Summary
The inability to predict long noncoding RNAs from genomic sequence has impeded the use of comparative genomics for studying their biology. Here, we develop methods that use RNA-seq data to annotate the transcriptomes of 16 vertebrates and the echinoid sea urchin, uncovering thousands of previously unannotated genes, most of which produce long intervening noncoding RNAs (lincRNAs). Although in each species >70% of lincRNAs cannot be traced to homologs in species that diverged >50 million years ago, thousands of human lincRNAs have homologs with similar expression patterns in other species. These homologs share short, 5′-biased patches of sequence conservation nested in exonic architectures that have been extensively rewired, in part by transposable element exonization. Thus, over a thousand human lincRNAs are likely to have conserved functions in mammals, and hundreds beyond mammals, but those functions require only short patches of specific sequences and can tolerate major changes in gene architecture.
Embryonic stem cells are characterized by unique epigenetic features including decondensed chromatin and hyperdynamic association of chromatin proteins with chromatin. Here we investigate the potential mechanisms that regulate chromatin plasticity in embryonic stem cells. Using epigenetic drugs and mutant embryonic stem cells lacking various chromatin proteins, we find that histone acetylation, G9a-mediated histone H3 lysine 9 (H3K9) methylation and lamin A expression, all affect chromatin protein dynamics. Histone acetylation controls, almost exclusively, euchromatin protein dynamics; lamin A expression regulates heterochromatin protein dynamics, and G9a regulates both euchromatin and heterochromatin protein dynamics. In contrast, we find that DNA methylation and nucleosome repeat length have little or no effect on chromatin-binding protein dynamics in embryonic stem cells. Altered chromatin dynamics associates with perturbed embryonic stem cell differentiation. Together, these data provide mechanistic insights into the epigenetic pathways that are responsible for chromatin plasticity in embryonic stem cells, and indicate that the genome’s epigenetic state modulates chromatin plasticity and differentiation potential of embryonic stem cells.
Background: Embryonic stem cell (ESC) chromatin is characterized by a unique set of histone modifications, including enrichment for H3K9ac. Recent studies suggest that HDAC inhibitors (HDACi) promote pluripotency. Results: Using H3K9ac ChIP-seq analyses and gene expression in E14 mouse ESCs before and after treatment with a low level of the HDACi valproic acid (VPA), we show that H3K9ac is enriched at gene promoters and is highly correlated with gene expression and with various genomic features, including different active histone marks and pluripotency-related transcription factors.
Conclusion:This study provides insights into the genomic response of ESCs to low level HDACi, which leads to increased pluripotency. The results suggest that a mild (averaging less than 40%) but global change in the chromatin state is involved in increased pluripotency and that specific mechanisms operate selectively in bivalent genes to maintain constant H3K9ac levels. Our data support the notion that H3K9ac has an important role in ESC biology. Significance: Understanding the mechanisms that improve and support pluripotency of ESCs, such as the use of the HDAC inhibitor VPA, will promote intelligent manipulation of ESCs and expedite their use in the clinic.
Summary
In mammals, neurons in the peripheral nervous system (PNS) have
regenerative capacity following injury, but it is generally absent in the
central nervous system (CNS). This difference is attributed, at least in part,
to the intrinsic ability of PNS neurons to activate a unique regenerative
transcriptional program following injury. Here we profiled gene expression
following sciatic nerve crush in mice, and identified long noncoding RNAs
(lncRNAs) that act in the regenerating neurons, and which are typically not
expressed in other contexts. We show that two of these lncRNAs regulate the
extent of neuronal outgrowth. We then focus on one of these,
Silc1, and show that it regulates neuroregeneration in
cultured cells and in vivo, through cis-acting activation of the transcription
factor Sox11.
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