RNA traffic control of chromatin complexes

doi:10.1016/j.gde.2010.03.003

Current Opinion in Genetics & Development

Volume 20, Issue 2, April 2010, Pages 142-148

https://doi.org/10.1016/j.gde.2010.03.003 Get rights and content

It is widely accepted that the genome is regulated by histone modifications that induce epigenetic changes on the genome. However, it is still not understood how ubiquitously expressed chromatin modifying complexes are ‘guided’ to specific genomic sites to induce intricate patterns of epigenetic modifications. Previously believed to represent ‘genome junk’, it is now becoming increasingly clear that large non-coding RNAs associate with chromatin modifying complexes. Here we explore an intriguing hypothesis that large non-coding RNA molecules might represent a molecular trafficking system that modulates chromatin modifying complexes to establish specific epigenetic landscapes.

Introduction

During development, the genome undergoes a complex choreography to establish distinctive gene expression patterns that define cellular identity. These changes are mediated through the presence of specific histone modifications and DNA methylation patterns, which are established by ubiquitously expressed chromatin modifying complexes with unknown specificity. However, what guides these complexes to distinct and specific sites under different cellular contexts is not understood. Almost 35 years ago a first clue came that perhaps RNA may play a role in this process on the basis of the observation that chromatin structure was found to be associated with several unknown RNAs [1]. Two key studies further demonstrated that RNA was a crucial component in the global localization of chromatin modifying complexes [2, 3]. For example, depletion of single-stranded (ss)RNA, but not ssDNA was shown to be required for the localization of key histone modifications [2, 3].

Indeed, several recent studies have begun to unravel the association of large non-coding RNAs with enzymatic complexes that establish these epigenetic landscapes [4, 5••, 6••]. These studies suggest a potential role for large non-coding RNAs in regulating chromatin state. Specifically, large non-coding RNA molecules might be required for the specificity of chromatin formation across the genome [4, 5••, 6••, 7, 8, 9••]. Thus, expression patterns of non-coding RNAs may influence specific epigenetic states by interfacing with chromatin modifying complexes and thereby imparting specificity.

These examples suggest a key role for RNA in epigenetic regulation, however it is not understood how RNA imparts specificity to otherwise ubiquitous chromatin modifying complexes. Although there is a wealth of information about small non-coding RNAs regulating chromatin [2, 3, 10, 11, 12, 13, 14], in this review we specifically focus on large non-coding RNAs in mammalian systems. Here, we discuss several recent studies that have gleaned insights into possible roles for large non-coding RNAs modulating the regulation of chromatin modifying complexes. By way of examples such as X inactivation, HOX gene regulation and imprinting, we propose putative models of how large non-coding RNAs could, in part, serve as a genetic trafficking system.

Section snippets

X inactivation

X chromosome inactivation is a classic and dramatic example of RNA-based establishment of epigenetic regulation. Briefly, X chromosome inactivation is a process in female mammalian cells in which one copy of the X chromosome is inactivated. This ensures that females produce the same dosage of X-linked genes as the male produces with only one X chromosome [15, 16]. Remarkably, a multi-exonic, spliced, capped and poly-adenylated large non-coding RNA known as Xist (X inactive specific transcript),

HOX gene regulation

The Homeobox transcription factors (HOX genes) were famously discovered for their ability to transform the identities of body segments in fruit flies [31]. In mammals 39 HOX genes are encoded across four loci (HOX-A: HOX-D) on different chromosomes. The relative position of each HOX gene within a cluster is reflective of its spatial and temporal expression along the proximal–distal and anterior–posterior axes in developing embryos that define a unique positional cellular identity [32, 33]. HOX

Imprinting

In mammals, somatic cells possess two copies of a gene (alleles), one inherited from the mother and the other from the father. Most of the alleles are expressed simultaneously. However, a small fraction referred to as imprinted genes, are differentially expressed depending on whether the gene was maternally or paternally inherited [45, 46]. Imprinted genes are regulated in cis by imprinting control regions (ICR), which can repress adjacent genes by utilizing large non-coding RNAs [47]. Despite

Possible mechanisms

Here we have surveyed several recent studies that demonstrate a common theme: large non-coding RNAs bind to chromatin modifying complexes such as PRC2, TRX and G9a and impart specific silencing of genomic loci both in cis and trans [4, 8, 9••, 42, 44]. Are these only distinct examples or can they be generalized to a common theme? A recent study demonstrated that numerous lincRNAs bind to PRC2 and multiple other chromatin modifying complexes [7]. This suggests a more global role of lincRNAs, and

Conclusion

In the 19th century, Lamarck's idea how organisms inherit beneficial, environmentally acquired characteristics were diminished by Darwin's theory of natural selection. However, the theory may still apply for non-coding RNA. Large non-coding RNAs might represent a way by which characteristics are propagated from mother to daughter cell and from generation to generation and perhaps in response to environmental cues. As we have summarized here, numerous large non-coding RNA molecules can attract

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

We would like to thank Sigrid Hart from the Broad Institute for the illustrations, M. Guttman, M. Cabili, M. Huarte, L. Goff, A.K. Khalil and J.S. Mattick for critical comments on the manuscript.

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RNA traffic control of chromatin complexes

Introduction

Section snippets

X inactivation

HOX gene regulation

Imprinting

Possible mechanisms

Conclusion

References and recommended reading

Acknowledgements

Cell

Proc Natl Acad Sci U S A

Cell Res

Nature

Nature

Nature

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Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome

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Imprinting along the Kcnq1 domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes

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