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HP1 dimerization drives the condensation and segregation of H3K9me-marked chromatin [RNA-seq]

ABSTRACT: Heterochromatin protein 1 (HP1) is a conserved chromatin-associated factor implicated in the establishment and maintenance of H3K9me-marked heterochromatin, potentially through phase separation–mediated condensation. Whether HP1 promotes heterochromatin condensation primarily through its dimerization or liquid–liquid phase separation (LLPS) remains unresolved. Using the C. elegans HP1 orthologue HPL-2 and a combined in vitro–in vivo approach, we systematically dissected the molecular determinants of HPL-2 function in heterochromatin condensation. Through specific mutants, we demonstrate that HPL-2 dimerization is essential for condensing H3K9me chromatin arrays in vitro and for maintaining H3K9me heterochromatin foci in C. elegans embryos. We further show that HPL-2 dimerization is sufficient to mediate segregation of H3K9me from unmodified chromatin arrays in vitro, forming spatially distinct H3K9me-enriched condensates. Surprisingly, HPL-2 mutants defective in heterochromatin foci formation cause only minor transcriptional changes among genes associated with H3K9me-marked heterochromatin, implying that HP1-dependent heterochromatin foci and gene silencing are not tightly coupled in vivo. Nonetheless, these mutant C. elegans exhibit profound physiological and developmental defects. Our findings establish dimerization as the principal molecular mechanism of HP1-driven H3K9me-chromatin condensation, elucidate an auxiliary role of LLPS, and reveal the uncoupling between HP1-dependent heterochromatin and transcriptional regulation.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE342086 | GEO | 2026/08/25

REPOSITORIES: GEO

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HP1 dimerization drives the condensation and segregation of H3K9me-marked chromatin

Project description:Heterochromatin protein 1 (HP1) is a conserved chromatin-associated factor implicated in the establishment and maintenance of H3K9me-marked heterochromatin, potentially through phase separation–mediated condensation. Whether HP1 promotes heterochromatin condensation primarily through its dimerization or liquid–liquid phase separation (LLPS) remains unresolved. Using the C. elegans HP1 orthologue HPL-2 and a combined in vitro–in vivo approach, we systematically dissected the molecular determinants of HPL-2 function in heterochromatin condensation. Through specific mutants, we demonstrate that HPL-2 dimerization is essential for condensing H3K9me chromatin arrays in vitro and for maintaining H3K9me heterochromatin foci in C. elegans embryos. We further show that HPL-2 dimerization is sufficient to mediate segregation of H3K9me from unmodified chromatin arrays in vitro, forming spatially distinct H3K9me-enriched condensates. Surprisingly, HPL-2 mutants defective in heterochromatin foci formation cause only minor transcriptional changes among genes associated with H3K9me-marked heterochromatin, implying that HP1-dependent heterochromatin foci and gene silencing are not tightly coupled in vivo. Nonetheless, these mutant C. elegans exhibit profound physiological and developmental defects. Our findings establish dimerization as the principal molecular mechanism of HP1-driven H3K9me-chromatin condensation, elucidate an auxiliary role of LLPS, and reveal the uncoupling between HP1-dependent heterochromatin and transcriptional regulation.

2026-08-25 | GSE339336 | GEO

H3K9 methylation-independent activity for HPL-2/HP1 in heterochromatin foci, gene repression, and organogenesis

Project description:Differentiated cells rely on segregation of the genome into heterochromatin and euchromatin, but the mechanisms that establish these domains in vivo are incompletely understood. The current models suggest that heterochromatin is marked by histone H3 lysine 9 methylation (H3K9me), which recruits heterochromatin protein 1 (HP1), to compact chromatin and repress transcription. In C. elegans, the SETDB1 homolog MET-2 is essential for H3K9me-mediated gene silencing; however, MET-2 also localizes to heterochromatic foci independently of H3K9me and exhibits non-catalytic functions that support both germline and somatic development. Here we extend these findings by examining the classical H3K9me reader HP1. We show that HPL-2/HP1 deficient in methyl-lysine binding or in the absence of H3K9me can still repress transcription, promote organogenesis and localize to heterochromatin foci. Whereas activity remains in the absence of the HPL-2:H3K9me interaction, complete loss of met-2 and hpl-2 shows synergistic phenotypes for organogenesis and gene de-repression, underscoring the existence of additional, H3K9me-independent functions. HPL-2 and MET-2 require distinct binding partners for their localization and activity: MET-2 associates with the disordered protein LIN-65/ATF7IP, while HPL-2 depends on the multi-zinc finger protein LIN-13, which interacts with the HPL-2 chromoshadow domain. Our findings suggest that HPL-2 and MET-2 operate in parallel pathways, localizing to heterochromatic foci and promoting gene silencing and organogenesis, with H3K9me acting as a reinforcing, but non-essential, element in these processes.

2025-07-01 | GSE278459 | GEO

HP1 can act independently of H3K9 methylation to promote heterochromatin focus formation, gene repression, and organogenesis [CUT&Tag]

Project description:Histone post-translational modifications (PTMs) segregate genomes into heterochromatin and euchromatin by recruiting readers, including HP1 proteins that bind H3 lysine 9 methylation (H3K9me). Here, we report H3K9me-independent functions for the HP1 orthologue HPL-2 and the H3K9 methyltransferase MET-2/SETDB1 in C. elegans. Both proteins co-localize in H3K9me-containing sub-nuclear foci independently. Their combined loss additively disrupts gene repression and organogenesis. HPL-2 remains functional in the absence of H3K9me: HPL-2 deficient for H3K9me-binding still localizes to heterochromatin foci, restricts cell fate decisions and represses developmental genes. MET-2, catalytically active or not, requires the disordered protein LIN-65 to form foci and silence genes in vivo, while HPL-2 requires a multi-zinc finger ligand, LIN-13. Molecular dynamics simulations and in vitro assays suggest that these cofactor-driven condensate assemblies underlie the H3K9me-independent formation of heterochromatic foci in vivo. We define parallel, H3K9me-independent pathways through which MET-2 and HPL-2 can repress genes essential for organogenesis, reinforcing H3K9me-dependent mechanisms.

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HP1 dimerization drives the condensation and segregation of H3K9me-marked chromatin

Project description:HP1 dimerization drives the condensation and segregation of H3K9me-marked chromatin

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Identification of a novel, tunable interface in the S.pombe HP1 protein, Swi6, that underpins epigenetic inheritance.

Project description:HP1 proteins bind dynamically to H3K9 methylation and are essential for establishing and maintaining transcriptionally silent epigenetic states, known as heterochromatin. HP1 proteins can dimerize, forming a binding interface that interacts with and recruits diverse chromatin-associated factors. HP1 proteins rapidly evolve through sequence changes and gene duplications, but the extent of variation required to achieve functional specialization is unknown. To investigate how changes in amino acid sequence impact epigenetic inheritance, we performed a targeted mutagenesis screen of the dimerization and protein interaction domain of the S.pombe HP1 homolog Swi6. We discovered that substitutions mapping to an auxiliary motif in Swi6 outside the dimerization interface can lead to complete functional divergence. Specifically, we identified point mutations at a single amino acid residue that resulted in either persistent gain or loss of function in epigenetic inheritance without affecting heterochromatin establishment. These substitutions increase Swi6 chromatin occupancy in vivo and alter Swi6-protein interactions that selectively affect H3K9me inheritance. Based on our findings, we propose that relatively minor changes in Swi6 amino acid composition can lead to profound changes in epigenetic inheritance, underscoring the remarkable plasticity associated with HP1 proteins and their ability to evolve new functions.

2024-08-10 | PXD047651 | Pride

HP1 dimerization drives the condensation and segregation of H3K9me-marked chromatin [RNA-seq]

Project description:HP1 dimerization drives the condensation and segregation of H3K9me-marked chromatin [RNA-seq]

| PRJNA1505562 | ENA

The C. elegans ortholog of TDP-43 regulates the chromatin localization of the heterochromatin protein 1 homolog, HPL-2

Project description:TDP-1 is the C. elegans ortholog of mammalian TDP-43, which is strongly implicated in the etiology of Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). We discovered that deletion of the tdp-1 gene results in enhanced transcriptional gene silencing leading to increased sensitivity to heritable RNA interference (RNAi). As heritable RNAi in C. elegans depends on chromatin changes moderated by HPL-2, a homolog of heterochromatin protein 1 (HP1), we investigated the interaction of TDP-1 and HPL-2. We find that TDP-1 and HPL-2 interact directly, and loss of TDP-1 dramatically alters the chromatin association of HPL-2. We have shown previously that deletion of the tdp-1 gene results in transcriptional alterations and the accumulation of double-stranded (ds) RNA. These molecular changes are replicated in an hpl-2 deletion strain, consistent with HPL-2 acting downstream of TDP-1 to modulate these aspects of RNA metabolism. Our observations identify novel mechanisms by which HP1 homologs can be recruited to chromatin, and by which nuclear depletion of human TDP-43 could lead to disease-relevant changes in RNA metabolism.

2018-05-17 | GSE100829 | GEO

RNA-seq

Project description:HP1 dimerization drives the condensation and segregation of heterochromatin

| PRJEB102446 | ENA

Genome-wide binding profiles of HP1a and Prospero in Drosophila central brain neural precursors and neurons

Project description:Compacted heterochromatin blocks are prevalent in differentiated cells and present a barrier to cellular reprogramming. It remains obscure how heterochromatin remodeling is orchestrated during cell differentiation. Here we find that the evolutionarily conserved homeodomain transcription factor Prospero (Pros)/Prox1 ensures neuronal differentiation by driving heterochromatin domain condensation and expansion. Intriguingly, in mitotically dividing Drosophila neural precursors, Pros is retained at H3K9me3+ pericentromeric heterochromatin regions of chromosomes via liquid-liquid phase separation (LLPS). During mitotic exit of neural precursors, mitotically retained Pros recruits and concentrates heterochromatin protein 1 (HP1) into phase-separated condensates and drives heterochromatin compaction. This establishes a transcriptionally repressive chromatin environment that guarantees cell-cycle exit and terminal neuronal differentiation. Importantly, mammalian Prox1 employs a similar “mitotic-implantation-ensured heterochromatin condensation” strategy to reinforce neuronal differentiation. Together, our results unveiled a new paradigm whereby mitotic implantation of a transcription factor via LLPS remodels H3K9me3+ heterochromatin and drives timely and irreversible terminal differentiation.

2019-12-21 | GSE136413 | GEO

Novel roles of C. elegans heterochromatin protein HP1 and linker histone HIS-24 in the regulation of innate immune gene expression and stress Response

Project description:Linker histone H1 and heterochromatin protein 1 (HP1) are essential components ofheterochromatin which contribute to the transcriptional repression of genes. It has been shown that the methylation mark on the histone H1 serves as a specific recognition code for the chromodomain of HP1, however, the functional role of the HP1/H1 complex remains elusive. Using C. elegans, we elucidate the function of the linker histone variant HIS-24 and heterochromatin proteins HPL/HP1 in the cooperative transcriptional regulation of immunerelevant and stress resistance genes. We also show that HIS-24 and HPL act redundantly in vulval cell fate specification and gonad development. Finally, we provide the first evidence that HPL-1 interacts with HIS-24 at mono-methylated lysine 14 and associates in vivo with promoters of infection-inducible genes: the caenacin (cnc)- and the thaumatin (thn)- gene clusters. Our results highlight a functional link between epigenetic regulation by HP1/H1 the innate immune system and stress response. The experiment was performed using biological independent replicates of pooled worms. For the KO mutants we used duplicates and for WT condition quadruplicates.

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