Take a walk on the KRAB side

Rosspopoff, Olga; Trono, Didier

doi:10.1016/j.tig.2023.08.003

Cited by 15 publications

(13 citation statements)

References 104 publications

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“…Of note, L1TD1 was also associated with the transcript of YY2 , a retrotransposon-derived paralogue of yin yang 1 (YY1) (Tahmasebi et al , 2016), whereas the negative control GAPDH did not show such enrichment ( Figure 2C ). Gene Ontology analyses of 228 common hits indicated enriched groups in cell division and cell cycle and, in accordance with a recent study (Jin et al ., 2024), enriched transcripts encoding zinc finger and in particular KRAB domain proteins which have been implicated in the restriction of endogenous retroviruses (Rosspopoff & Trono, 2023) ( Suppl. Figure S1B ).…”

Section: Resultsmentioning

confidence: 99%

The domesticated transposon protein L1TD1 associates with its ancestor L1 ORF1p to promote LINE-1 retrotransposition

Kavaklıoğlu,

Podhornik,

Vcelkova

et al. 2024

Preprint

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Repression of retrotransposition is crucial for the successful fitness of a mammalian organism. The domesticated transposon protein L1TD1, derived from LINE-1 ORF1p, is an RNA-binding protein that is expressed only in some cancers and early embryogenesis. In human embryonic stem cells it is found to be essential for maintaining pluripotency. In cancer, L1TD1 expression is highly correlative with malignancy progression and as such considered a potential prognostic factor for tumors. However, its molecular role in cancer remains largely unknown. Our findings reveal that DNA hypomethylation induces the expression of L1TD1 in HAP1 human tumor cells. L1TD1 depletion significantly modulates both the proteome and transcriptome and thereby reduces cell viability. Notably, L1TD1 associates with LINE-1 transcripts and interacts with LINE-1 ORF1p protein, thereby facilitating LINE-1 retrotransposition. Our data suggest that L1TD1 collaborates with its ancestral LINE-1 ORF1p as an RNA chaperone, ensuring the efficient retrotransposition of LINE-1 retrotransposons, rather than directly impacting the abundance of L1TD1 targets. In this way, L1TD1 might have an important role not only during early development but also in tumorigenesis.

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Section: Resultsmentioning

confidence: 99%

The domesticated transposon protein L1TD1 associates with its ancestor L1 ORF1p to promote LINE-1 retrotransposition

Kavaklıoğlu,

Podhornik,

Vcelkova

et al. 2024

Preprint

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“…It is also likely that transcription-dependent mechanisms of H3K9me3 regulation further contribute to the shifting patterns of H3K9me3 that we observe following EGA. For example, although zebrafish lack KRAB-ZF proteins, an important component of H3K9me3 targeting in tetrapod animals, they do encode for an alternative group of zinc finger proteins called FiNZ-ZNF proteins that may play a similar role in zebrafish, and are first expressed at EGA (Rosspopoff and Trono 2023; Wells et al 2023). It is also possible that post-EGA transcription of transposons themselves may generate RNAs that are recognized by host machinery to drive their silencing (Almeida et al 2022).…”

Section: Discussionmentioning

confidence: 99%

The emerging H3K9me3 chromatin landscape during zebrafish embryogenesis

Duval,

Artis,

Goll

2024

Preprint

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The structural organization of eukaryotic genomes is contingent upon the fractionation of DNA into transcriptionally active euchromatin and repressive heterochromatin. However, we have a limited understanding of how these distinct states are first established during animal embryogenesis. Histone 3 lysine 9 trimethylation (H3K9me3) is critical to heterochromatin formation and bulk establishment of this mark is thought to help drive large-scale remodeling of an initially naive chromatin state during animal embryogenesis. However, a detailed understanding of this process is lacking. Here, we leverage CUT&RUN to define the emerging H3K9me3 landscape of the zebrafish embryo with high sensitivity and temporal resolution. Despite the prevalence of DNA transposons in the zebrafish genome, we found that LTR transposons are preferentially targeted for embryonic H3K9me3 deposition, with different families exhibiting distinct establishment timelines. High signal-to-noise ratios afforded by CUT&RUN revealed new, emerging sites of low-amplitude H3K9me3 that initiated prior to the major wave of embryonic genome activation (EGA). Early sites of establishment predominated at specific subsets of transposons and were enriched for sequences with maternal piRNAs or pericentromeric localization. Notably, the number of H3K9me3 enriched sites increased linearly across blastula development, while quantitative comparison revealed a >10-fold genome-wide increase in H3K9me3 signal at established sites over just 30 minutes at the onset of EGA. Continued maturation of the H3K9me3 landscape was observed beyond the initial wave of bulk establishment. Our findings uncover distinct features of pre- and post-EGA H3K9me3 targeting and reveal temporal decoupling of H3K9me3 establishment and signal reinforcement during zebrafish heterochromatin formation.

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“…The enhancer function of LTRs is influenced not only by transcription activators but also by the de-repression of KRAB zinc-finger transcription repressors that play a role in the defense mechanism of the host genome (Friedli and Trono 2015; Rosspopoff and Trono 2023). In our study, we observed that various KRAB repressor binding sequences were enriched in different LTR phyletic groups ( Figure 2B ).…”

Section: Discussionmentioning

confidence: 99%

Cryptic endogenous retrovirus subfamilies in the primate lineage

Chen,

Zhang,

Yan

et al. 2023

Preprint

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Many endogenous retroviruses (ERVs) in the human genome are primate-specific and have contributed novel cis-regulatory elements and transcripts. However, current approaches for classifying and annotating ERVs and their long terminal repeats (LTRs) have limited resolution and are inaccurate. Here, we developed a new annotation based on phylogenetic analysis and cross-species conservation. Focusing on the evolutionary young MER11A/B/C subfamilies, we revealed the presence of 4 ‘phyletic groups’, that better explained the epigenetic heterogeneity observed within these subfamilies, suggesting a new annotation for 412 (19.8%) of the MER11 instances. Furthermore, we functionally validated the regulatory potential of these four phyletic groups using a massively parallel reporter assay (MPRA), which also identified motifs associated with their differential activities. Combining MPRA with phyletic groups across primates revealed an apes-specific gain of SOX related motifs through a single-nucleotide deletion. Lastly, by applying our approach across 53 primate-specific LTR subfamilies, we determined the presence of 75 phyletic groups and found that 3,807 (30.0%) instances from 26 LTR subfamilies could be categorized into a novel phyletic group, many of which with a distinct epigenetic profile. Thus, with our refined annotation of primate-specific LTRs, it will be possible to better understand the evolution in primate genomes and potentially identify new roles for ERV/LTRs in their hosts.

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Take a walk on the KRAB side

Cited by 15 publications

References 104 publications

The domesticated transposon protein L1TD1 associates with its ancestor L1 ORF1p to promote LINE-1 retrotransposition

The domesticated transposon protein L1TD1 associates with its ancestor L1 ORF1p to promote LINE-1 retrotransposition

The emerging H3K9me3 chromatin landscape during zebrafish embryogenesis

Cryptic endogenous retrovirus subfamilies in the primate lineage

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