Shaping the landscape: mechanistic consequences of ubiquitin modification of chromatin

Abstract

The organization of eukaryotic chromosomes into transcriptionally active euchromatin and repressed heterochromatin requires mechanisms that establish, maintain and distinguish these canonical chromatin domains. Post-translational modifications are fundamental in these processes. Monoubiquitylation of histones was discovered more than three decades ago, but its precise function has been enigmatic until recently. It is now appreciated that the spectrum of chromatin ubiquitylation is not restricted to monoubiquitylation of histones, but includes degradatory ubiquitylation of histones, histone-modifying enzymes and non-histone chromatin factors. These occur in a spatially and temporally controlled manner. In this review, we summarize our understanding of these mechanisms with a particular emphasis on how ubiquitylation shapes the physical landscape of chromatin.

Figure 1. Mechanisms of ubiquitylation on chromatin.

(A) Structural changes: attachment of ubiquitin interferes with chromatin compaction. (B) Recruitment: monoubiquitin or non-degradatory polyubiquitin chains serve as a docking site for recruiting other factors to chromatin. (C) Degradation: polyubiquitin such as Lys 11 or Lys 48-linked chains serve as a recognition signal for proteasomal degradation. Note that the spectrum of ubiquitylated substrates is not restricted to histone proteins but includes also other chromatin-associated factors. K, lysine (Lys).

Figure 2. Shaping of chromatin through monoubiquitylation of histones H2B and H2A.

(A) H2Bub mediates recruitment of the COMPASS subunit Swd2 required for trimethylation of H3K4. Swd2 itself is ubiquitylated in a manner dependent on Rad6–Bre1, which mediates the association with Spp1, another COMPASS subunit involved in H3K4 trimethylation. (B) RNF20 and H2Bub negatively regulate chromatin recruitment of TFIIS. (C) H2Bub mediates structural changes by interfering with chromatin compaction, thereby facilitating the association of FACT to chromatin. (D) Ubiquitylation of H2A by the E3s 2A-HUB and RING1B negatively regulates the function or recruitment of the mammalian HMTase complex MLL and FACT. (E) H2Aub mediates binding of PRC1 to chromatin, possibly through direct recognition by RING1B. (F) H2Aub mediates the recruitment of ZRF1, which competes with PRC1 for binding to chromatin and facilitates the binding and/or function of the H2A deubiquitylase USP21. COMPASS, complex proteins associated with Set1, H3K4 HTMase complex; FACT, facilitates chromatin transcription, heterodimeric histone chaperone; H2Bub, H2B ubiquitylation; HMTase, histone methyltransferase; K, lysine (Lys); MLL, mixed leukaemia lineage complex, mammalian H3K4 HMTase; PAF, polymerase II association factor; PC, Polycomb; PRC1, Polycomb repressor complex 1; RING1B, really interesting new gene 1B; TFIIS, transcription factor IIS; USP21, ubiquitin-specific protease 21; ZRF1, zuotin-related factor 1.

Figure 3. Shaping of chromatin by ubiquitin-dependent degradation.

(A) Shaping of centromeric chromatin by degradation of the histone H3 variant Cse4 by the E3 Psh1 at ectopic sites outside centromeres. (B) Shaping of S-phase-specific chromatin by degradation of the histone H4K20 mono-HMTase Set8/PR-Set7 by the E3 Cul4–Ddb1^Cdt2. Polyubiquitylation requires the formation of a trimeric complex of Set8, Cul4–Ddb1^Cdt2 and PCNA. (C) Shaping of heterochromatin boundaries through degradation of the anti-silencing factor Epe1 by Cul4–Ddb1^Cdt2. Epe1 is recruited uniformly to heterochromatin by binding to HP1 proteins. Epe1 degradation within the body of heterochromatin results in its local accumulation at the boundaries. The signals preventing degradation of Epe1 at the boundaries are unknown. Cul4, Cullin 4; Cdt2, chromatin licensing and DNA replication factor 2; Ddb1, DNA damage-binding protein 1; Epe1, enhancer of position effect 1; HP1, heterochromatin protein 1; Set7/8, Sul(Var)3–9, Enhancer-of-zeste, Trithorax protein 7/8; PCNA, proliferating cell nuclear antigen processivity factor for DNA polymerase δ.

Sigurd Braun

Hiten D Madhani