DNMT3L facilitates assembly of a repressive epigenetic modifying complex for retroviral silencing
Date Issued
2014
Date
2014
Author(s)
Kao, Tzu-Hao
Abstract
Mammalian genomes are replete with retrotranspoable elements including endogenous retroviruses. DNA methyltransferase 3-like (DNMT3L), an epigenetic regulator highly expressed in germ cells and embryonic stem (ES) cells, is crucial for the long-term suppression of endogenous retrotransposons. Here we demonstrate that DNMT3L enhances the interaction of repressive epigenetic modifiers including histone deacetylase 1 (HDAC1), SET domain, bifurcated 1 (SETDB1), DNA methylatransfearse 3A (DNMT3A), and tripartite motif-containing protein 28 (TRIM28)/ KRAB-associated protein 1 (KAP1) in ES cells, and orchestrates retroviral-silencing activity with TRIM28 by mechanisms including but not limited to facilitating de novo DNA methylation. Gain of function studies by the introduction of ectopic DNMT3L into somatic cells demonstrate its DNA-methylation independent retroviral silencing activity by recruitment of the TRIM28/HDAC1/SETDB1/DNMT3A/DNMT3L complex to the newly infected Moloney-Murine Leukemia Virus (Mo-MuLV). Concurrent with this recruitment, we also observe the accumulation of histone H3 lysine 9 trimethylation (H3K9me3) and heterochromatin protein 1 gamma, as well as reduced H3K9 and H3K27 acetylation at newly integrated Mo-MuLV proviral sequences. Ectopic DNMT3L also re-distributes cytoplasmically localized HDAC1 to the nucleus in late passage mouse embryonic fibroblasts (MEFs) and 3T3 cell line. Formation of this epigenetic modifying complex formation requires Dnmt3L interaction with DNMT3A as well as with histone H3 tail. In fetal testes at embryonic day 17.5, endogenous DNMT3L also enhanced the binding between TRIM28, DNMT3A, SETDB1, and HDAC1. We have therefore uncovered a potential histone-level epigenetic silencing activity of DNMT3L, and this activity is beyond the known scope of DNMT3L in facilitating de novo DNA methylation and interpretation of histone modifications and chromatin context. We propose that DNMT3L may be involved in initiating a cascade of repressive epigenetic modifications by assisting in the preparation of a chromatin context that further attracts DNMT3A-DNMT3L binding and installs longer-term DNA methylation marks on endogenous retrotransposons and imprinting control regions.
Subjects
上位遺傳
甲基化
反轉錄病毒
抗病毒
胚幹細胞
Type
thesis
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