Histone sumoylation and chromatin dynamics

Abstract

Chromatin structure and gene expression are dynamically controlled by post-translational modifications (PTMs) on histone proteins, including ubiquitylation, methylation, acetylation and small ubiquitin-like modifier (SUMO) conjugation. It was initially thought that histone sumoylation exclusively suppressed gene transcription, but recent advances in proteomics and genomics have uncovered its diverse functions in cotranscriptional processes, including chromatin remodeling, transcript elongation, and blocking cryptic initiation. Histone sumoylation is integral to complex signaling codes that prime additional histone PTMs as well as modifications of the RNA polymerase II carboxy-terminal domain (RNAPII-CTD) during transcription. In addition, sumoylation of histone variants is critical for the DNA double-strand break (DSB) response and for chromosome segregation during mitosis. This review describes recent findings on histone sumoylation and its coordination with other histone and RNAPII-CTD modifications in the regulation of chromatin dynamics.

Figure 1.

Models for the functions of histone sumoylation in transcriptional repression. (A) During switching from transcriptional activation to repression in mammals, p300 HAT-mediated histone acetylation promotes histone sumoylation by activating Ubc9 and SUMO E3 ligase. Sumoylated histones then recruits both HDAC6, which attenuates transcription, and HP1, which contributes to chromatin compaction. However, it is still unclear whether histone sumoylation stimulates H3K9 methylation, a marker for HP1 binding. (B) Histone sumoylation in yeast potentially interferes with histone acetylation by HATs or H2BK123 ubiquitylation by Rad6 and Bre1, thereby inhibiting transcription. (C) LSD1−CoREST−HDAC1 complex is associated with sumoylated histone through the SUMO-interacting motif (SIM) in the CoREST subunit, allowing LSD1 and HDAC1 to reverse H3K4 methylation and histone acetylation, respectively; both of the latter histone marks normally promote transcription.

Figure 2.

Histone sumoylation promotes chromatin binding of RSC. The Sth1 subunit of RSC recognize H3K14 acetylation, and an unknown RSC component recognizes sumoylated histones. This dual recognition has been implicated in chromosome segregation, but its function in other RSC-controlled processes has not yet been determined.

Figure 3.

Model of histone sumoylation in the prevention of cryptic initiation. (A–C) Illustrations show the relevant components, but not the precise physical association or order of events. Triangles at the bottom indicate gradients of H3K4me3 and H3K4me2 modifications over the promoter and 5′ regions of the open reading frame (ORF). (A) At the early stage of transcription, the CTD S5 phosphorylated forms of RNAPII and PAFC are required for H2BK123 ubiquitylation by Rad6 and Bre1. H2B ubiquitylation drives two sequential modifications, COMPASS/Set1-mediated H3K4 methylation and histone poly-sumoylation by Ubc9 and a SUMO E3. Both H2B ubiquitylation and histone sumoylation inhibit Ctk1 (the major S2 kinase) association with the RNAPII transcription machinery. (B) Ubiquitin removal from histones by SAGA component Ubp8 and polySUMO disassembly by Ulp2 together facilitate Ctk1 recruitment and CTD S2 phosphorylation for subsequent transcription elongation, while Rtr1 dephosphorylates S5 in the CTD. The Gcn5 HAT, another SAGA subunit, mediates histone acetylation during transcription elongation. (C) In the transcription elongation step, repeated rounds of H2B ubiquitylation and histone sumoylation and their reversal occur while an H3K4 methylation gradient is gradually established. Recognition of H3K4me2 by Set3 and sumoylated histones by Cpr1, both subunits of the SET3C deacetylase, is required for recruitment of SET3C to the 5′ regions of ORFs. Hst1 and Hos2, the catalytic subunits of SET3C, block accumulation of hyperacetylated histones in these ORF regions. (D) Inhibition of spurious transcription initiation by cotranscriptional histone modifications. H2B ubiquitylation functions cooperatively with the FACT complex to suppress cryptic transcription of genes. H3K4 methylation and histone sumoylation facilitate histone deacetylation by SET3C in 5′ ORF regions, and H3K36 methylation promotes histone deacetylation by Rpd3S in 3′ ORF regions. In mammals, Dnmt3b-mediated DNA methylation restricts the generation of cryptic transcripts in a H3K36 methylation-dependent manner.

Figure 4.

Genome-wide distribution pattern of histone modifications that crosstalk with histone sumoylation in active genes. (A) Schematic diagram depicting the distinct roles of histone sumoylation in transcription and its crosstalk with other histone modifications. (B) The genomic localization of histone modifications is mapped on a generalized gene aligned from transcription start site (TSS) to transcription end site (TES). The curves represent their distribution patterns determined by genome-wide analyses in yeast.

Figure 5.

Sumoylation of Cse4 mediates its appropriate localization. (A and B) Cse4-K215/216 sumoylation triggers Scm3-dependent incorporation of Cse4−H4 dimers into the CEN regions of chromosomes in normal cells (A), while CAF-1 also interacts with K215/216-sumoylated Cse4 and promotes deposition of overexpressed Cse4−H4 dimers into non-CEN regions (and CEN domains when Scm3 levels are low) (B). The SIMs of Scm3 and CAF-1 are not yet determined. (C) Sumoylation of K65 in Cse4 limits its levels or prevents its mislocalization in a manner dependent on Slx5/Slx8-mediated ubiquitylation and proteasome-mediated proteolysis. The Psh1 ubiquitin ligase independently facilitates proteasomal degradation of mislocalized Cse4.