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November 5, 2015

Neonatal-to-Adult Liver Maturation Depends on Alternative Splicing

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    Alternative splicing generates mRNA diversity to support postnatal liver development. [Model by Adit Kalsotra]

    When a baby is born, many of its tissues are still only partly formed. They need to be further developed before they are capable of performing adult functions. In general, neonatal-to-adult tissue remodeling is poorly understood, but at least one particularly challenging type of remodeling has yielded some of its secrets. The tissue of interest here is liver tissue. And its remodeling secrets are at the level of gene expression.

    The liver is hematopoietic in the embryo but converts into a major metabolic tissue in the adult. This transition, according to a new study, is possible because of a gene expression mechanism known as alternative splicing. Thanks to alternative splicing, a given stretch of protein-coding DNA can give rise to multiple messenger RNA (mRNA) molecules and, hence, multiple proteins. Some of the mRNA molecules may reflect the entire stretch of DNA available for transcription, and the other mRNA molecules may reflect portions of the DNA, in spliced-together forms. Moreover, all these alternative mRNAs can give rise to proteins that have different forms and functions.

    In the postnatal liver, transcriptional and post-transcriptional transitions occur on a large scale, and these transitions are accompanied by extensive tissue remodeling. This observation, made by researchers at the University of Illinois at Urbana-Champaign, came from cell culture studies and next-generation RNA sequencing.

    Details of this work appeared November 4 in the journal Nature Communications, in an article entitled, “ESRP2 controls an adult splicing programme in hepatocytes to support postnatal liver maturation.” As the title indicates, the researchers’ determined that the RNA-binding protein known as ESRP2 controls the developmental program that ramps up alternative splicing.

    The alternative splicing mechanism, said University of Illinois biochemistry professor Auinash Kalsotra, Ph.D., is different from simply turning gene expression on and off. "Turning gene expression on or off leads to a quantitative change in gene expression—you make more or less of a particular RNA,” Dr. Kalsotra explained. “Alternative splicing, however, provides means to produce a qualitative change. You are making the same amounts of RNA but of different kinds.”

    More to the point, Dr. Kalsotra added, "The diversity of RNAs and proteins generated in this way allows the liver to acquire new functions tailored for the adult needs."

    Dr. Kalsotra and colleagues employed global analyses of the mouse liver transcriptome to demonstrate that postnatal remodeling of the liver involves transcriptional and post-transcriptional transitions that are cell-type-specific and temporally coordinated.

    “Combining detailed expression analyses with gain- and loss-of-function studies, we identify epithelial splicing regulatory protein 2 (ESRP2) as a conserved regulatory factor that controls the neonatal-to-adult switch of ~20% of splice isoforms in mouse and human hepatocytes,” wrote the authors of the Nature Communications paper. “The normal shift in splicing coincides tightly with dramatic postnatal induction of ESRP2 in hepatocytes.”

    "We were amazed to see how clean the results were," Dr. Kalsotra commented. He added that his group's study was the first to provide a direct link betwen splicing regulation and liver maturation.

    In the absence of ESRP2, the adult liver remains immature. This tells us how important this RNA binding protein is for optimizing adult functions,” Dr. Kalsotra concluded. “We are excited to investigate this link further and determine the exact function of these splicing switches in postnatal liver development."

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