H4K16ac activates the transcription of transposable elements and contributes to their cis-regulatory function.

Mammalian genomes harbor abundant transposable elements (TEs) and their remnants, with numerous epigenetic repression mechanisms enacted to silence TE transcription. However, TEs are upregulated during early development, neuronal lineage, and cancers, although the epigenetic factors contributing to the transcription of TEs have yet to be fully elucidated. Here, we demonstrate that the male-specific lethal (MSL)-complex-mediated histone H4 acetylation at lysine 16 (H4K16ac) is enriched at TEs in human embryonic stem cells (hESCs) and cancer cells. This in turn activates transcription of subsets of full-length long interspersed nuclear elements (LINE1s, L1s) and endogenous retrovirus (ERV) long terminal repeats (LTRs). Furthermore, we show that the H4K16ac-marked L1 and LTR subfamilies display enhancer-like functions and are enriched in genomic locations with chromatin features associated with active enhancers. Importantly, such regions often reside at boundaries of topologically associated domains and loop with genes. CRISPR-based epigenetic perturbation and genetic deletion of L1s reveal that H4K16ac-marked L1s and LTRs regulate the expression of genes in cis. Overall, TEs enriched with H4K16ac contribute to the cis-regulatory landscape at specific genomic locations by maintaining an active chromatin landscape at TEs.

Long Noncoding RNAs in Pluripotency of Stem Cells and Cell Fate Specification.

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.

Long noncoding RNAs in development and cancer: potential biomarkers and therapeutic targets.

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.