title: Circadian yin-yang regulation and its manipulation to globally reprogram gene expression.
abstract: BACKGROUND
  The cyanobacterial circadian program exerts genome-wide control of gene expression. KaiC undergoes rhythms of phosphorylation that are regulated by interactions with KaiA and KaiB. The phosphorylation status of KaiC is thought to mediate global transcription via output factors SasA, CikA, LabA, RpaA, and RpaB. Overexpression of kaiC has been reported to globally repress gene expression.
  
  
  RESULTS
  Here, we show that the positive circadian component KaiA upregulates "subjective dusk" genes and that its overexpression deactivates rhythmic gene expression without significantly affecting growth rates in constant light. We analyze the global patterns of expression that are regulated by KaiA versus KaiC and find in contrast to the previous report of KaiC repression that there is a "yin-yang" regulation of gene expression whereby kaiA overexpression activates "dusk genes" and represses "dawn genes," whereas kaiC overexpression complementarily activates dawn genes and represses dusk genes. Moreover, continuous induction of kaiA latched KaiABC-regulated gene expression to provide constitutively increased transcript levels of diverse endogenous and heterologous genes that are expressed in the predominant subjective dusk phase. In addition to analyzing KaiA regulation of endogenous gene expression, we apply these insights to the expression of heterologous proteins whose products are of potential value, namely human proinsulin, foreign luciferase, and exogenous hydrogenase.
  
  
  CONCLUSIONS
  Both KaiC and KaiA complementarily contribute to the regulation of circadian gene expression via yin-yang switching. Circadian patterns can be reprogrammed by overexpression of kaiA or kaiC to constitutively enhance gene expression, and this reprogramming can improve 24/7 production of heterologous proteins that are useful as pharmaceuticals or biofuels.
authors.affiliation: Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Xu
authors.forename: Philip D
authors.initials: PD
authors.lastname: Weyman
authors.forename: Miki
authors.initials: M
authors.lastname: Umetani
authors.forename: Jing
authors.initials: J
authors.lastname: Xiong
authors.forename: Ximing
authors.initials: X
authors.lastname: Qin
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.forename: Hideo
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Carl Hirschie
authors.initials: CH
authors.lastname: Johnson
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics*; D056926:CLOCK Proteins / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics*; D056925:Circadian Rhythm Signaling Peptides and Proteins / Q000235:genetics*; D015870:Gene Expression; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial; D006859:Hydrogen / Q000737:chemistry; D006864:Hydrogenase / Q000235:genetics / Q000378:metabolism*; D005810:Multigene Family / Q000235:genetics; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D046940:Synechococcus / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D001426:Bacterial Proteins; D056925:Circadian Rhythm Signaling Peptides and Proteins; C114269:KaiA protein, cyanobacteria; C114270:KaiB protein, cyanobacteria; C114271:KaiC protein, cyanobacteria; D006859:Hydrogen; D006864:Hydrogenase; D056926:CLOCK Proteins