title: Impact of gestational chronodisruption on fetal cardiac genomics.
abstract: We recently reported that gestational chronodisruption induces fetal growth restriction and marked effects on fetal adrenal physiology. Here, whole-transcriptome profiling was used to test whether gestational chronodisruption modifies gene expression in the fetal heart, potentially altering cardiac development. At day 10 of gestation (E10), pregnant rats were randomized in two groups: constant light (LL) and control 12 h light/12 h dark photoperiod (LD). RNA isolated from E18 heart was subjected to microarray analysis (Affymetrix platform for 28,000 genes). Integrated transcriptional changes were assessed by gene ontology and pathway analysis. Significant differential expression was found for 383 transcripts in LL relative to LD fetal heart (280 up-regulated and 103 down-regulated); with 42 of them displaying a 1.5-fold or greater change in gene expression. Deregulated markers of cardiovascular disease accounted for alteration of diverse gene networks in LL fetal heart, including local steroidogenesis and vascular calcification, as well as cardiac hypertrophy, stenosis and necrosis/cell death. DNA integrity was also overrepresented, including a 2.1-fold increase of Hmga1 mRNA, which encodes for a profuse architectural transcription factor. microRNA analysis revealed up-regulation of miRNAs 218-1 and 501 and concurrent down-regulation of their validated target genes. In addition, persistent down-regulation of Kcnip2 mRNA and hypertrophy of the left ventricle were found in the heart from 90 days-old offspring from LL mothers. The dysregulation of a relevant fraction of the fetal cardiac transcriptome, together with the diversity and complexity of the gene networks altered by gestational chronodisruption, suggest enduring molecular changes which may shape the hypertrophy observed in the left ventricle of adult LL offspring.
authors.affiliation: Laboratory of Developmental Chronobiology, Institute of Anatomy, Histology and Pathology, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Chile. Electronic address: hugogaldames168@gmail.com.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Galdames
authors.affiliation: Laboratory of Developmental Chronobiology, Institute of Anatomy, Histology and Pathology, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Chile. Electronic address: claudia.torres@uach.cl.
authors.forename: Claudia
authors.initials: C
authors.lastname: Torres-Farfan
authors.affiliation: Laboratory of Developmental Chronobiology, Institute of Anatomy, Histology and Pathology, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Chile. Electronic address: cspichiger@uach.cl.
authors.forename: Carlos
authors.initials: C
authors.lastname: Spichiger
authors.affiliation: Laboratory of Developmental Chronobiology, Institute of Anatomy, Histology and Pathology, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Chile. Electronic address: natamendezc@gmail.com.
authors.forename: Natalia
authors.initials: N
authors.lastname: Mendez
authors.affiliation: Laboratory of Developmental Chronobiology, Institute of Anatomy, Histology and Pathology, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Chile. Electronic address: lorena.abarzua@gmail.com.
authors.forename: Lorena
authors.initials: L
authors.lastname: Abarzua-Catalan
authors.affiliation: Laboratory of Developmental Chronobiology, Institute of Anatomy, Histology and Pathology, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Chile. Electronic address: pamelalonso.1@gmail.com.
authors.forename: Pamela
authors.initials: P
authors.lastname: Alonso-Vazquez
authors.affiliation: Laboratory of Developmental Chronobiology, Institute of Anatomy, Histology and Pathology, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Chile. Electronic address: hrichter@uach.cl.
authors.forename: Hans G
authors.initials: HG
authors.lastname: Richter
mesh_terms: D000818:Animals; D001024:Aortic Valve Stenosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D002114:Calcinosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002940:Circadian Rhythm / Q000235:genetics*; D004622:Embryo, Mammalian; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D023281:Genomics; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D051605:Kv Channel-Interacting Proteins / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D058977:Molecular Sequence Annotation; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D017440:Photoperiod; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D013256:Steroids / Q000096:biosynthesis; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D006609:High Mobility Group Proteins; C496758:Kcnip2 protein, rat; D051605:Kv Channel-Interacting Proteins; D035683:MicroRNAs; D012333:RNA, Messenger; D013256:Steroids
keywords: Cardiac gene networks; Fetal programming of adult disease; Gestational chronodisruption; Left ventricle hypertrophy; Whole transcriptome