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Alternative splicing of genes promotes postnatal liver maturation

Researchers found that the alternative splicing of specific genes, including epithelial splicing regulatory protein 2, supports postnatal liver maturation and continues over time.

“Although major genetic networks controlling early liver specification and morphogenesis are known, the mechanisms responsible for postnatal hepatic maturation are poorly understood,” Auinash Kalsotra, PhD, assistant professor, departments of biochemistry and medical biochemistry, Institute of Genomic Biology, University of Illinois, and colleagues wrote.

Auinash Kalsotra

Using next-generation RNA sequencing, the researchers used human and mouse liver cells to show that postnatal remodeling of the liver is supported by transcriptional and post-transcriptional transitions that are “cell-type-specific and temporally coordinated,” according to the research. Thousands of genes were looked at for the researchers to “pinpoint” the exact genes that undergo regulated changes in alternative splicing as the liver develops, according to the release.

“This mechanism is different from simply turning gene expression on or off,” Kalsotra said in the release. “Turning gene expression on or off leads to a quantitative change in gene expression — you make more or less of a particular RNA. Alternative splicing, however, provides means to produce a qualitative change.”

According to the release, alternative splicing is similar to the building of LEGOS, where exons, or parts of DNA, can be pieced together or removed to create different kinds of proteins.

“The diversity of RNAs and proteins generated in this way allows the liver to acquire new functions tailored for the adult needs,” Kalsotra said.

From detailed expression and computational analyses, the researchers found over 4,000 genes that changed in mRNA abundance, nearly 500 changed their alternative splicing profiles and over 200 changed their 3'- untranslated regions. The overlap between the three ways of gene regulation described above was minimal indicating they comprise separate regulatory programs. Among the RNA binding proteins that were previously known to directly influence tissue-specific alternative splicing, epithelial splicing regulatory protein 2 (ESRP2) and muscleblind-like splicing regulator 2 (MBNL2) genes showed the most significant upregulation of mRNA in both human and mice liver development.

These observations indicated that ESRP2 expression is induced as liver cells mature and this “coincides with the developmental period,” the researchers wrote.

Further analysis showed ESRP2 controlled the neonatal-to-adult switch of 20% of splice isoforms among the human and mice hepatocytes.

“We were amazed to see how clean the results were,” Kalsotra said. “In the absence of ESRP2, the adult liver remains immature. This tells us how important this RNA binding protein is for optimizing adult functions.

“We are excited to investigate this link further and determine the exact function of these splicing switches in postnatal liver development.” – by Melinda Stevens

Disclosures: The researchers report no relevant financial disclosures.