Molecular Signatures Reveal Circadian Clocks May Orchestrate the Homeorhetic Response to Lactation

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 the onset 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 tissues remains 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 were performed. 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 complex assembly 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 the onset of lactation illustrate the complexity of homeorhetic adaptations and suggest that these changes are coordinated through molecular clocks.

Transcriptomes reveal alterations in gravity impact circadian clocks and activate mechanotransduction pathways with adaptation through epigenetic change

“…Our previous transcriptome analysis of the impact of 629 the transition from pregnancy to lactation highlighted changes in ECM as well as 630 accompanied changes in cytoskeletal parts, particularly actin cytoskeleton, and genes 631 that encode integrin subunits (15,51). These changes in mechanotransduction on 632…”

Vascular gene expression in mice overexpressing human endothelin-1 targeted to the endothelium

“…In particular, nfil3, also known as e4bp4, has been shown to be a critical transcription factor for natural killer (NK) cell development (12), and could participate in ET-1-induced vascular inflammation (2). Finally, 3 genes in the transcription and translation category and nfil3 could be of interest as they are circadian clock genes and might be involved in lipid metabolism, hypertension, and diabetes (7,53,57).…”

Biosynthesis of milk fat, protein, and lactose: roles of transcriptional and posttranscriptional regulation

“…The use of large transcriptomic analysis (i.e., microarray or RNA sequencing) by which to study the adaptation of mammary gland to lactation and/or change in milk production under specific conditions has been carried out in mouse (4,54,122,123,143,189,191,217,236,256), rat (3,47,187), bovine (31,36,56,75,96,144,183,209,218,233,239), sheep (209), goat (71,163,164), human (121,139,147), pig (204), kangaroo (120), and seal (144). It is beyond the scope of the current review to present a thorough discussion of the results from those studies.…”