and E2F interactions in jawed vertebrates

screen-shot-2017-05-09-at-12-53-45-pmThe retinoblastoma protein (Rb) was the first cloned tumor suppressor gene, and its study established the paradigm for how loss of cell cycle control contributes to tumorigenesis.  One long-standing question is why is Rb a more potent tumor suppressor than its close Rb-like homologs p107 and p130. Here, we addressed this question by identifying differences in Rb and p107 structure and the source of their preferences in binding different E2F transcription factor family members. We combined these insights with comparative genomics to show that Rb evolved structural features that confer a unique ability to bind those E2Fs that most potently activate cell division. This protein-protein evolution occurred at the base of jawed vertebrates after their divergence from Agnatha (jawless fish). This was a fun cell cycle collaboration between the Rubin (biochemists) and Buchler labs (genomicists).

Liban TJ, Medina EM, Tripathi S, Sengupta S, Henry RW, Buchler NE, Rubin SM. Conservation and divergence of C-terminal domain structure in the retinoblastoma protein family. Proc. Natl. Acad. Sci. USA 114: 4942 (2017)