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Anchoring of Heterochromatin to the Nuclear Lamina Reinforces Dosage Compensation-Mediated Gene Repression

ABSTRACT: Higher order chromosome structure and nuclear architecture can have profound effects on gene regulation. We analyzed how compartmentalizing the genome by tethering heterochromatic regions to the nuclear lamina affects dosage compensation in the nematode C. elegans. In this organism, the dosage compensation complex (DCC) binds both X chromosomes of hermaphrodites to repress transcription two-fold, thus balancing gene expression between XX hermaphrodites and XO males. X chromosome structure is disrupted by mutations in DCC subunits. Using X chromosome paint fluorescence microscopy, we found that X chromosome structure and subnuclear localization are also disrupted when the mechanisms that anchor heterochromatin to the nuclear lamina are defective. Strikingly, the heterochromatic left end of the X chromosome is less affected than the gene-rich middle region, which lacks heterochromatic anchors. These changes in X chromosome structure and subnuclear localization are accompanied by small, but significant levels of derepression of X-linked genes as measured by RNA-seq, without any observable defects in DCC localization and DCC-mediated changes in histone modifications. We propose a model in which heterochromatic tethers on the left arm of the X cooperate with the DCC to compact and peripherally relocate the X chromosomes, contributing to gene repression.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE79597 | GEO | 2016/03/25

SECONDARY ACCESSION(S): PRJNA316338

REPOSITORIES: GEO

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Anchoring of heterochromatin to the nuclear lamina helps stabilize dosage compensation-mediated gene repression

Project description:Higher order structure of interphase chromosomes and their spatial organization within the nucleus can have profound effects on regulation of gene expression. We show how compartmentalizing the genome by tethering heterochromatic regions to the nuclear lamina can affect gene expression during C. elegans dosage compensation. In this organism, the dosage compensation complex (DCC) binds both X chromosomes of hermaphrodites to repress gene expression two-fold, thus balancing gene expression between XX hermaphrodites and XO males. X chromosome structure is disrupted by mutations in DCC subunits. We found that X chromosome structure and subnuclear localization are also disrupted when the mechanisms that anchor heterochromatin to the nuclear lamina are defective. Strikingly, the heterochromatic left end of the X chromosome is less affected than the gene-rich middle region which lacks heterochromatic anchors. Our results suggest a model in which tethers at the left of the chromosome nucleate formation of a compact structure, which, by the action of the DCC, is propagated to the rest of the chromosome. These changes in X chromosome structure and subnuclear localization are accompanied by small, but significant levels of derepression of X-linked genes, without any observable defects in DCC localization and DCC-mediated changes in histone modification. RNA-seq profiles of C. elegans L1 wild type hermaphrodites, cec-4, met-2 set-25, and DPY-27 RNAi. RNA-seq profiles or C. elegans. Strains are N2 Bristol strain (wild type), RB2301 cec-4(ok3124) IV, and EKM99 met-2(n4256) set-25(n5021) III. Biological replicates for each strain/stage listed separately.

2016-03-25 | E-GEOD-79597 | biostudies-arrayexpress

Differential spatial and structural organization of the X chromosome underlies dosage compensation in C. elegans.

Project description:The essential adaptation of X-linked gene expression to the X chromosome copy number variation (called dosage compensation, DC) has been widely studied as a model of chromosome-wide gene regulation. In C. elegans, DC is achieved by two fold downregulation of gene expression from both X copies in hermaphrodites. The dosage compensation complex (DCC), a multiprotein complex structurally similar to mitotic condensins, restricts RNA polymerase progression. Higher order chromatin structures have therefore long been suggested to regulate X-linked gene expression. Here we show that in C. elegans males, the single X chromosome interacts broadly with nuclear pores, while in hermaphrodites the DCC impairs this interaction. Using microscopic measurements we find that the X chromosome is located at the nuclear periphery in males and internal in hermaphrodites, while compaction was higher for the X chromosome than for autosomes but surprisingly comparable between sexes. Mechanistically, we show that a single motif enriched on X, sufficient for DCC loading in hermaphrodites, autonomously targets an autosomal locus to the nuclear periphery specifically in males. Using DNA adenine methyltransferase identification (DamID), we demonstrate that the perinuclear interaction domains are nuclear pores. Dynamic polymer modeling shows that this discrete pore anchoring can explain the high compaction of the male X chromosome. Together, our results put forward a structural model of DC, by demonstrating that X-specific sequences mediate interactions with nuclear pores, thereby locating the X chromosome in active perinuclear domains, while the DCC physically moves X-linked genes away from these transcriptionally active neighborhoods.

2014-12-01 | GSE56270 | GEO

Condensin-Driven Remodeling of X-Chromosome Topology during Dosage Compensation [Hi-C]

Project description:The three-dimensional (3D) organization of a genome plays a critical role in regulating gene expression, yet little is known about the machinery and mechanisms that determine higher-order chromosome structure or how structure influences gene expression. Here we exploit the X-chromosome-wide process of dosage compensation to dissect these mechanisms. The dosage compensation complex (DCC) of C. elegans, a condensin complex, binds to both X chromosomes of hermaphrodites via sequence-specific recruitment sites (rex sites) to reduce chromosome-wide gene expression by half. Using genome-wide chromosome conformation capture and single-cell FISH to compare chromosome structure in wild-type and DCC-defective embryos (DC mutants), we show that the DCC remodels X chromosomes of hermaphrodites into a spatial conformation distinct from autosomes. The dosage-compensated X chromosomes are composed of Topologically Associating Domains (TADs) that have sharper boundaries and more regular spacing than TADs on autosomes. Most TAD boundaries on X coincide with the highest-affinity rex sites, and these boundaries are lost or diminished in DC mutants, thereby restoring the topology of X to a native conformation resembling that of autosomes. Although most rex sites engage in multiple strong DCC-dependent long-range interactions, the strongest interactions occur between rex sites at the DCC-dependent TAD boundaries. We propose the DCC actively shapes the topology of the entire X chromosome by forming new TAD boundaries and reinforcing pre-existing weak TAD boundaries through interactions between its highest affinity sites. Such changes in higher-order X-chromosome structure then influence gene expression over long distances.

2015-06-03 | GSE63717 | GEO

Condensin-Driven Remodeling of X-Chromosome Topology during Dosage Compensation [RNA-Seq]

2015-06-03 | GSE59715 | GEO

Condensin-Driven Remodeling of X-Chromosome Topology during Dosage Compensation [ChIP-Seq]

2015-06-03 | GSE59597 | GEO

ChIP-chip analysis of Dosage Compensation complex members SDC-3 and DPY-27 in C elegans wild type embryos.

Project description:Among organisms with chromosome-based mechanisms of sex determination, failure to equalize expression of X-linked genes between the sexes is typically lethal. In C. elegans, XX hermaphrodites halve transcription from each X chromosome to match the output of XO males1. Here, we mapped the binding location of the condensin homolog DPY-27 and the zinc finger protein SDC-3, two components of the C. elegans dosage compensation complex (DCC)2,3. Strong foci of DCC binding were observed on X, around which broader regions of localization were centered. Binding foci, but not adjacent regions of localization, were distinguished by clusters of a stereotypic 10-bp DNA sequence, suggesting a recruitment-and-spreading mechanism for X recognition. In contrast to the Drosophila DCC, the C. elegans DCC was bound preferentially upstream of genes, suggesting modulation of transcriptional initiation and transcription-coupled spreading. A mechanism for tuning DCC activity at specific loci was indicated by stronger DCC binding upstream of genes with high transcriptional activity. These data provide a basis for understanding how proteins involved in higher-order chromosome dynamics can regulate transcription at individual loci. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf Keywords: ChIP-chip dosage compensation complex

2007-02-11 | GSE6739 | GEO

X chromosome domain architecture regulates Caenorhabditis elegans lifespan but not dosage compensation [RNA-seq]

Project description:Mechanisms establishing higher-order chromosome structures and their roles in gene regulation are elusive. We analyzed chromosome architecture during nematode X-chromosome dosage compensation, which represses transcription via a dosage-compensation condensin complex (DCC) that binds hermaphrodite Xs and establishes megabase-size topologically associating domains (TADs). We show that DCC binding at high-occupancy sites (rex sites) defines eight TAD boundary locations. Single rex deletions disrupted boundaries, and single insertions created new boundaries, demonstrating one rex site is necessary and sufficient for DCC-dependent boundary formation. Deleting eight rex sites (8rexΔ) recapitulated TAD structure of DCC mutants, permitting analysis when chromosome-wide domain architecture was disrupted but most DCC binding remained. 8rexΔ animals exhibited no changes in X expression and lacked dosage-compensation mutant phenotypes. Hence, TAD boundaries are neither the cause nor consequence of gene repression during dosage compensation. Abrogating TAD structure did, however, reduce thermotolerance, accelerate aging, and shorten lifespan, implicating chromosome architecture in regulating stress responses and aging.

2019-09-05 | GSE128566 | GEO

X chromosome domain architecture regulates Caenorhabditis elegans lifespan but not dosage compensation [ChIP-seq]

2019-09-05 | GSE128564 | GEO

X chromosome domain architecture regulates Caenorhabditis elegans lifespan but not dosage compensation [Hi-C]

2019-09-05 | GSE128559 | GEO

Examination of DPY-30, DPY-27, SDC-3, DPY-26, DPY-28, SDC-2, and SUMOylated DPY-27 binding in wild type embryos and smo-1 RNAi treated embryos

Project description:The essential process of dosage compensation equalizes X-chromosome gene expression between C. elegans XO males and XX hermaphrodites through a dosage compensation complex (DCC) that resembles condensin. The DCC binds to both X chromosomes of hermaphrodites to repress transcription by half. Here we show that post-translational modification by the SUMO conjugation pathway is essential for sex-specific assembly of the DCC onto X. Depletion of the SUMO peptide in vivo severely disrupts binding of particular DCC subunits and causes changes in X-linked gene expression similar to those caused by disrupting genes encoding DCC subunits. Three DCC subunits are themselves SUMOylated, and depletion of SUMO preferentially reduces their binding to X, suggesting that SUMOylation of DCC subunits is essential for robust association with X. DCC SUMOylation is triggered by the signal that initiates DCC assembly onto X. The initial step of assembly--binding of X-targeting factors to recruitment sites on X (rex sites)--is independent of SUMOylation, but robust binding of the complete complex requires SUMOylation. SUMOylated DCC subunits are enriched at rex sites, and SUMOylation enhances interactions between X-targeting factors and condensin subunits that facilitate DCC binding beyond the low level achieved without SUMOylation. DCC subunits also participate in condensin complexes essential for chromosome segregation, but their SUMOylation occurs only in the context of the DCC. Our results reinforce a newly emerging theme in which multiple proteins of a complex are SUMOylated in response to a specific stimulus, leading to accelerated complex formation and enhanced function.

2013-08-31 | GSE48413 | GEO

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