Tumor-suppressive activities for pogo transposable element derived with KRAB domain via ribosome biogenesis restriction

Molecular Cell, Год журнала: 2024, Номер 84(21), С. 4209 - 4223.e6

Опубликована: Окт. 31, 2024

Язык: Английский

---

Retrotransposon life cycle and its impacts on cellular responses

RNA Biology, Год журнала: 2024, Номер 21(1), С. 11 - 27

Опубликована: Окт. 13, 2024

Approximately 45% of the human genome is comprised transposable elements (TEs), also known as mobile genetic elements. However, their biological function remains largely unknown. Among them, retrotransposons are particularly abundant, and some copies still capable mobilization within through RNA intermediates. This review focuses on life cycle summarizes regulatory mechanisms impacts cellular processes. Retrotransposons generally epigenetically silenced in somatic cells, but transcriptionally reactivated under certain conditions, such tumorigenesis, development, stress, ageing, potentially leading to instability. We explored dual nature genomic parasites elements, focusing roles diversity innate immunity. Furthermore, we discuss how host factors regulate retrotransposon cDNA intermediates binding, modification, degradation. The interplay between machinery provides insight into complex regulation potential for dysregulation cause aberrant responses inflammation autoimmune diseases.

Язык: Английский

---

Insertion of short L1 sequences generates inter-strain histone acetylation differences in the mouse

Mobile DNA, Год журнала: 2024, Номер 15(1)

Опубликована: Май 10, 2024

Abstract Background Gene expression divergence between populations and individuals can emerge from genetic variations within the genes and/or in cis regulatory elements. Since epigenetic modifications regulate gene expression, it is conceivable that elements also be a source of divergence. Results In this study, we compared histone acetylation (namely, H3K9ac) profiles two mouse strains different subspecies origin, C57BL/6 J (B6) MSM/Ms (MSM), as well their F1 hybrids. This identified 319 regions strain-specific acetylation, about half which were observed alleles While allele-specific presence interferon factor 3 (IRF3) binding sequence was associated with revealed B6-specific insertions short 3′ fragment LINE-1 (L1) retrotransposon occur or proximal to MSM-specific acetylated regions. Furthermore, even hyperacetylated domains, flanking non-polymorphic L1 fragments hypoacetylated, suggesting general activity induce hypoacetylation. Indeed, confirmed region by three Krüppel-associated box domain-containing zinc finger proteins (KZFPs), interact deacetylases. These results suggest insertion would excluded gene- acetylation-rich natural selection. Finally, mRNA-seq analysis for hybrids carried out, disclosed link promoter/enhancer expression. Conclusions study number changes have changed levels during evolution subspecies, part changes. Insertions very decrease level neighboring thereby been counter-selected gene-rich regions, may explain long-standing mystery discrete genomic distribution LINEs SINEs.

Язык: Английский

---

The emerging H3K9me3 chromatin landscape during zebrafish embryogenesis

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Март 5, 2024

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

Язык: Английский

---

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

Опубликована: Апрель 26, 2024

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

Язык: Английский

---

RNA-Independent Regulatory Functions of lncRNA in Complex Disease

Cancers, Год журнала: 2024, Номер 16(15), С. 2728 - 2728

Опубликована: Июль 31, 2024

During the metagenomics era, high-throughput sequencing efforts both in mice and humans indicate that non-coding RNAs (ncRNAs) constitute a significant fraction of transcribed genome. past decades, regulatory role these transcripts along with their interactions other molecules have been extensively characterized. However, study long (lncRNAs), an ncRNA class transcript lengths exceed 200 nucleotides, revealed certain are transcriptional “by-products”, while loci exert downstream functions through RNA-independent mechanisms. Such mechanisms include, but not limited to, chromatin complex promoter-enhancer competition schemes involve underlying locus or without its nascent transcription, mediating even exclusive roles regulation target genes mammals. Interestingly, such often drive pathological manifestations, including oncogenesis. In this review, we summarize selective examples lncRNAs regulate independently produced transcripts.

Язык: Английский

---

The emerging H3K9me3 chromatin landscape during zebrafish embryogenesis

Genetics, Год журнала: 2024, Номер 228(2)

Опубликована: Авг. 21, 2024

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

Язык: Английский

---

ZNF8 Orchestrates with Smad3 to Promote Lung Metastasis by Recruiting SMYD3 in Breast Cancer

Advanced Science, Год журнала: 2024, Номер 11(40)

Опубликована: Сен. 3, 2024

Abstract Most deaths in breast cancer patients are attributed to metastasis, and lung metastasis is associated with a particularly poor prognosis; therefore it imperative identify potential target for intervention. The transforming growth factor‐β (TGF‐β) pathway plays vital role which Smad3 the key mediator performs specific functions by binding different cofactors. However, cofactors involved have not yet been identified. This study first establishes interactome of cells identifies ZNF8 as novel cofactor. Furthermore, results reveal that closely prognosis, specifically facilitates TGF‐β pathway‐mediated participating multiple processes. Mechanistically, binds enhance H3K4me3 modification promote expression signature genes recruiting SMYD3. SMYD3 inhibition BCI121 effectively prevents ZNF8‐mediated metastasis. Overall, cofactor TGF‐β/Smad3 promotes introduces therapeutic strategies early management

Язык: Английский

---

Human CCR4-NOT is a global regulator of gene expression and is a novel silencer of retrotransposon activation

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 10, 2024

CCR4-NOT regulates multiple steps in gene regulation, including transcription, mRNA decay, protein ubiquitylation, and translation. It has been well studied budding yeast; however, relatively less is known about its regulation functions mammals. To characterize the of human complex, we developed a rapid auxin-induced degron system to deplete CNOT1 (the scaffold complex) CNOT4 (E3 ubiquitin ligase) cell culture. Transcriptome-wide measurements gene-expression revealed that depleting changed several thousand transcripts, wherein most mRNAs were increased resulted global decrease decay rates. In contrast what was observed CNOT1-depleted cells, depletion only modestly RNA steady-state levels and, surprisingly, led acceleration decay. further investigate role used transient transcriptome sequencing (TT-seq) measure ongoing synthesis. Depletion either subunit synthesis genes. genome, reduction KRAB-Zinc-Finger-proteins (KZNFs) genes, especially those clustered on chromosome 19, observed. KZNFs are transcriptional repressors retro-transposable elements (rTEs), consistent with decreased expression, significant activation rTEs, mainly Long interspersed Nuclear Elements (LINEs). Our data reveal expression silences retrotransposons across genome by maintaining KZNF expression. These establish as regulator have identified novel mammalian-specific function suppression rTEs.

Язык: Английский

---

Epigenomic and phenotypic characterization of DEGCAGS syndrome

European Journal of Human Genetics, Год журнала: 2024, Номер 32(12), С. 1574 - 1582

Опубликована: Окт. 18, 2024

Язык: Английский

---