RNA traffic control of chromatin complexes
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.
References (56)
- et al.
Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs
Cell
(2007) - et al.
Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression
Proc Natl Acad Sci U S A
(2009) - et al.
Epigenetics: heterochromatin meets RNAi
Cell Res
(2009) Gene action in the X-chromosome of the mouse (Mus musculus L.)
Nature
(1961)- et al.
Characterization of a murine gene expressed from the inactive X chromosome
Nature
(1991) - et al.
Requirement for Xist in X chromosome inactivation
Nature
(1996) - et al.
Mechanisms of polycomb gene silencing: knowns and unknowns
Nat Rev Mol Cell Biol
(2009) - Maenner S, Blaud M, Fouillen L, Savoye A, Marchand V, Dubois A, Sanglier-Cianferani S, Van Dorsselaer A, Clerc P, Avner...
- et al.
Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation
Genome Res
(2008) - et al.
Genomic imprinting: parental influence on the genome
Nat Rev Genet
(2001)
RNA induction and inheritance of epigenetic cardiac hypertrophy in the mouse
Dev Cell
Chromatin-associated RNA content of heterochromatin and euchromatin
Mol Cell Biochem
Mouse polycomb proteins bind differentially to methylated histone H3 and RNA and are enriched in facultative heterochromatin
Mol Cell Biol
Higher-order structure in pericentric heterochromatin involves a distinct pattern of histone modification and an RNA component
Nat Genet
Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome
Science
Kcnq1ot11 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation
Mol Cell
Imprinting along the Kcnq1 domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes
Nat Genet
The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin
Science
Arabidopsis epigenetics: when RNA meets chromatin
Curr Opin Plant Biol
Small RNAs in transcriptional gene silencing and genome defence
Nature
Regulation of heterochromatin by histone methylation and small RNAs
Curr Opin Cell Biol
22G-RNAs in transposon silencing and centromere function
Mol Cell
X chromosome dosage compensation: how mammals keep the balance
Annu Rev Genet
Conservation of position and exclusive expression of mouse Xist from the inactive X chromosome
Nature
The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus
Cell
A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome
Nature
Localization of the X inactivation centre on the human X chromosome in Xq13
Nature
Xist has properties of the X-chromosome inactivation centre
Nature
Cited by (151)
An intricate rewiring of cancer metabolism via alternative splicing
2023, Biochemical PharmacologySUV39H2 controls trophoblast stem cell fate
2021, Biochimica et Biophysica Acta - General SubjectsGene regulatory networks controlling neuronal development: enhancers, epigenetics, and functional RNA
2020, Patterning and Cell Type Specification in the Developing CNS and PNS: Comprehensive Developmental Neuroscience, Second EditionTransgenerational epigenetic inheritance: from phenomena to molecular mechanisms
2019, Current Opinion in Neurobiology