ATF7IP regulates SETDB1 nuclear localization and increases its ubiquitination

Abstract

Understanding of the appropriate regulation of enzymatic activities of histone‐modifying enzymes remains poor. The lysine methyltransferase, SETDB1, is one of the enzymes responsible for the methylation of histone H3 at lysine 9 (H3K9) and plays a key role in H3K9 trimethylation‐mediated silencing of genes and retrotransposons. Here, we reported that how SETDB1's enzymatic activities can be regulated by the nuclear protein, ATF7IP, a known binding partner of SETDB1. Mechanistically, ATF7IP mediates SETDB1 retention inside the nucleus, presumably by inhibiting its nuclear export by binding to the N‐terminal region of SETDB1, which harbors the nuclear export signal motifs, and also by promoting its nuclear import. The nuclear localization of SETDB1 increases its ubiquitinated, enzymatically more active form. Our results provided an insight as to how ATF7IP can regulate the histone methyltransferase activity of SETDB1 accompanied by its nuclear translocation.

The Fibronectin Type-III (FNIII) Domain of ATF7IP Contributes to Efficient Transcriptional Silencing Mediated by The SETDB1 Complex

“…showed that ATF7IP plays a pivotal role in the nuclear localization of SETDB1 (16). Our new study using the dSETDB1 mutant of ATF7IP further indicates that interaction with ATF7IP is essential for ATF7IPdependent SETDB1 nuclear localization.…”

“…We have previously established Atf7ip KO cells using mESCs infected with the murine stem cell virus (MSCV) carrying the GFP gene as a background (21) and observed that the Atf7ip KO ESCs showed increased expression of SETDB1-regulated ERVs and the MSCV-GFP reporter (16). For rescue experiments with ATF7IP, we used a piggyBac transposase-based vector for the expression of 3xFLAG-tagged mouse ATF7IP with either WT or each domain's deletion mutants: dSETDB1 lacking residues 627-694, which is within the corresponding SETDB1 binding domain of mouse ATF7IP and covering two estimated a-helix regions, and dFNIII lacking residues 1190-1306 of the FNIII domain, which is highly conserved between human and mouse ATF7IP ( Fig.…”

“…Loss of ATF7IP results in a phenotype similar to that conferred by SETDB1 inactivation, that is, the de-repression of SETDB1regulated genes, ERVs, and the transgene integrated by retroviruses, concomitant with a decreased H3K9me3 (10)(11)(12)(13)(14)(15). Recently, we reported one role of ATF7IP in SETDB1, in which ATF7IP regulated SETDB1 nuclear localization and increased levels of its ubiquitinated and more enzymatically active forms (16). Prior studies identi ed two functional regions within human ATF7IP: SETDB1-and MBD1binding regions (9,17).…”

A nuclear licence to silence transposons

“…Future work aimed at understanding SETDB1 chromatin targeting and function will shed light on how histone-modifying enzymes can fine-tune gene expression programmes and tame transposons. , SETDB1 nuclear entry depends on its nuclear localisation signal (NLS) and interaction with its cofactor, ATF7IP [1]. SETDB1 is then retained in the nucleus by ATF7IP, which docks at and masks its nuclear export signal, allowing it to become monoubiquitinated (essential for its catalytic function [8]).…”

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Transposon silencing requires the histone methyltransferase SETDB1. In this issue of EMBO Reports, Tsusaka et al [1] and Osumi et al [2] illustrate how the cofactor ATF7IP and its fly homolog Windei (Wde) regulate the methyltransferase function of SETDB1 through its nuclear licensing. The new insight gained from these two articles will shift how we think about epigenetic regulation and its multiple layers of control.

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