RNA-mediated epigenetic regulation of gene expression

Key Points

  • Small RNAs, which function within Argonaute (AGO) complexes that target nascent transcript scaffolds, and long non-coding RNAs (lncRNAs), or even mRNAs, that themselves act as chromatin-associated scaffolds recruit chromatin-modifying activities to mediate stable changes in gene expression.

  • Small RNAs maintain a persistent memory of epigenetic silencing by forming positive feedback loops with chromatin-based signals. These self-reinforcing loops are best understood in the pericentromeric heterochromatin of Schizosaccharomyces pombe and the RNA-directed DNA methylation pathway of Arabidopsis thaliana.

  • In Drosophila melanogaster, recent evidence suggests the existence of a self-reinforcing relationship between Piwi-interacting RNA (piRNA) biogenesis and histone H3 lysine 9 (H3K9) methylation at piRNA source loci. In mice, piRNAs direct DNA methylation, but these signals do not seem to form a self-reinforcing loop.

  • In Caenorhabditis elegans, the AGO protein HRDE-1 maintains heritable silencing of foreign sequences after recognition by the piRNA pathway, while the AGO protein CSR-1 protects 'self' sequences from silencing.

  • Numerous lncRNAs have been proposed to directly recruit the Polycomb repressive complex 2 (PRC2) histone methyltransferase, but a lack of specificity in PRC2–RNA interactions suggests a more complicated picture.

  • The well-studied lncRNA X inactive specific transcript X (XIST) spreads along the inactive X chromosome and mediates gene silencing by recruiting PRC2. Recent studies show that this occurs indirectly through the RNA-binding protein JARID2.

  • lncRNAs transcribed from enhancer regions can activate gene expression by acting as scaffolds that bring enhancer and promoter regions into proximity, while also recruiting co-activators to modify histones.

  • The mRNAs of meiotic genes in S. pombe are silenced during vegetative growth in a process that involves (but does not require) recruitment of H3K9 methylation activity by the mRNA transcripts themselves. This mechanism may represent an ancestral step in the evolution of lncRNAs, in which RNAs have acquired a scaffold function to recruit histone modifiers but have not yet lost protein-coding potential.


Diverse classes of RNA, ranging from small to long non-coding RNAs, have emerged as key regulators of gene expression, genome stability and defence against foreign genetic elements. Small RNAs modify chromatin structure and silence transcription by guiding Argonaute-containing complexes to complementary nascent RNA scaffolds and then mediating the recruitment of histone and DNA methyltransferases. In addition, recent advances suggest that chromatin-associated long non-coding RNA scaffolds also recruit chromatin-modifying complexes independently of small RNAs. These co-transcriptional silencing mechanisms form powerful RNA surveillance systems that detect and silence inappropriate transcription events, and provide a memory of these events via self-reinforcing epigenetic loops.

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Figure 1: The 'nascent transcript' model and a self-reinforcing epigenetic loop in S. pombe.
Figure 2: A self-reinforcing loop linking siRNAs to DNA and histone methylation in A. thaliana.
Figure 3: Small-RNA-driven transcriptional silencing of gene expression in C. elegans.
Figure 4: RNAs, both short and long, represent an alternative to DNA-binding proteins as specificity determinants for epigenetic regulation of gene expression.


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D.H. was supported by the US National Science Foundation Graduate Research Fellowship Program. Research in D.M.'s laboratory is supported by grants from the US National Institutes of Health. D.M. is an Investigator of the Howard Hughes Medical Institute.

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Correspondence to Danesh Moazed.

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Supplementary information

Supplementary information S1 (figure)

Conservation and divergence of RNA silencing pathways. (PDF 205 kb)

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RNA interference

(RNAi). Broadly refers to RNA silencing pathways that use Argonaute and PIWI proteins and small RNAs to silence gene expression.

Small interfering RNAs

(siRNAs). 22–24-nucleotide small RNAs that are generated from longer double-stranded RNA precursors by the ribonuclease Dicer.


Regions of chromatin that retain the condensed appearance of mitotic chromosomes throughout the cell cycle. Heterochromatic regions are associated with repressive histone modifications and structural proteins, and are transcriptionally silent.


(AGO). A family of proteins that bind to small RNAs and that are conserved in all domains of life. They mediate target recognition via base-pairing interactions between their bound small RNA and complementary coding or non-coding RNAs.

Heterochromatic gene silencing

Silencing of gene expression within heterochromatin. It was originally thought to exclusively involve transcriptional gene silencing mechanisms, but recent findings indicate that co-transcriptional degradation of nascent RNA, or co-transcriptional gene silencing, also play important parts in silencing.

Pericentromeric DNA repeat

A repeated DNA sequence that surrounds the centromeres of most eukaryotic chromosomes. These repeats are assembled into heterochromatin, which has been demonstrated to have roles in cohesin recruitment in fission yeast and mammals, and de novo centromere assembly in fission yeast.

RNA-induced transcriptional silencing

(RITS). A protein complex first identified in Schizosaccharomyces pombe. In addition to Argonaute 1, the RITS complex contains a GW domain protein, Tas3, and a chromodomain protein, Chp1, which tether the complex to the chromosome via interactions with nascent long non-coding RNAs and nucleosomes with methylated histone H3 lysine 9.

Long terminal repeat

(LTR). A DNA sequence that is repeated at the ends of retrotransposons or pro-viral DNA that is formed from retroviral RNA by reverse transcription. Plant and mammalian genomes contain thousands of LTRs.

Epigenetic phenomena

Phenomena in which changes in gene expression occur without a corresponding change in the DNA sequence; such changes are stable in the absence of initiating signals.


The ability of a silent allele to convert an active allele to the silent (and paramutagenic) form. It was first described in Zea mays.

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Holoch, D., Moazed, D. RNA-mediated epigenetic regulation of gene expression. Nat Rev Genet 16, 71–84 (2015). https://doi.org/10.1038/nrg3863

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