Abstract
In a survey of 20 knockout mouse lines designed to examine the biological functions of large intergenic non-coding RNAs (lincRNAs), we have found a variety of phenotypes, ranging from perinatal lethality to defects associated with premature aging and morphological and functional abnormalities in the lungs, skeleton, and muscle. Each mutant allele carried a lacZ reporter whose expression profile highlighted a wide spectrum of spatiotemporal and tissue-specific transcription patterns in embryos and adults that informed our phenotypic analyses and will serve as a guide for future investigations of these genes. Our study shows that lincRNAs are a new class of encoded molecules that, like proteins, serve essential and important functional roles in embryonic development, physiology, and homeostasis of a broad array of tissues and organs in mammals.
Highlights
It has recently become clear that an in-depth understanding of the relationship between genotype and phenotype in mammals requires that we expand our investigations beyond the protein-coding genes to include the non-coding portion of the genome [1]
We chose to mutate members of the large intergenic noncoding RNA class because, by definition, lincRNA genes are isolated from neighboring protein-coding genes and their transcripts do not overlap [6]
Consistent with the frequent brain expression seen among human tissue-specific long noncoding RNAs (lncRNAs) [5], we found that half of the 20 targeted mouse lincRNA genes were transcriptionally active in the adult brain
Summary
It has recently become clear that an in-depth understanding of the relationship between genotype and phenotype in mammals requires that we expand our investigations beyond the protein-coding genes to include the non-coding portion of the genome [1]. Among the non-coding transcripts is a diverse class known as long noncoding RNAs (lncRNAs). Representing approximately 15,000 transcripts from nearly 10,000 genomic loci in human cells [5], lncRNAs and a subclass known as large intergenic non-coding RNAs (lincRNAs) [6,7] resemble protein-coding mRNAs in structure, synthesis, and the chromatin character of their genes. Whether or not this structural similarity extends to a functional diversity that matches that of proteins remains an open question.
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