Deciphering the Developmental Dynamics of the Mouse Liver Transcriptome.
During development, liver undergoes a rapid transition from a hematopoietic organ to a major organ for drug metabolism and nutrient homeostasis. However, little is known on a transcriptome level of the genes and RNA-splicing variants that are differentially regulated with age, and which up-stream regulators orchestrate age-specific biological functions in liver. We used RNA-Seq to interrogate the developmental dynamics of the liver transcriptome in mice at 12 ages from late embryonic stage (2-days before birth) to maturity (60-days after birth). Among 21,889 unique NCBI RefSeq-annotated genes, 9,641 were significantly expressed in at least one age, 7,289 were differently regulated with age, and 859 had multiple (> = 2) RNA splicing-variants. Factor analysis showed that the dynamics of hepatic genes fall into six distinct groups based on their temporal expression. The average expression of cytokines, ion channels, kinases, phosphatases, transcription regulators and translation regulators decreased with age, whereas the average expression of peptidases, enzymes and transmembrane receptors increased with age. The average expression of growth factors peak between Day-3 and Day-10, and decrease thereafter. We identified critical biological functions, upstream regulators, and putative transcription modules that seem to govern age-specific gene expression. We also observed differential ontogenic expression of known splicing variants of certain genes, and 1,455 novel splicing isoform candidates. In conclusion, the hepatic ontogeny of the transcriptome ontogeny has unveiled critical networks and up-stream regulators that orchestrate age-specific biological functions in liver, and suggest that age contributes to the complexity of the alternative splicing landscape of the hepatic transcriptome.
Department of Molecular and Integrative Physiology, Department of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas, 66160, United States of America.
Sumedha S
SS
Gunewardena
Children's Mercy Hospital, Kansas City, Missouri, 64108, United States of America.
Byunggil
B
Yoo
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, 06269, United States of America.
Lai
L
Peng
Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York, 13210, United States of America.
Hong
H
Lu
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, 06269, United States of America.
Xiaobo
X
Zhong
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, 98195, United States of America.
Curtis D
CD
Klaassen
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, 98195, United States of America.
Julia Yue
JY
Cui
D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D004622:Embryo, Mammalian; D005333:Fetus; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D008099:Liver / Q000254:growth & development / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058977:Molecular Sequence Annotation; D009024:Morphogenesis / Q000235:genetics; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D017423:Sequence Analysis, RNA; D059467:Transcriptome
D012333:RNA, Messenger