Non-essential function of KRAB zinc finger gene clusters in retrotransposon suppression

Wolf, Gernot; A, de Iaco; Sun, Min; Bruno, Melania; Tinkham, Matthew; Hoang, Don; Mitra, Apratim; Ralls, Sherry; Trono, Didier; Ts, Macfarlan

doi:10.1101/2020.01.17.910679

Cited by 3 publications

(3 citation statements)

References 53 publications

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“…KRAB-ZPFs are known to regulate VM-IAPs (Bertozzi et al, 2020), and mechanistically, the Mtrr gt locus contains a cluster of 129P2Ola/Hsd-derived KRAB zinc finger proteins (ZFPs) in an otherwise C57Bl/6J background because of the mutagenesis process (Bertozzi et al, 2021). However, the KRAB-ZFP clusters within the Mtrr locus do not appear to regulate RLTR4 expression (Wolf et al, 2020). Others have shown that paternal Mthfr deficiency in mice causes hypomethylation of L1Md subfamily of LINE-1 retrotransposons (Karahan et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

One-carbon metabolism is required for epigenetic stability in the mouse placenta

Senner

Dong

Prater

et al. 2023

Front. Cell Dev. Biol.

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One-carbon metabolism, including the folate cycle, has a crucial role in fetal development though its molecular function is complex and unclear. The hypomorphic Mtrrgt allele is known to disrupt one-carbon metabolism, and thus methyl group availability, leading to several developmental phenotypes (e.g., neural tube closure defects, fetal growth anomalies). Remarkably, previous studies showed that some of the phenotypes were transgenerationally inherited. Here, we explored the genome-wide epigenetic impact of one-carbon metabolism in placentas associated with fetal growth phenotypes and determined whether specific DNA methylation changes were inherited. Firstly, methylome analysis of Mtrrgt/gt homozygous placentas revealed genome-wide epigenetic instability. Several differentially methylated regions (DMRs) were identified including at the Cxcl1 gene promoter and at the En2 gene locus, which may have phenotypic implications. Importantly, we discovered hypomethylation and ectopic expression of a subset of ERV elements throughout the genome of Mtrrgt/gt placentas with broad implications for genomic stability. Next, we determined that known spermatozoan DMRs in Mtrrgt/gt males were reprogrammed in the placenta with little evidence of direct or transgenerational germline DMR inheritance. However, some spermatozoan DMRs were associated with placental gene misexpression despite normalisation of DNA methylation, suggesting the inheritance of an alternative epigenetic mechanism. Integration of published wildtype histone ChIP-seq datasets with Mtrrgt/gt spermatozoan methylome and placental transcriptome datasets point towards H3K4me3 deposition at key loci. These data suggest that histone modifications might play a role in epigenetic inheritance in this context. Overall, this study sheds light on the mechanistic complexities of one-carbon metabolism in development and epigenetic inheritance.

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Section: Discussionmentioning

confidence: 99%

One-carbon metabolism is required for epigenetic stability in the mouse placenta

Senner

Dong

Prater

et al. 2023

Front. Cell Dev. Biol.

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“…Molecular evolutionary arms races are known to play a role in genome size evolution (Ågren and Wright 2015;Kapusta et al 2017;Cosby et al 2019). An arms race in which zinc-finger proteins evolve to bind to and suppress transcription of endogenous retroviruses (ERVs) has been well documented in mammalian genomes (Bruno et al 2019;Wolf et al 2020). Oreochromines have an average amount of zinc-finger proteins compared to other teleosts, but…”

Section: Discussionmentioning

confidence: 99%

Evolution of a sex megachromosome

Conte

Clark

Roberts

et al. 2020

Preprint

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AbstractChromosome size and morphology vary within and among species, but little is known about either the proximate or ultimate causes of these differences. Cichlid fish species in the tribe Oreochromini share an unusual megachromosome that is ~3 times longer than any of the other chromosomes. This megachromosome functions as a sex chromosome in some of these species. We explore two hypotheses of how this sex megachromosome may have evolved. The first hypothesis proposes that it developed by the accumulation of repetitive elements as recombination was reduced around a dominant sex-determination locus, as suggested by traditional models of sex chromosome evolution. An alternative hypothesis is that the megachromosome originated via the fusion of an autosome with a highly-repetitive B chromosome, one of which had carried a sex-determination locus. Here we test these hypotheses using comparative analysis of several chromosome-scale cichlid and teleost genomes. We find the megachromosome consists of three distinct regions based on patterns of recombination, gene and transposable element content, and synteny to the ancestral autosome. A WZ sex-determination locus encompasses the last ~105Mbp of the 134Mbp megachromosome and the last 47Mbp of the megachromosome shares no obvious homology to any ancestral chromosome. Comparisons across 69 teleost genomes reveal the megachromosome contains unparalleled amounts of endogenous retroviral elements, immunoglobulin genes, and long non-coding RNAs. Although the origin of this megachromosome remains ambiguous, it has clearly been a focal point of extensive evolutionary genomic conflicts. This megachromosome represents an interesting system for studying sex chromosome evolution and genomic conflicts.

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“…The family of Krüppel-associated box (KRAB) domain containing zinc finger (ZF) transcriptional regulators has expanded greatly during vertebrate evolution ( 1–3 ), largely in response to a need to repress transposable elements ( 4 , 5 ). Transposable elements make up a large fraction of the genome and are mostly considered genetic threats in need of the strictest silencing during embryogenesis and differentiation.…”

Section: Introductionmentioning

confidence: 99%

KRAB domain of ZFP568 disrupts TRIM28-mediated abnormal interactions in cancer cells

et al. 2020

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Interactions of KRAB (Krüppel-associated box)-associated protein KAP1 [also known as TRIM28 (tripartite motif containing protein 28)] with DNA-binding KRAB zinc finger (KRAB-ZF) proteins silence many transposable elements during embryogenesis. However, in some cancers, TRIM28 is upregulated and interacts with different partners, many of which are transcription regulators such as EZH2 in MCF7 cells, to form abnormal repressive or activating complexes that lead to misregulation of genes. We ask whether a KRAB domain—the TRIM28 interaction domain present in native binding partners of TRIM28 that mediate repression of transposable elements—could be used as a tool molecule to disrupt aberrant TRIM28 complexes. Expression of KRAB domain containing fragments from a KRAB-ZF protein (ZFP568) in MCF7 cells, without the DNA-binding zinc fingers, inhibited TRIM28–EZH2 interactions and caused degradation of both TRIM28 and EZH2 proteins as well as other components of the EZH2-associated polycomb repressor 2 complex. In consequence, the product of EZH2 enzymatic activity, trimethylation of histone H3 lysine 27 level, was significantly reduced. The expression of a synthetic KRAB domain significantly inhibits the growth of breast cancer cells (MCF7) but has no effect on normal (immortalized) human mammary epithelial cells (MCF10a). Further, we found that TRIM28 is a positive regulator of TRIM24 protein levels, as observed previously in prostate cancer cells, and expression of the KRAB domain also lowered TRIM24 protein. Importantly, reduction of TRIM24 levels, by treatment with either the KRAB domain or a small-molecule degrader targeted to TRIM24, is accompanied by an elevated level of tumor suppressor p53. Taken together, this study reveals a novel mechanism for a TRIM28-associated protein stability network and establishes TRIM28 as a potential therapeutic target in cancers where TRIM28 is elevated. Finally, we discuss a potential mechanism of KRAB-ZF gene expression controlled by a regulatory feedback loop of TRIM28–KRAB.

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Non-essential function of KRAB zinc finger gene clusters in retrotransposon suppression

Cited by 3 publications

References 53 publications

One-carbon metabolism is required for epigenetic stability in the mouse placenta

One-carbon metabolism is required for epigenetic stability in the mouse placenta

Evolution of a sex megachromosome

KRAB domain of ZFP568 disrupts TRIM28-mediated abnormal interactions in cancer cells

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