The C. elegans Dosage Compensation Complex Propagates Dynamically and Independently of X Chromosome Sequence

Department of Biology, Carolina Center for Genome Sciences and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Current biology: CB (Impact Factor: 9.57). 10/2009; 19(21):1777-87. DOI: 10.1016/j.cub.2009.09.047
Source: PubMed


The C. elegans dosage compensation complex (DCC) associates with both X chromosomes of XX animals to reduce X-linked transcript levels. Five DCC members are homologous to subunits of the evolutionarily conserved condensin complex, and two noncondensin subunits are required for DCC recruitment to X.
We investigated the molecular mechanism of DCC recruitment and spreading along X by examining gene expression and the binding patterns of DCC subunits in different stages of development, and in strains harboring X;autosome (X;A) fusions. We show that DCC binding is dynamically specified according to gene activity during development and that the mechanism of DCC spreading is independent of X chromosome DNA sequence. Accordingly, in X;A fusion strains, DCC binding propagates from X-linked recruitment sites onto autosomal promoters as a function of distance. Quantitative analysis of spreading suggests that the condensin-like subunits spread from recruitment sites to promoters more readily than subunits involved in initial X targeting.
A highly conserved chromatin complex is appropriated to accomplish domain-scale transcriptional regulation during C. elegans development. Unlike X recognition, which is specified partly by DNA sequence, spreading is sequence independent and coupled to transcriptional activity. Similarities to the X recognition and spreading strategies used by the Drosophila DCC suggest mechanisms fundamental to chromosome-scale gene regulation.

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    • "The validity of this location-induced gene regulation for an entire chromosome remains to be tested. Our DC model offers a simple explanation for the observation that in hermaphrodites carrying X:autosome fusions, the DCC and associated H4K20 methylation spread from the X onto the autosome for megabases, but little difference was observed for the transcriptional levels of the autosomal genes (Ercan et al. 2009; Pferdehirt et al. 2011; Vielle et al. 2012). As the autosomal part of the chromosome fusion is devoid of rex sites, it does not undergo pore-mediated upregulation ; therefore, DCC binding is expected to have little effect on transcriptional levels. "
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    ABSTRACT: The adjustment of X-linked gene expression to the X chromosome copy number (dosage compensation [DC]) has been widely studied as a model of chromosome-wide gene regulation. In Caenorhabditis elegans, DC is achieved by twofold down-regulation of gene expression from both Xs in hermaphrodites. We show that in males, the single X chromosome interacts with nuclear pore proteins, while in hermaphrodites, the DC complex (DCC) impairs this interaction and alters X localization. Our results put forward a structural model of DC in which X-specific sequences locate the X chromosome in transcriptionally active domains in males, while the DCC prevents this in hermaphrodites. © 2014 Sharma et al.; Published by Cold Spring Harbor Laboratory Press.
    Genes & Development 12/2014; 28(23):2591-6. DOI:10.1101/gad.248864.114 · 10.80 Impact Factor
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    • "We do not know why the X chromosome has fewer interactions with LMN-1 compared to the autosomes, nor can we explain the particular enrichment of ‘EMR-1 only’ elements on the X chromosome. Our experiments were performed with C. elegans hermaphrodites, in which both X chromosomes undergoes approximately two-fold chromosome-wide transcriptional repression to achieve dosage compensation [47]. It is possible that the interaction with EMR-1 or other INM proteins could be important for this transcriptional repression. "
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    ABSTRACT: Laminopathies are diseases characterized by defects in nuclear envelope structure. A well-known example is Emery-Dreifuss muscular dystrophy, which is caused by mutations in the human lamin A/C and emerin genes. While most nuclear envelope proteins are ubiquitously expressed, laminopathies often affect only a subset of tissues. The molecular mechanisms underlying these tissue-specific manifestations remain elusive. We hypothesize that different functional subclasses of genes might be differentially affected by defects in specific nuclear envelope components. Here we determine genome-wide DNA association profiles of two nuclear envelope components, lamin/LMN-1 and emerin/EMR-1 in adult Caenorhabditis elegans. Although both proteins bind to transcriptionally inactive regions of the genome, EMR-1 is enriched at genes involved in muscle and neuronal function. Deletion of either EMR-1 or LEM-2, another integral envelope protein, causes local changes in nuclear architecture as evidenced by altered association between DNA and LMN-1. Transcriptome analyses reveal that EMR-1 and LEM-2 are associated with gene repression, particularly of genes implicated in muscle and nervous system function. We demonstrate that emr-1, but not lem-2, mutants are sensitive to the cholinesterase inhibitor aldicarb, indicating altered activity at neuromuscular junctions. We identify a class of elements that bind EMR-1 but do not associate with LMN-1, and these are enriched for muscle and neuronal genes. Our data support a redundant function of EMR-1 and LEM-2 in chromatin anchoring to the nuclear envelope and gene repression. We demonstrate a specific role of EMR-1 in neuromuscular junction activity that may contribute to Emery-Dreifuss muscular dystrophy in humans.
    Genome biology 02/2014; 15(2):R21. DOI:10.1186/gb-2014-15-2-r21 · 10.81 Impact Factor
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    • "We identified a set of high confidence condensin I-IDC and II binding sites by selecting only those ChIP-seq peaks that were consistent across two or more non-SMC subunits (Figure 1D). As noted previously, 97% of condensin I-IDC binding occured on the X chromosome [16,19]. Condensin II was similarly distributed between autosomes and the X. "
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    ABSTRACT: Background Condensins are multi-subunit protein complexes that are essential for chromosome condensation during mitosis and meiosis, and play key roles in transcription regulation during interphase. Metazoans contain two condensins, I and II, which perform different functions and localize to different chromosomal regions. Caenorhabditis elegans contains a third condensin, IDC, that is targeted to and represses transcription of the X chromosome for dosage compensation. Results To understand condensin binding and function, we performed ChIP-seq analysis of C. elegans condensins in mixed developmental stage embryos, which contain predominantly interphase nuclei. Condensins bind to a subset of active promoters, tRNA genes and putative enhancers. Expression analysis in kle-2-mutant larvae suggests that the primary effect of condensin II on transcription is repression. A DNA sequence motif, GCGC, is enriched at condensin II binding sites. A sequence extension of this core motif, AGGG, creates the condensin IDC motif. In addition to differences in recruitment that result in X-enrichment of condensin IDC and condensin II binding to all chromosomes, we provide evidence for a shared recruitment mechanism, as condensin IDC recruiter SDC-2 also recruits condensin II to the condensin IDC recruitment sites on the X. In addition, we found that condensin sites overlap extensively with the cohesin loader SCC-2, and that SDC-2 also recruits SCC-2 to the condensin IDC recruitment sites. Conclusions Our results provide the first genome-wide view of metazoan condensin II binding in interphase, define putative recruitment motifs, and illustrate shared loading mechanisms for condensin IDC and condensin II.
    Genome biology 10/2013; 14(10):R112. DOI:10.1186/gb-2013-14-10-r112 · 10.81 Impact Factor
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