MGA directly recruits SETDB1/ATF7IP for histone H3K9me3 on meiosis-related genes in mouse embryonic stem cells.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1119445 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR29264036_1.fastq.gz | Fastqsanger.gz | |||
| SRR29264036_2.fastq.gz | Fastqsanger.gz | |||
| SRR29264037_1.fastq.gz | Fastqsanger.gz | |||
| SRR29264037_2.fastq.gz | Fastqsanger.gz |
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Project description:Many of meiosis-related genes in mouse embryonic stem cells (ESCs) bear substantial amounts of trimethylated lysine 9 of histone H3 (H3K9me3) modification. However, how meiosis-related genes in ESCs acquire this histone modification is totally obscure. We hypothesize that the specific functional domain termed FAM of MGA that is the scaffolding component of PRC1.6, one of atypical subtypes of PRC1 is directly involved in the deposition of this histone modification by recruiting SETDB1 via its interaction with ATF7IP. To address the hypothesis, we generated ESCs producing MGA that lacks FAM domain and examined effects of the mutation on global expression profile and H3K9me3 levels by RNA- and ChIP-sequence analyses, respectively. We also generated ESCs producing mutant ATF7IP lacking its FNIII domain that is considered to be crucial for the interaction with MGA in our hypothesis to assess the role of the domain for the deposition of H3K9me3 by ChIP-seq analyses.
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Project description:Despite substantial progress that has been made in understanding how tumors escape immune surveillance, measures to counteract tumor immune evasion have been limited. Suppression of tumor antigen expression is a common adaptive mechanism that cancers use to evade detection and destruction by the immune system. Epigenetic modifications play a critical role in in various aspects of immune invasion, including the regulation of tumor antigen expression. To identify novel epigenetic regulators of tumor antigen expression, we established a transplantable syngeneic tumor model of immune escape with silenced antigen expression and used this system as a platform for a CRISPR-Cas9 suppressor screen targeting genes encoding epigenetic modifiers. We found that genetic disruption of the chromatin modifiers Atf7ip or its interacting partner Setdb1 in tumor cells restored tumor antigen expression, resulting in augmented tumor immunogenicity concomitant with elevated endogenous retroviral antigens (ERVs), mRNA intron retention. ERVs disinhibition was associated with a robust type I interferon response and increased T cell infiltration, leading to rejection of cells lacking intact Atf7ip or Setdb1. ATF7IP or SETDB1 expression inversely correlated with antigen processing and presentation pathways, interferon signaling, and T cell infiltration and cytotoxicity in human cancers. Our results provide a rationale for targeting Atf7ip or Setdb1 in cancer immunotherapy.
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2006-08-31 | GSE4598 | GEO
Project description:The transcriptional regulator Mga of Streptococcus pyogenes (the group A streptococcus, GAS) is known to directly activate several virulence genes important for colonization and immune evasion during exponential growth. Transcriptome analysis comparing two mga-1 serotypes (M1 SF370, M6 JRS4) and one mga-2 serotype (M4 GA40634) against their isogenic mga-inactivated strains uncovered a broader Mga regulon profile containing both activated and repressed genes with predicted functions primarily related to the uptake and metabolism of sugars. Although the divergent M1 and M4 Mga profiles were similar in size and content, the M6 JRS4 strain was clearly distinct, even from other M6 strains. Real-time RT-PCR and northern blot analysis validated our microarray results and confirmed that established core Mga regulon genes directly activated by Mga (emm, scpA, sof, fba) exhibited the highest activation levels across all strains tested. A novel ORF (Spy2036) encoding a cytosolic hypothetical protein was highly activated in all three serotypes and was called gene regulated by Mga or grm. Mga was shown to bind directly to Pgrm, which overlaps the Mga-regulated Psof in OF+ strains, suggesting that grm is part of the core Mga regulon and is able to activate two divergently transcribed genes from a single site in a class II background. Both class and serotype specific Mga-regulated genes, such as speB, were apparent. In fact, Mga activated speB as long as it was expressed in the wild type strain, although direct binding of Mga to the PspeB promoter could not be demonstrated. Thus, Mga is able to both directly and indirectly regulate genes shown to be important for virulence and the metabolic homeostasis of GAS. Keywords: Wild-type vs Mga-
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