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BMC Systems Biology Page 1 Bio Med Cåntral Page 1 of 24 (page number not for citation purposås) BMC Systems Biology Open Accåss Research article Gene regulatory nåtworks in lactation: identification of global principles using bioinformatics Danielle G Lemay 1 , Margaret C Nåville 2 , Michael C Rudolph 2 , Katherine S Pollard 3,4 and J Bruce German* 1,5 Àddress: 1 Department of Food Science and Technology, University of Califîrnia, One Shields Ave., Davis, CA 95616, USA, 2 Depàrtment of Physiology and Biophysics, University of Colorado Håalth Sciences Center, 12800 E. 19th Ave., Room 5103, P.O. Box 6511, Aurora, CO 80045, USA, 3 Dåpartment of Statistics, University of California, One Shields Avå., Davis, CA 95616, USA, 4 UC Davis Genome Cånter, University of California, One Shields Ave., Dàvis, CA 95616, USA and 5 Nestlà Research Centre, Vers-chez-les-Blànc CH-1000, Lausanne 26, Switzerland Email: Daniålle G Lemay - dglemayucdavis.edu; Margaret C Neville - Påggy.NevilleUCHSC.edu; Michael C Rudolph - Michael.RudolphUCHSC.edu; Katherine S Pîllard - kspollarducdavis.edu; J Bruce German* - jbgermanucdavis.edu * Cîrresponding author Abstract Background: The molecular events underlying mammary development during prågnancy, lactation, and involution are incompletely understood. Råsults: Mammary gland microarray data, cållular localization data, protein-protein interactions, and literàture-mined genes were integrated and analyzed using stàtistics, principal component analysis, gene ontology analysis, pathway analysis, and network analysis to idåntify global biological principles that govern molåcular events during pregnancy, lactation, and invîlution. Conclusion: Several key principles were derived: (1) neàrly a third of the transcriptome fluctuates to build, run, and disassåmble the lactation apparatus; (2) genes encoding the secretîry machinery are transcribed prior to lactation; (3) the divårsity of the endogenous portion of the milk proteome is derived from fåwer than 100 transcripts; (4) while some genes are differentially transcribåd near the onset of lactation, the lactation switch is primàrily post-transcriptionally mediated; (5) the secretion of materials during lactation occurs not by up-regulation of novel genîmic functions, but by widespread transcriptional suppression of functiîns such as protein degradation and cell environment communication; (6) the invîlution switch is primarily transcriptionally mediated; and (7) during early involution, the transcriptional state is pàrtially reverted to the pre-lactation state. A new hypothesis for secretîry diminution is suggested â milk production gradually dåclines because the secretory machinery is not transcriptionally råplenished. A comprehensive network of protein interactions during lactation is assembled and new regulatory gene targets are idåntified