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Review
. 2020 May 30;12(6):596.
doi: 10.3390/v12060596.

SETDB1-Mediated Silencing of Retroelements

Kei Fukuda  1 , Yoichi Shinkai  1
Affiliations
Review

SETDB1-Mediated Silencing of Retroelements

Kei Fukuda et al. Viruses. .

Abstract

SETDB1 (SET domain bifurcated histone lysine methyltransferase 1) is a protein lysine methyltransferase and methylates histone H3 at lysine 9 (H3K9). Among other H3K9 methyltransferases, SETDB1 and SETDB1-mediated H3K9 trimethylation (H3K9me3) play pivotal roles for silencing of endogenous and exogenous retroelements, thus contributing to genome stability against retroelement transposition. Furthermore, SETDB1 is highly upregulated in various tumor cells. In this article, we describe recent advances about how SETDB1 activity is regulated, how SETDB1 represses various types of retroelements such as L1 and class I, II, and III endogenous retroviruses (ERVs) in concert with other epigenetic factors such as KAP1 and the HUSH complex and how SETDB1-mediated H3K9 methylation can be maintained during replication.

Keywords: H3K9me3; SETDB1; heterochromatin.

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Conflict of interest statement

The authors declare no conflicts of interest associated with this manuscript.

Figures

Figure 1
Figure 1
Protein domain structure of SETDB1. The human SETDB1 protein (1291 amino acids, 143 kDa) contains triple Tudor domains (TTDs) and a methyl-CpG binding domain (MBD) in its N-terminal part, followed by a split SET domain (pre-SET, SET, and post-SET). The TTDs bind to histone H3 tails that have been modified by K14 acetylation combined with K9 methylation. The C-terminal region containing the pre-SET, SET, and post-SET domains is responsible for H3K9 specific lysine methylation [21,24]. The SET domain of SETDB1 has a long insertion, which is monoubiquitinated by UBE2E enzymes independent of E3 ligase (on K867 in human or K885 in mouse), and this monoubiquitination highly enhances the methyltransferase activity of SETDB1 [39,40]. At the N-terminal region of SETDB1, there is a functional SUMO interacting motif (SIM) [41] in close proximity to a nuclear export signal (NES) and a nuclear localization signal (NLS) [42].
Figure 2
Figure 2
SETDB1 recruitment and H3K9me3 spreading. SETDB1 is mainly localized in cytoplasm and nuclear SETDB1 is degraded by proteasomal pathway [65]. ATF7IP promotes nuclear import of SETDB1 and inhibits nuclear export and proteasomal degradation of SETDB1 [70]. In addition, ATF7IP-mediated SETDB1 nuclear accumulation enhances its ubiquitinated, enzymatically more active form [70]. SETDB1 interacts with SUMOylated KAP1 and is recruited to retroelement by KRAB-ZFP/KAP1 pathway, then SETDB1 mediates H3K9me3 in retroelement [41]. The Human Silencing Hub (HUSH) component bind H3K9me3 via chromodomain of MPP8, which might require for H3K9me3 spreading [76]. ATF7IP harbors H3K9-like sequence, which is methylated by G9a/GLP. The methylation of ATF7IP is recognized by MPP8 and the residue methylated by G9a/GLP is required for efficient provirus silencing [77]. The HUSH complex might be recruited to SETDB1 target via interaction between methylated ATF7IP and MPP8.
Figure 3
Figure 3
Retroelement-type specific regulation. (A) Model of class III endogenous retroviruses (ERVs) silencing. CHAF1A recruits KDM1A and HDAC2 to class III ERVs to remove active chromatin marks such as H3K4me2/3 and H3K9ac [111]. KAP1 and SUMO2 also represses SETDB1-independent class III ERVs. Since KAP1 SUMOylation is required for its interaction with CHD3, which is a component of the NuRD complex [41], and HDAC, which is involved in MERVL repression [112], KAP1 SUMOylation might function in HDAC recruitment to class III ERV. (B) Model of class I/II ERVs silencing. Recruitment of SETDB1 by interaction with SUMOylated KAP1. SMARCAD1 and RESF1 might enhance SETDB1 enrichment in class I/II ERVs [71,113]. ATRX/DAXX deposits H3.3 to class I/II ERVs and play a role for silencing of such ERVs [114]. H3.3 stabilizes the DAXX protein to promote interaction between KAP1 and HDAC1 [115]. Replication-dependent H3/H4 deposition by CHAF1 is also involved in provirus and class I/II ERVs silencing [111]. (C) Model of L1 silencing by the HUSH complex and MORC2. MORC2 and the HUSH complex target young, full-length L1s, especially when they are located within introns of actively transcribed genes, and L1 transcription increases MORC2 and MPP8 occupancy at the L1 transgene [104]. The disordered N-terminal domain of Periphilin1 (PPHLN) might bind RNA non-specifically and forms insoluble aggregates [116], which might enhance the HUSH complex targeting to transcriptionally active L1. MORC2 interacts with the HUSH complex and MORC2 enrichment at HUSH targets is dependent on the HUSH complex [117]. The MORC2 ATPase module dimerizes upon ATP binding and MORC2 binds both free dsDNA and nucleosomal DNA [118]. MORC2 might be recruited by the HUSH complex to chromatin, where dimerization of two DNA-bound MORC2 can promote DNA loop formation and chromatin compaction [118].
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