Developmental Programming of Long Non-Coding RNAs during Postnatal Liver Maturation in Mice
December
Developmental Programming of Long Non-Coding RNAs during Postnatal Liver Maturation in Mice
Lai Peng 0 2 3
Ariel Paulson 1 2 3
Hua Li 1 2 3
Stephanie Piekos 0 2 3
Xi He 1 2 3
Linheng Li 1 2 3
Xiao-bo Zhong * 0 2 3
0 Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut , Storrs, Connecticut , United States of America,
1 Stowers Institute for Medical Research , Kansas City, Missouri , United States of America
2 Funding: This work was supported by the National Institutes of Health National Institute for Environmental Health Sciences [R01ES-019487 to X.B.Z.] and the National Institutes of Health National Institute of General Medical Sciences [R01GM-087376 to X.B.Z.]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manu- script
3 Editor: Wendong Huang, Beckman Research Institute of City of Hope , United States of America
The liver is a vital organ with critical functions in metabolism, protein synthesis, and immune defense. Most of the liver functions are not mature at birth and many changes happen during postnatal liver development. However, it is unclear what changes occur in liver after birth, at what developmental stages they occur, and how the developmental processes are regulated. Long non-coding RNAs (lncRNAs) are involved in organ development and cell differentiation. Here, we analyzed the transcriptome of lncRNAs in mouse liver from perinatal (day 22) to adult (day 60) by RNA-Sequencing, with an attempt to understand the role of lncRNAs in liver maturation. We found around 15,000 genes expressed, including about 2,000 lncRNAs. Most lncRNAs were expressed at a lower level than coding RNAs. Both coding RNAs and lncRNAs displayed three major ontogenic patterns: enriched at neonatal, adolescent, or adult stages. Neighboring coding and noncoding RNAs showed the trend to exhibit highly correlated ontogenic expression patterns. Gene ontology (GO) analysis revealed that some lncRNAs enriched at neonatal ages have their neighbor protein coding genes also enriched at neonatal ages and associated with cell proliferation, immune activation related processes, tissue organization pathways, and hematopoiesis; other lncRNAs enriched at adolescent ages have their neighbor protein coding genes associated with different metabolic processes. These data reveal significant functional transition during postnatal liver development and imply the potential importance of lncRNAs in liver maturation.
-
As a vital organ of the digestive system, a matured adult liver plays a major role in
nutrient homeostasis, including the synthesis, metabolism, and transport of
carbohydrates, proteins, and fats. Bioactivation, detoxification, and filtration of
compounds are other critical functions of the adult liver [1]. Venous blood from
the stomach and intestine flows through the liver by the portal vein before
entering systemic circulation. Thus liver is the first organ to encounter and deal
with ingested drugs, environmental toxicants, and intestinal bacteria. However,
these functions in adult liver are not mature yet in fetal and neonatal liver. Fetal
liver is the major hematopoietic organ responsible for generating blood cells, and
hematopoiesis is still active in liver even shortly after birth [2]. From neonatal to
adult after birth, dramatic changes happen in liver to achieve the organ growth
and functional transition from hematopoiesis to metabolism. Such functional
transition has been implicated in clinical practice. Age-related sensitivity to drugs
is at least partly attributable to differences in hepatic metabolic activity [3].
Functional transition over time during liver maturation is relied on finely
programmed alteration of gene expression. Mouse has been served as a laboratory
model to systematically study the alteration of gene expression in liver during
development [4]. Mouse liver originates from the gut endoderm on embryonic
day 8.5 when epigenetic markings, such as unwinding of the chromatin by FoxA
transcription factors, contribute to the competence of embryonic liver
development [5]. Signals, such as FGF-1, FGF-2, and BMP4 from the cardiac mesoderm,
specify the foregut endoderm to begin expressing liver-specific genes. One day
later, cells forming the hepatic endoderm assume a columnar morphology and are
ready to form the liver bud. Expression of homeobox and prospero-related
homeobox 1 genes is essential to the formation of liver bud. By embryonic day 15,
hepatoblasts begin to differentiate into hepatocytes and bile-duct epithelial cells.
HNF-6, HNF-1b, and the Notch/Jagged signaling pathways induce differentiation
toward a biliary epithelial lineage, while HNF-4a followed by C/EBPa produces
mature hepatocytes [6, 7]. The differentiation process is also driven by the
secretion of oncostatin M by blood cells in fetal liver [8]. Although extensive
researches have been done and advanced knowledge has accumulated on (...truncated)