Abstract
Recent genome-wide expression profiling studies have uncovered a huge amount of novel, long non-protein-coding RNA transcripts (lncRNA). In general, these transcripts possess a low, but tissue-specific expression, and their nucleotide sequences are often poorly conserved. However, several studies showed that lncRNAs can have important roles for normal tissue development and regulate cellular pluripotency as well as differentiation. Moreover, lncRNAs are implicated in the control of multiple molecular pathways leading to gene expression changes and thus, ultimately modulate cell proliferation, migration and apoptosis. Consequently, deregulation of lncRNA expression contributes to carcinogenesis and is associated with human diseases, e.g., neurodegenerative disorders like Alzheimer’s Disease. Here, we will focus on some major challenges of lncRNA research, especially loss-of-function studies. We will delineate strategies for lncRNA gene targeting in vivo, and we will briefly discuss important consideration and pitfalls when investigating lncRNA functions in knockout animal models. Finally, we will highlight future opportunities for lncRNAs research by applying the concept of cross-species comparison, which might contribute to novel disease biomarker discovery and might identify lncRNAs as potential therapeutic targets.
Highlights
Recent genome-wide expression profiling studies have uncovered a huge amount of novel, long non-protein-coding RNA transcripts
While “transcription” per se does not automatically equal “function”, research over the last decade has shown that long non-protein-coding RNA transcripts (lncRNA) can have important functions in developmental processes, influence differentiation, and play a role in human diseases, e.g., cancer [10] or neurodegenerative disorders like Alzheimer’s Disease [11,12]
I.e., transgenic overexpression or knockout animals are the gold standard for functional genomics and are routinely used to analyze the function of protein-coding genes
Summary
For more than five decades it has been known that DNA sequences are transcribed into RNA but never get translated into protein. In the mid-1990s, researchers like John Mattick started to argue that these RNAs transmit regulatory information, which might be associated with the emergence of multicellular organisms [1] Malat1-derived element at the beginning of a transcript would cause a cleavage and silencing of the downstream sequences This does not depend on RNA polymerase II and its associated factors, and represents an interesting strategy to target RNA polymerase II, and I and III transcripts. The tRNA-like mascRNA will be exported to the cytoplasm where it might have a so far unknown function [29]
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