Abstract
Genomic imprinting is a parent-of-origin dependent phenomenon that restricts transcription to predominantly one parental allele. Since the discovery of the first long noncoding RNA (lncRNA), which notably was an imprinted lncRNA, a body of knowledge has demonstrated pivotal roles for imprinted lncRNAs in regulating parental-specific expression of neighboring imprinted genes. In this Review, we will discuss the multiple functionalities attributed to lncRNAs and how they regulate imprinted gene expression. We also raise unresolved questions about imprinted lncRNA function, which may lead to new avenues of investigation. This Review is dedicated to the memory of Denise Barlow, a giant in the field of genomic imprinting and functional lncRNAs. With her passion for understanding the inner workings of science, her indominable spirit and her consummate curiosity, Denise blazed a path of scientific investigation that made many seminal contributions to genomic imprinting and the wider field of epigenetic regulation, in addition to inspiring future generations of scientists.
Highlights
The H19 RNA was the first long noncoding RNA within the mammalian genome to be discovered, followed shortly by the X-inactive-specific transcript (Xist) lncRNA [1,2]
Premature termination of the Nespas lncRNA to less than 100 bp fails to repress the paternal Nesp allele, while truncation of the Nespas lncRNA at 10 kb retains paternal Nesp silencing [28,54,55]. These findings suggest that any scaffold function enabling repressive function of the Nespas lncRNA is contained within the first 10 kb of the Nespas lncRNA
With respect to lncRNA coating of an imprinted domain, is the entire domain coated or only specific regions? If varying lncRNA levels lead to different levels of histone modifications, what are the mechanisms controlling lncRNA levels? Does lncRNAs scaffold function lead to lncRNA tethering to chromatin? Alternatively, is tethering an integral component of scaffold function and does it enable spreading of repression across the imprinted domain? Does the lncRNA form multiple scaffolds for numerous independent chromatin modifiers or does the scaffold exist as one large multimeric, macromolecular complex, executing multiple silencing mechanisms simultaneously?
Summary
Since the discovery of the first long noncoding RNA (lncRNA), which notably was an imprinted lncRNA, a body of knowledge has demonstrated pivotal roles for imprinted lncRNAs in regulating parental-specific expression of neighboring imprinted genes. In this Review, we will discuss the multiple functionalities attributed to lncRNAs and how they regulate imprinted gene expression. We raise unresolved questions about imprinted lncRNA function, which may lead to new avenues of investigation.
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