Jordan Xiao

All Publications

• Whi5 hypo- and hyper-phosphorylation dynamics control cell-cycle entry and progression. Current biology : CB Xiao, J., Turner, J. J., Kõivomägi, M., Skotheim, J. M. 2024

  Abstract

  Progression through the cell cycle depends on the phosphorylation of key substrates by cyclin-dependent kinases. In budding yeast, these substrates include the transcriptional inhibitor Whi5 that regulates G1/S transition. In early G1 phase, Whi5 is hypo-phosphorylated and inhibits the Swi4/Swi6 (SBF) complex that promotes transcription of the cyclins CLN1 and CLN2. In late G1, Whi5 is rapidly hyper-phosphorylated by Cln1 and Cln2 in complex with the cyclin-dependent kinase Cdk1. This hyper-phosphorylation inactivates Whi5 and excludes it from the nucleus. Here, we set out to determine the molecular mechanisms responsible for Whi5's multi-site phosphorylation and how they regulate the cell cycle. To do this, we first identified the 19 Whi5 sites that are appreciably phosphorylated and then determined which of these sites are responsible for G1 hypo-phosphorylation. Mutation of 7 sites removed G1 hypo-phosphorylation, increased cell size, and delayed the G1/S transition. Moreover, the rapidity of Whi5 hyper-phosphorylation in late G1 depends on "priming" sites that dock the Cks1 subunit of Cln1,2-Cdk1 complexes. Hyper-phosphorylation is crucial for Whi5 nuclear export, normal cell size, full expression of SBF target genes, and timely progression through both the G1/S transition and S/G2/M phases. Thus, our work shows how Whi5 phosphorylation regulates the G1/S transition and how it is required for timely progression through S/G2/M phases and not only G1 as previously thought.

  View details for DOI 10.1016/j.cub.2024.04.052

  View details for PubMedID 38749424

• How subtle changes in 3D structure can create large changes in transcription. eLife Xiao, J. Y., Hafner, A., Boettiger, A. N. 2021; 10

  Abstract

  Animal genomes are organized into topologically associated domains (TADs). TADs are thought to contribute to gene regulation by facilitating enhancer-promoter (E-P) contacts within a TAD preventing these contacts across TAD borders. However, the absolute difference in contact frequency across TAD boundaries is usually less than two-fold, even though disruptions of TAD borders can change gene expression by ten-fold. Existing models fail to explain this hypersensitive response. Here, we propose a futile cycle model of enhancer-mediated regulation that can exhibit hypersensitivity through bistability and hysteresis. Consistent with recent experiments, this regulation does not exhibit strong correlation between enhancer-promoter contact and promoter activity, even though regulation occurs through contact. Through mathematical analysis and stochastic simulation, we show that this system can create an illusion of enhancer-promoter biochemical specificity and explain the importance of weak TAD boundaries. It also offers a mechanism to reconcile apparently contradictory results from recent global TAD disruption with local TAD boundary deletion experiments. Together, these analyses advance our understanding of cis-regulatory contacts in controlling gene expression, and suggest new experimental directions.

  View details for DOI 10.7554/eLife.64320

  View details for PubMedID 34240703