LncRNA-driven H4K20 Trimethylation Contributes to Quiescence

The establishment of heterochromatin at pericentric and telomeric regions is catalyzed by SUV39H-driven trimethylation of histone H3 lysine 9 (H3K9me3), which recruits heterochromatin protein 1 (HP1) to loci and stimulates SUV4-20H2–dependent establishment of H4K20me3. Long noncoding RNAs (lncRNA) have been suggested to play a role in transcriptional repression and heterochromatin formation by recruiting chromatin modifiers to specific genomic loci. Bierhoff and colleagues showed that levels of promoter and pre-rRNA antisense (PAPAS) transcripts, a group of antisense lncRNAs that bind pre-rRNA coding regions and the rDNA promoter, were upregulated in response to serum deprivation despite low levels of pre-RNA synthesis. In support of a potential role for PAPAS in transcriptional suppression, PAPAS levels correlated with increased H4K20me3 at the rDNA promoter. In contrast with pericentric and telomeric regions, quiescence-induced H4K20me3 occurred independently of SUV39H and was reversible following mitogen stimulation. Serum deprivation led to increased binding of PAPAS to SUV4-20H2 at active chromatin regions, and ectopic PAPAS expression stimulated SUV4-20H2 nucleolar localization and H4K20me3 levels at rDNA. Conversely, suppression of PAPAS via siRNA or α-amanitin treatment prevented H4K20me3 induction in response to antiproliferative stimuli, further suggesting that PAPAS mediates SUV4-20H2 recruitment. PAPAS-driven H4K20me3 establishment was found to play a functional role in heterochromatic formation, as serum-deprivation promoted a SUV4-20H2–dependent increase in tightly compacted rDNA. The global increases in H4K20me3 levels observed following growth suppression suggested that lncRNA-mediated mechanisms of transcriptional inhibition may occur at other genomic elements. Indeed, serum starvation stimulated an increase of retrotransposon lncRNAs, which recruited SUV4-20H2 retrotransposon elements and promoted H4K20me3-mediated transcriptional repression. Together, these findings suggest that lncRNAs play a central role in the establishment of compact heterochromatin in quiescent cells and raise the possibility that loss of H4K20me3 in tumors may reverse the effects of quiescence-induced heterochromatin formation.

Bierhoff H, Dammert MA, Brocks D, Dambacher S, Schotta G, Grummt I. Quiescence-induced lncRNAs trigger H4K20 trimethylation and transcriptional silencing. Mol Cell 2014 Apr 24 [Epub ahead of print].