The Arms Race Between KRAB–Zinc Finger Proteins and Endogenous Retroelements and Its Impact on Mammals

Bruno, Melania; Mahgoub, Mohamed; Macfarlan, Todd S.

doi:10.1146/annurev-genet-112618-043717

Cited by 117 publications

(114 citation statements)

References 138 publications

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“…The targeting of the repressive complex that contains TRIM28 and OGT to methylated promoters and imprinting control regions is likely to involve the very large and rapidly evolving group of KRAB-Zinc finger proteins that are restricted to tetrapod vertebrates and are especially numerous and diverse in mammals (39). We propose a model under which a class of methylationindependent KRAB-Zinc finger proteins nucleate TRIM28 complexes that lack OGT while methylation-dependent KRAB-Zinc finger proteins recruit TRIM28 and activate OGT.…”

Section: Discussionmentioning

confidence: 98%

Methylation-directed glycosylation of chromatin factors represses retrotransposon promoters

Boulard

Rucli

Edwards

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The mechanisms by which methylated mammalian promoters are transcriptionally silenced even in the presence of all of the factors required for their expression have long been a major unresolved issue in the field of epigenetics. Repression requires the assembly of a methylation-dependent silencing complex that contains the TRIM28 protein (also known as KAP1 and TIF1β), a scaffolding protein without intrinsic repressive or DNA-binding properties. The identity of the key effector within this complex that represses transcription is unknown. We developed a methylation-sensitized interaction screen which revealed that TRIM28 was complexed withO-linked β-N-acetylglucosamine transferase (OGT) only in cells that had normal genomic methylation patterns. OGT is the only glycosyltransferase that modifies cytoplasmic and nuclear protein by transfer ofN-acetylglucosamine (O-GlcNAc) to serine and threonine hydroxyls. Whole-genome analysis showed thatO-glycosylated proteins and TRIM28 were specifically bound to promoters of active retrotransposons and to imprinting control regions, the two major regulatory sequences controlled by DNA methylation. Furthermore, genome-wide loss of DNA methylation caused a loss ofO-GlcNAc from multiple transcriptional repressor proteins associated with TRIM28. A newly developed Cas9-based editing method for targeted removal ofO-GlcNAc was directed against retrotransposon promoters. Local chromatin de-GlcNAcylation specifically reactivated the expression of the targeted retrotransposon family without loss of DNA methylation. These data revealed thatO-linked glycosylation of chromatin factors is essential for the transcriptional repression of methylated retrotransposons.

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Section: Discussionmentioning

confidence: 98%

Methylation-directed glycosylation of chromatin factors represses retrotransposon promoters

Boulard

Rucli

Edwards

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Unlike other transcriptional regulators, zinc-finger proteins have undergone bursts of duplication in vertebrates, including the primate lineage 98,99 , and are rapidly evolving (dN/dS >1) 100 , indicating they may have evolved specific functions in primate spermatogenesis. Specifically, KRAB-ZFPs are rapidly expanding and evolving ZF family 101 , and several lines of experimental evidence demonstrate that endogenous retro elements are the primary target sequences, suggesting this diversity may stem from dynamic competition between TEs and KRAB-ZFPs (reviewed in 102,103 ). Based on the timing of expression of the primate-specific KRAB-ZF genes shown here, these genes may be activated in order to protect against the sequelae of active or inactive EREs, which are often also species-specific.…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA sequencing of human, macaque, and mouse testes uncovers conserved and divergent features of mammalian spermatogenesis

Shami

Zheng

Munyoki

et al. 2020

Preprint

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Spermatogenesis is a highly regulated process that produces sperm to transmit genetic information to the next generation. Although extensively studied in mice, our current understanding of primate spermatogenesis is limited to populations defined by state-specific markers defined from rodent data. As between-species differences have been reported in the process duration and cellular differentiation hierarchy, it remains unclear how molecular markers and cell states are conserved or have diverged from mice to man. To address this challenge, we employ single-cell RNA-sequencing to identify transcriptional signatures of major germ and somatic cell-types of the testes in human, macaque and mice. This approach reveals differences in expression throughout spermatogenesis, including the stem/progenitor pool of spermatogonia, classical markers of differentiation, potential regulators of meiosis, the kinetics of RNA turnover during spermatid differentiation, and germ cell-soma communication. These datasets provide a rich foundation for future targeted mechanistic studies of primate germ cell development and in vitro gametogenesis. potential communications with the germline. Overall, this study provides the first single-cell comparative analysis of the spermatogenesis program between primates and rodents. Such a new resource is expected to improve our knowledge base for future studies of germ cell development in primates, and ultimately improve our understanding of the intrinsic and extrinsic evolutionary changes of the gametogenesis program. Knowledge gained from these data will inform fertility restoration efforts, including SSC culture and in vitro gametogenesis. ResultsSingle-cell sequencing identifies major germ and somatic cell types of adult human and macaque testes. Using the Drop-seq platform, we generated single cell transcriptome data from ~14K and ~22K adult human and rhesus macaque testes, respectively. Using these datasets, our overall strategy was to first identify major cell types and states in the adult human and rhesus macaque testes separately, then combine them, along with our previous reported mouse data 12 , to define evolutionarily conserved or diverged programs within germ cells and the somatic cells of the testis (Figure 1A). The doublet rates for the human and macaque datasets is estimated to be <2%, therefore, allowing reliable analysis of individual cells (Figure S1A). After QC filtering (see Methods), 13,837 and 21,574 cells were retained from human and macaque, respectively, with an average of 3,210 unique molecular identifiers (UMIs) per cell, and 1,304 genes detected per cell. This sequencing depth and the number of detected genes was sufficient to define major cell types 13,14 . Systematic comparisons of technical batches (such as Human 1.1-1.5, Figure S1B-C) and biological replicates (4 humans and 5 macaques, Figure S1D-E) confirmed high batch-to-batch or individual-to-individual concordance, despite the variable proportions of cell types in different samples, likely due to differences i...

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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 Arms Race Between KRAB–Zinc Finger Proteins and Endogenous Retroelements and Its Impact on Mammals

Cited by 117 publications

References 138 publications

Methylation-directed glycosylation of chromatin factors represses retrotransposon promoters

Methylation-directed glycosylation of chromatin factors represses retrotransposon promoters

Single-cell RNA sequencing of human, macaque, and mouse testes uncovers conserved and divergent features of mammalian spermatogenesis

Evolution of a sex megachromosome

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