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Reversible acetylation of the chromatin remodelling complex NoRC is required for non-coding RNA-dependent silencing
Yonggang Zhou1,3, Kerstin-Maike Schmitz1,3, Christine Mayer1, Xuejun Yuan1, Asifa Akhtar2 and Ingrid Grummt1,4
The SNF2h (sucrose non-fermenting protein 2 homologue)-containing chromatin-remodelling complex NoRC silencesa fraction of ribosomal RNA genes (rDNA) by establishing a heterochromatic structure at the rDNA promoter13. Here we show that the acetyltransferase MOF (males absent on the first) acetylates TIP5, the largest subunit of NoRC, at a single lysine residue, K633, adjacent to the TIP5 RNA-binding domain,and that the NAD+-dependent deacetylase SIRT1 (sirtuin-1) removes the acetyl group from K633. Acetylation regulates the interaction of NoRC with promoter-associated RNA (pRNA), which in turn affects heterochromatin formation, nucleosome positioning and rDNA silencing. Significantly, NoRC acetylation is responsive to the intracellular energy status and fluctuates during S phase. Activation of SIRT1 on glucose deprivation leads to deacetylation of K633, enhanced pRNA binding and an increase in heterochromatic histone marks. These results suggest a mechanism that links the epigenetic state of rDNA to cell metabolism and reveal another layer of epigenetic control that involves post-translational modification of a chromatin remodelling complex.
Plasticity in transcription regulation can be achieved by dynamic regulation of the chromatin structure, involving ATP-dependent changes in nucleosome positions, modification of histone tails or DNA methylation.Acetylation of K16 on histone H4 (H4K16ac) is critical for chromatin decondensation, transcriptional activity and dosage compensation inDrosophila melanogaster47. Many transcriptional regulators, such as p300/CBP, GCN5 and MOF, have been proven to be histone acetyltransferases8,9. Drosophila MOF acetylates histone H4 (at K16) and other proteins, including MSL3, a subunit of the dosage compensation complex.Acetylation modulates the interaction of MSL3 with roX2 RNA7,10,11.
Here, we present data showing that the activity of NoRC, which consists of TIP5 and SNF2h (ref. 1), is regulated by mammalian MOF- and SIRT1-dependent acetylation and deacetylation. NoRC mediates silencing of a
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fraction of rDNA by recruiting histone-modifying enzymes and DNA methyltransferases, leading to heterochromatin formation and transcriptional silencing13,12. NoRC also shifts the promoter-bound nucleosome into a position that prevents transcription complex formation13. As binding of NoRC to rDNA requires the interaction of TIP5 with acetylatedH4K16, which is acetylated by MOF1417, we surmised that MOF might regulate the...