Mammalian genomes encode several hundred Krüppel-associated box zinc finger proteins (KRAB-ZFPs) that bind DNA in a sequence-specific manner through tandem arrays of C2H2-type zinc fingers and repress transcription via KRAB-dependent recruitment of the silencing cofactor KAP1. The KRAB-ZFP family rapidly amplified and diversified in mammals by segmental gene duplications, mutations, and zinc finger rearrangements likely in response to continued transposable element invasions, but the biological functions and in vivo requirement of these proteins has gone largely unexplored. We determined the genomic binding sites of 61 murine KRAB-ZFPs and genetically deleted five large KRAB-ZFP gene clusters encoding more than 100 of the approximately 360 mouse KRAB-ZFPs. We demonstrate that most KRAB-ZFPs bind to specific retrotransposon families and that many of these retrotransposons are transcriptionally activated in KRAB-ZFP cluster KO ESCs, licensing retrotransposon-derived enhancers to activate nearby genes. Overall design: RNA-seq analysis of KRAB-ZFP cluster KO ES cells and tissues.
KRAB-zinc finger protein gene expansion in response to active retrotransposons in the murine lineage.
Age, Specimen part, Cell line, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Embryonic stem cell potency fluctuates with endogenous retrovirus activity.
Specimen part, Cell line, Treatment
View SamplesWe compared gene expression from 2C::tomato+/- ES cells from Kdm1a wt and mutant ES cultures
Embryonic stem cell potency fluctuates with endogenous retrovirus activity.
Cell line
View SamplesTo determine gene expression in 2 cell stage embryos Overall design: 3 Replicates of litters of wild type 2 cell stage embryos
Embryonic stem cell potency fluctuates with endogenous retrovirus activity.
Specimen part, Subject
View SamplesTo measure gene expression difference between wt and g9A knockout ES cells Overall design: G9A TT2 ES cells (Yokochi et al) were treated with Veh. Or 4OHT (to delete G9A)
Embryonic stem cell potency fluctuates with endogenous retrovirus activity.
Specimen part, Treatment, Subject
View SamplesWe identified/quantified genes and repeat elements enriched within 2C::tomato+ cells vs. 2C::tomato - cells Overall design: 2C::tomato + and - cells were collected by FACS for RNA-Seq analysis
Embryonic stem cell potency fluctuates with endogenous retrovirus activity.
Specimen part, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
A KRAB/KAP1-miRNA cascade regulates erythropoiesis through stage-specific control of mitophagy.
Specimen part, Cell line
View SamplesA multilayered transcription regulatory system is unveiled, where protein- and RNA-based repressors are super-imposed in combinatorial fashion to govern the timely triggering of an essential step of erythropoiesis
A KRAB/KAP1-miRNA cascade regulates erythropoiesis through stage-specific control of mitophagy.
Specimen part
View SamplesHere we show that in neural progenitor cells (NPCs) TRIM28 silences transcription of two groups of endogenous retroviruses (ERVs): IAP1 and MMERVK10C. Derepression of ERVs in Trim28-deficient NPCs was associated with a loss of H3K9me3 and resulted in transcriptional upregulation and reverse transcription. These findings demonstrate a unique dynamic transcriptional regulation of ERVs in NPCs. Overall design: Analysis of upregulation of ERVs in Trim28-deficient NPCs
TRIM28 represses transcription of endogenous retroviruses in neural progenitor cells.
Specimen part, Cell line, Subject
View SamplesHepatocellular carcinoma (HCC) represents the fifth most common form of cancer worldwide and carries a high mortality rate due to lack of effective treatment. Males are eight times more likely to develop HCC that females, an effect largely driven by sex hormones, albeit through still poorly understood mechanisms. We previously identified TRIM28, a scaffold protein capable of recruiting a number of chromatin modifiers, as a crucial mediator of sexual dimorphism in the liver, with Trim28hep-/- mice displaying sex-specific transcriptional deregulation of a wide range of bile and steroid metabolism genes and development of liver adenomas in males. We now demonstrate that obesity and ageing precipitate alterations of TRIM28-dependent transcriptional dynamics, leading to a metabolic infection state responsible for highly penetrant male-restricted hepatic carcinogenesis. Molecular analyses implicate aberrant androgen receptor stimulation, biliary acid disturbances and altered responses to gut microbiota in the pathogenesis of Trim28hep-/--associated HCC. Correspondingly, androgen deprivation markedly attenuates the frequency and severity of tumors, and raising animals under axenic conditions completely abrogates their abnormal phenotype, even upon high-fat diet challenge. This work underpins how discrete polyphenic traits in epigenetically unstable conditions can contribute to a cancer-prone state, and more broadly provides new evidence linking hormonal imbalances, metabolic disturbances, gut microbiota and cancer. Overall design: Transcriptome profiling of liver tissues from TgAlbCre or TgAlbCreKap1lox mice in HFD settings
Polyphenic trait promotes liver cancer in a model of epigenetic instability in mice.
Specimen part, Subject, Time
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