Long noncoding RNAs are emerging as key players in various fundamental biological processes. We highlight the varied molecular mechanisms by which lncRNAs modulate gene expression in diverse cellular contexts and their role in early mammalian development in this review. Furthermore, it is being increasingly recognized that altered expression of lncRNAs is specifically associated with tumorigenesis, tumor progression and metastasis. We discuss various lncRNAs implicated in different cancer types with a focus on their clinical applications as potential biomarkers and therapeutic targets in the pathology of diverse cancers.

For the last four decades, we have known that noncoding RNAs maintain critical housekeeping functions such as transcription, RNA processing, and translation. However, in the late 1990s and early 2000s, the advent of high-throughput sequencing technologies and computational tools to analyze these large sequencing datasets facilitated the discovery of thousands of small and long noncoding RNAs (lncRNAs) and their functional role in diverse biological functions. For example, lncRNAs have been shown to regulate dosage compensation, genomic imprinting, pluripotency, cell differentiation and development, immune response, etc. Here we review how lncRNAs bring about such copious functions by employing diverse mechanisms such as translational inhibition, mRNA degradation, RNA decoys, facilitating recruitment of chromatin modifiers, regulation of protein activity, regulating the availability of miRNAs by sponging mechanism, etc. In addition, we provide a detailed account of different mechanisms as well as general principles by which lncRNAs organize functionally different nuclear sub-compartments and their impact on nuclear architecture.

Since the annotation of the mouse genome (FANTOM project) [Kawai J et al (2001) Functional annotation of a full-length mouse cDNA collection. Nature 409(6821):685-690] or the human genome [An integrated encyclopedia of DNA elements in the human genome. (2012) Nature 489(7414):57-74; Harrow J et al (2012) GENCODE: the reference human genome annotation for the ENCODE project. Genome Res 22(9):1760-1774], the roles of long noncoding RNAs in coordinating specific signaling pathways have been established in a wide variety of model systems. They have emerged as crucial and key regulators of stem cell maintenance and/or their differentiation into different lineages. In this chapter we have discussed the recently discovered lncRNAs that have been shown to be necessary for the maintenance of pluripotency of both mouse and human ES cells. We have also highlighted the different lncRNAs which are involved in directed differentiation of stem cells into any of the three germ layers. In recent years stem cell therapies including bone marrow transplantation are becoming an integral part of modern medicinal practices. However, there are still several challenges in making stem cell therapy more reproducible so that the success rate reaches a high percentage in the clinic. It is hoped that understanding the molecular mechanisms pertaining to the role of these newly discovered lncRNAs in the differentiation process of stem cells to specific lineages should pave the way to make stem cell therapy and regenerative medicine as a normal clinical practice in the near future.

Mammalian genomes harbor a large number of transposable elements (TEs) and their remnants. Most TEs are incapable of retrotransposition. Although most TEs are epigenetically repressed, transcriptional silencing is partially released to permit developmental or tissue-specific expression of TEs. Some TEs have also evolved as cis-regulatory elements (CREs), enabling them to recruit host-encoded transcription factors. Understanding the contribution of TEs in the regulation of the mammalian genome is an active area of research. Previously, the noncoding long terminal repeat (LTR) part of the endogenous retrovirus (ERV) families has been shown to function as enhancers. We show that new LTR families and the promoter region of LINE1 (L1) are enriched with H4K16ac and H3K122ac and the chromatin features associated with active enhancers. Depletion of MSL complex and H4K16ac levels leads to a significant reduction in the expression of L1 and ERV/LTRs. We demonstrate that H4K16ac regulates TE transcription by maintaining a permissive chromatin structure. Furthermore, CRISPR-based perturbation of candidate TEs led to the downregulation of genes in cis. We conclude that H4K16ac and H3K122ac regulate a significant portion of the mammalian genome by opening local chromatin structure and transcriptional activity at TEs.

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