More than half of the human genome is comprised of EREs of various types. Appropriate control of their activity is crucial not only for limiting insertional mutagenesis (for the subset of EREs that are mobilization competent) but also because EREs can function as cis-regulatory elements to influence the expression of nearby cellular genes to modulate cell behaviour and differentiation potential. An emerging theme is that in human and mouse ESCs many EREs remain silenced, whereas others become transiently and selectively derepressed, and their transcripts have active roles in maintaining the pluripotent state.
TRIM28 (also known as KAP1 and TIF1β) is a transcriptional corepressor that is brought to genomic sites by various zinc-finger protein partners. Once there, this complex recruits the SETDB1 histone methyltransferase to deposit repressive trimethylation marks at histone H3 lysine 9 (H3K9me3). Already known to be an important mediator of ERE silencing in mouse ESCs, Turelli et al. investigated the role of TRIM28 in human ESCs. They used chromatin immunoprecipitation followed by sequencing (ChIPseq) to identify TRIM28-binding sites in the genome and also characterized the EREs that become upregulated following TRIM28 knockdown. Overall, they found that TRIM28 is involved in silencing a broad range of ERE types, including human-specific EREs. Through a more global analysis of the transcriptomic and chromatin changes caused by TRIM28 depletion, the authors showed that derepressed EREs can spread activating histone marks into neighbouring genes, thus emphasizing how the occupancy of ERE sequences by TRIM28-containing complexes has effects outside the EREs themselves to regulate cellular genes. Finally, Turelli et al. characterized the complex interplay between DNA methylation and TRIM28-triggered histone methylation for the differential repression of different classes of EREs.
NCBI Summary:
The protein encoded by this gene mediates transcriptional control by interaction with the Kruppel-associated box repression domain found in many transcription factors. The protein localizes to the nucleus and is thought to associate with specific chromatin regions. The protein is a member of the tripartite motif family. This tripartite motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. [provided by RefSeq, Jul 2008]
General function
Nucleic acid binding, DNA binding, Transcription factor
, Epigenetic modifications
Comment
Cellular localization
Nuclear
Comment
Ovarian function
Early embryo development
Comment
During preimplantation embryogenesis nuclear reprogramming resets the epigenome to a ground state, an essential measure ensuring totipotency and development. Global DNA demethylation is a prominent feature of nuclear reprogramming, yet poses a danger to a subset of methylated sequences that must be preserved for germ-line to soma inheritance. Prominently, imprinted loci must retain their differential methylation status acquired during gametogenesis throughout embryogenesis and in adult tissues. A complex, formed by maternal TRIM28/KAP1 and its binding partner ZFP57, play an essential role preventing detrimental demethylation of imprinted genes during reprogramming. Its absence leads to epigenetic variability in embryos, resulting in highly variant phenotypes and ultimately embryonic lethality. A full rescue of all developmental defects can however be achieved by mere pronuclear transfer of maternal mutant pronuclei into normal enucleated zygotes, thus timing the requirement of maternal TRIM28 protein to the zygote shortly after fertilization. These results shed light on the long elusive players protecting imprinting marks in the shifting epigenetic environment of the early preimplantation embryo, reveal the long-ranging effects of a maternal gene deletion on epigenetic memory, and illustrate the delicate timing and equilibrium of maternal and zygotic factors during nuclear reprogramming.
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Single-cell DNA-methylation analysis reveals epigenetic chimerism in preimplantation embryos. Lorthongpanich C 2013 et al.
Epigenetic alterations are increasingly recognized as causes of human cancers and disease. These aberrations are likely to arise during genomic reprogramming in mammalian preimplantation embryos, when their epigenomes are most vulnerable. However, this process is only partially understood because of the experimental inaccessibility of early-stage embryos. Here, we introduce a methodologic advance, probing single cells for various DNA-methylation errors at multiple loci, to reveal failed maintenance of epigenetic mark results in chimeric mice, which display unpredictable phenotypes leading to developmental arrest. Yet we show that mouse pronuclear transfer can be used to ameliorate such reprogramming defects. This study not only details the epigenetic reprogramming dynamics in early mammalian embryos but also suggests diagnostic and potential future therapeutic applications.
(Recent studies suggest that imprints are established
in a two-step process of DNA methylation
in the germline and subsequent, site-specific
DNA-methylation maintenance during reprogramming
in the preimplantation embryo (4, 5). DNA
methyl transferase 1 (DNMT1), primordial germ
cell protein 7 (PGC7)/STELLA, zinc finger protein
57 (ZFP57), and tripartite motif?containing 28
(TRIM28) are each required for DMR protection
in the face of global DNA demethylation
(6?13). It has been proposed that detrimental
epimutations most likely occur when these maintenance
mechanisms fail (2, 4). ZFP57, which
only binds methylated imprinted alleles, mediates specific DNA-methylation maintenance, recruiting
DNMT1 through the scaffolding protein
TRIM28 (10, 14, 15). Active targeting of DNMT1
is thought to be required because nuclear DNMT1
levels are very low in the preimplantation embryo
facilitating genome-wide DNA demethylation
(16). Disrupting this targeting complex very
early in development, by eliminating maternal
Trim28, causes stochastic DMR demethylation,
which results in the phenotypic variability proposed
to be caused by epigenetic chimerism. We next used a Zp3-cre
knock-out strategy (11) to genetically remove
Trim28 from oocytes (Trim28matΔ) and addressed
the effect of its absence on DMR methylation.
DMR-methylation patterns remained unchanged
compared with those of controls (Fig. 1, B and C,
Trim28matΔ), demonstrating that TRIM28 is not
required for imprinting maintenance in growing
and mature oocytes.//// Although highly expressed in oocytes (11),
the role of TRIM28 in imprint maintenance is
restricted to postfertilization stages.) /////////////////////////
Expression regulated by
Comment
Ovarian localization
Oocyte
Comment
Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET. Matsui T et al. Endogenous retroviruses (ERVs), retrovirus-like elements with long terminal repeats, are widely dispersed in the euchromatic compartment in mammalian cells, comprising approximately 10% of the mouse genome. These parasitic elements are responsible for >10% of spontaneous mutations. Whereas DNA methylation has an important role in proviral silencing in somatic and germ-lineage cells, an additional DNA-methylation-independent pathway also functions in embryonal carcinoma and embryonic stem (ES) cells to inhibit transcription of the exogenous gammaretrovirus murine leukaemia virus (MLV). Notably, a recent genome-wide study revealed that ERVs are also marked by histone H3 lysine 9 trimethylation (H3K9me3) and H4K20me3 in ES cells but not in mouse embryonic fibroblasts. However, the role that these marks have in proviral silencing remains unexplored. Here we show that the H3K9 methyltransferase ESET (also called SETDB1 or KMT1E) and the Kr?associated box (KRAB)-associated protein 1 (KAP1, also called TRIM28) are required for H3K9me3 and silencing of endogenous and introduced retroviruses specifically in mouse ES cells. Furthermore, whereas ESET enzymatic activity is crucial for HP1 binding and efficient proviral silencing, the H4K20 methyltransferases Suv420h1 and Suv420h2 are dispensable for silencing. Notably, in DNA methyltransferase triple knockout (Dnmt1(-/-)Dnmt3a(-/-)Dnmt3b(-/-)) mouse ES cells, ESET and KAP1 binding and ESET-mediated H3K9me3 are maintained and ERVs are minimally derepressed. We propose that a DNA-methylation-independent pathway involving KAP1 and ESET/ESET-mediated H3K9me3 is required for proviral silencing during the period early in embryogenesis when DNA methylation is dynamically reprogrammed.
Follicle stages
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: embryonic lethal Comment: Trim28 Is Required for Epigenetic Stability During Mouse Oocyte to Embryo Transition. Messerschmidt DM et al. Phenotypic variability in genetic disease is usually attributed to genetic background variation or environmental influence. Here, we show that deletion of a single gene, Trim28 (Kap1 or Tif1?, from the maternal germ line alone, on an otherwise identical genetic background, results in severe phenotypic and epigenetic variability that leads to embryonic lethality. We identify early and minute epigenetic variations in blastomeres of the preimplantation embryo of these animals, suggesting that the embryonic lethality may result from the misregulation of genomic imprinting in mice lacking maternal Trim28. Our results reveal the long-range effects of a maternal gene deletion on epigenetic memory and illustrate the delicate equilibrium of maternal and zygotic factors during nuclear reprogramming.