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Molecular Signatures Reveal Circadian Clocks May Orchestrate the Homeorhetic Response to Lactation
Theresa Casey1*, Osman Patel2, Karl Dykema3, Heather Dover1, Kyle Furge3, Karen Plaut1
1 Department of Animal Science, Michigan State University, East Lansing, Michigan, United States of America, 2 Department of Biology, Grand Valley State University, Allendale, Michigan, United States of America,3 Van Andel Research Institute, Grand Rapids, Michigan, United States of America

Abstract
Genes associated with lactation evolved more slowly than other genes in the mammalian genome. Higher conservation of milk and mammary genes suggest that species variation in milk composition is due in part to the environment and that we must look deeper into the genome for regulation of lactation. At theonset of lactation, metabolic changes are coordinated among multiple tissues through the endocrine system to accommodate the increased demand for nutrients and energy while allowing the animal to remain in homeostasis. This process is known as homeorhesis. Homeorhetic adaptation to lactation has been extensively described; however how these adaptations are orchestrated among multiple tissuesremains elusive. To develop a clearer picture of how gene expression is coordinated across multiple tissues during the pregnancy to lactation transition, total RNA was isolated from mammary, liver and adipose tissues collected from rat dams (n = 5) on day 20 of pregnancy and day 1 of lactation, and gene expression was measured using Affymetrix GeneChips. Two types of gene expression analysis wereperformed. Genes that were differentially expressed between days within a tissue were identified with linear regression, and univariate regression was used to identify genes commonly up-regulated and down-regulated across all tissues. Gene set enrichment analysis showed genes commonly up regulated among the three tissues enriched gene ontologies primary metabolic processes, macromolecular complexassembly and negative regulation of apoptosis ontologies. Genes enriched in transcription regulator activity showed the common up regulation of 2 core molecular clock genes, ARNTL and CLOCK. Commonly down regulated genes enriched Rhythmic process and included: NR1D1, DBP, BHLHB2, OPN4, and HTR7, which regulate intracellular circadian rhythms. Changes in mammary, liver and adipose transcriptomes at theonset of lactation illustrate the complexity of homeorhetic adaptations and suggest that these changes are coordinated through molecular clocks.
Citation: Casey T, Patel O, Dykema K, Dover H, Furge K, et al. (2009) Molecular Signatures Reveal Circadian Clocks May Orchestrate the Homeorhetic Response to Lactation. PLoS ONE 4(10): e7395. doi:10.1371/journal.pone.0007395 Editor: Paul A. Bartell,Pennsylvania State University, United States of America Received July 1, 2009; Accepted September 18, 2009; Published October 9, 2009 Copyright: ß 2009 Casey et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Funding: Supported by NASA NCC2-1373, NASA EPSCoR NCC5-581 and NIH Grant HD50201 NASA Grant NNA04CK83. These funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: ande1218@msu.edu

Introduction
Taxonomic variation in milk composition isextensive, and is driven by neonatal requirements as well as life history and reproductive strategies of the dam. Maternal substrate demands of lactation are either met by increased dietary intake or by mobilization of nutrients stored in tissues [1,2]. Recently, several high impact studies showed that although gene duplication and genomic rearrangement contribute to differences in the milk...
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