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Repetitive sequences drive the condensation of H3K9me3 Methyltransferase complex to promote epigenetic inheritance in Caenorhabditis elegans [transgenes]

ABSTRACT: Histone H3K9 trimethylation (H3K9me3) plays a pivotal role in the establishment and maintenance of heterochromatin and is essential for facilitating epigenetic inheritance. H3K9me3 is often biasedly deposited and associated with repetitive sequence region, although the underlying mechanism remain poorly understood. In this study, we identify two proteins, SECP-1 and SECP-2, as crucial cofactors for the genome-wide deposition of H3K9me3 in Caenorhabditis elegans. SECP-1 interacts directly with SECP-2 and the primary H3K9me3 methyltransferase, SET-25, forming a protein complex that bridges SECP-2 with SET-25. This complex assembles in the cytoplasm and is transported into the nucleus through SET-25. Once in the nucleus, the complex is recruited to and concentrated at SET-25’s genomic targets in an interdependent manner. The accumulation of this complex correlates with the formation of condensates at repetitive sequences, the perinuclear localization of heterochromatin, and the epigenetic inheritance of small RNA-mediated gene silencing. The introduction of transgenic arrays leads to the redistribution of the SECP-1/SECP-2/SET-25 complex to the transgene locus, a genome-wide decrease in H3K9me3 levels, and an increase in repetitive sequence expression. We propose that repetitive sequences drive the formation of condensates containing H3K9me3 methyltransferase complexes, which in turn causes a biased deposition of H3K9me3 at these genomic regions.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE297992 | GEO | 2025/05/28

REPOSITORIES: GEO

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Repetitive sequences drive the condensation of H3K9me3 Methyltransferase complex to promote epigenetic inheritance in Caenorhabditis elegans [mutants]

Project description:Histone H3K9 trimethylation (H3K9me3) plays a pivotal role in the establishment and maintenance of heterochromatin and is essential for facilitating epigenetic inheritance. H3K9me3 is often biasedly deposited and associated with repetitive sequence region, although the underlying mechanism remain poorly understood. In this study, we identify two proteins, SECP-1 and SECP-2, as crucial cofactors for the genome-wide deposition of H3K9me3 in Caenorhabditis elegans. SECP-1 interacts directly with SECP-2 and the primary H3K9me3 methyltransferase, SET-25, forming a protein complex that bridges SECP-2 with SET-25. This complex assembles in the cytoplasm and is transported into the nucleus through SET-25. Once in the nucleus, the complex is recruited to and concentrated at SET-25’s genomic targets in an interdependent manner. The accumulation of this complex correlates with the formation of condensates at repetitive sequences, the perinuclear localization of heterochromatin, and the epigenetic inheritance of small RNA-mediated gene silencing. The introduction of transgenic arrays leads to the redistribution of the SECP-1/SECP-2/SET-25 complex to the transgene locus, a genome-wide decrease in H3K9me3 levels, and an increase in repetitive sequence expression. We propose that repetitive sequences drive the formation of condensates containing H3K9me3 methyltransferase complexes, which in turn causes a biased deposition of H3K9me3 at these genomic regions.

2025-05-28 | GSE297991 | GEO

The INO80 complex regulates epigenetic inheritance of heterochromatin (RNA-seq)

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DAXX adds a de novo H3.3K9me3 deposition pathway to the histone chaperone network (part 2)

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2023-03-02 | PXD038263 | Pride

DAXX adds a de novo H3.3K9me3 deposition pathway to the histone chaperone network (part 1)

2023-03-02 | PXD034888 | Pride

A Composite DNA Element that Functions as a Maintainer Required for Epigenetic Inheritance of Heterochromatin

Project description:Epigenetic inheritance of heterochromatin requires DNA sequence-independent propagation mechanisms, coupling to RNAi, or input from DNA sequence, but how DNA contributes to inheritance is not understood. Here, we identify a DNA element (termed “maintainer”) that is sufficient for epigenetic inheritance of preexisting histone H3 lysine 9 methylation (H3K9me) and heterochromatin in Schizosaccharomyces pombe, but cannot establish de novo gene silencing in wild-type cells. This maintainer is a composite DNA element with binding sites for the Atf1/Pcr1 and Deb1 transcription factors and the Origin Recognition Complex (ORC), located within a 130-base pair region, and can be converted to a silencer in cells with lower rates of H3K9me turnover, suggesting that it participates in recruiting the H3K9 methyltransferase Clr4/Suv39h. These results suggest that, in the absence of RNAi, histone H3K9me is only heritable when it can collaborate with maintainer-associated DNA-binding proteins that help recruit the enzyme responsible for its epigenetic deposition.

2022-10-14 | PXD027214 | Pride

The Local Density of H3K9me3 Dictates The Stability of HP1a Condensates-mediated Genomic Interactions

Project description:The human genome can be demarcated into different domains based on distinct epigenetic states. The trimethylation of histone H3 lysine 9 (H3K9me3) is essential for the formation of constitutive heterochromatin nanodomains. It is unclear what degrees or densities of H3K9me3 in genomic regions are required for their stable interactions. We demonstrate that the levels of H3K9me3 at the loci are positively correlated with their association with HP1a condensates. Epigenetic perturbation-induced Genome organization (EpiGo)-KRAB introduces ~20 kilobases of H3K9me3 at the TCF3 locus, which is sufficient to establish a stable association between TCF3 and HP1a condensates. In addition, EpiGo-mediated H3K9me3 also led to stable genomic interaction between IDR3 and TCF3. In sum, these data suggest that the density of H3K9me3 could dictate the stability of interactions between genomic loci and HP1a condensates.

2024-07-01 | GSE227780 | GEO

Neurospora crassa genome organization requires subtelomeric facultative heterochromatin

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The dimeric SFiNX complex enables piRNA-guided co-transcriptional silencing through molecular condensate formation

Project description:Nuclear Argonaute proteins, guided by their bound small RNAs, orchestrate heterochromatin formation at transposon insertions and repetitive genomic loci. The molecular mechanisms that, besides recruiting heterochromatin effector proteins, are required for this silencing process are poorly understood. Here, we show that the SFiNX complex, the central silencing mediator downstream of nuclear Piwi-piRNA complexes in Drosophila, enables co-transcriptional silencing via the formation of molecular condensates. Condensate formation is stimulated by nucleic acid binding and requires SFiNX to form a homodimer. The dynein light chain dLC8, a highly conserved dimerization hub protein, mediates homo-dimerization of SFiNX. Point mutations preventing dLC8-mediated SFiNX dimerization result in transposon de-repression and sterility. dLC8’s function can be bypassed with a heterologous dimerization domain, suggesting that dimerization is a constitutive rather than a regulated feature of SFiNX. We propose that nucleic-acid stimulated condensate formation enables co-transcriptional silencing through the retention of the target RNA at chromatin, thereby allowing effector proteins to establish heterochromatin at the target locus.

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