The role of Smarcad1 in retroviral repression in mouse embryonic stem cells

Abstract

The replication of Moloney murine leukemia virus (MLV) is suppressed in mouse embryonic stem cells (ESCs) by the Trim28-SETDB1 complex. The chromatin remodeler Smarcad1 interacts with Trim28 and was suggested to enable the deposition of histone variant H3.3. However, the role of Trim28, H3.3, and Smarcad1 in the repression of MLV in ESCs is not fully understood. In this study, we investigate the role of Smarcad1 in the silencing of incoming MLV retroviruses, specifically focusing on the role of the chromatin structure. We found that Smarcad1 binds to proviral DNA and that Smarcad1 depletion leads to up-regulation of retroviral expression. Additionally, our findings demonstrate that Smarcad1 is necessary to properly recruit Trim28 and deposition of H3.3 on the MLV provirus and other Trim28-repressed genomic loci. Finally, we also show that the mutual depletion of Smarcad1 and Trim28 results in enhanced de-repression of the MLV provirus, indicating that these two proteins may also function independently to maintain repressive chromatin states. Our results provide evidence for the crucial role of Smarcad1 in the silencing of retroviral elements in embryonic stem cells. Further research is needed to fully understand how Smarcad1 and Trim28 cooperate and their implications for gene expression and genomic stability.

The Conserved Chromatin Remodeler SMARCAD1 Interacts with TFIIIC and Architectural Proteins in Human and Mouse

“…In mammals, SMARCAD1 is a critical component of the machinery that establishes and maintains heterochromatin domains characterized by tri-methylation of histone 3 at lysine 9 [ 51 , 52 , 57 ]. Its activity is required for the repression of endogenous and incoming exogenous retroviruses in mESCs, primarily modulating the local nucleosome structure [ 51 , 52 , 53 , 57 , 59 ]. Moreover, SMARCAD1 appears to remodel nucleosomes at sites of DNA damage to allow resection [ 86 , 87 ].…”

“…Expressed throughout development and in virtually all adult tissues, SMARCAD1 levels are particularly high in the central nervous system, oocytes, and embryonic stem cells (ESCs) [ 48 , 49 , 50 ]. In mESCs, SMARCAD1 functions in transposon and provirus silencing by modulating the local chromatin structure [ 51 , 52 , 53 ]. Moreover, this remodeler has been linked to anti-microbial defense [ 54 ] and in somatic cells has acknowledged roles during DNA damage repair [ 55 , 56 ], in heterochromatin stability, and in epigenetic inheritance [ 57 , 58 ].…”