Publication Date:
2015-06-02
Description:
The three-dimensional 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. Here we perform genome-wide chromosome conformation capture analysis, fluorescent in situ hybridization (FISH), and RNA-seq to obtain comprehensive three-dimensional (3D) maps of the Caenorhabditis elegans genome and to dissect X chromosome dosage compensation, which balances gene expression between XX hermaphrodites and XO males. The dosage compensation complex (DCC), a condensin complex, binds to both hermaphrodite X chromosomes via sequence-specific recruitment elements on X (rex sites) to reduce chromosome-wide gene expression by half. Most DCC condensin subunits also act in other condensin complexes to control the compaction and resolution of all mitotic and meiotic chromosomes. By comparing chromosome structure in wild-type and DCC-defective embryos, we show that the DCC remodels hermaphrodite X chromosomes into a sex-specific spatial conformation distinct from autosomes. Dosage-compensated X chromosomes consist of self-interacting domains ( approximately 1 Mb) resembling mammalian topologically associating domains (TADs). TADs on X chromosomes have stronger boundaries and more regular spacing than on autosomes. Many TAD boundaries on X chromosomes coincide with the highest-affinity rex sites and become diminished or lost in DCC-defective mutants, thereby converting the topology of X to a conformation resembling autosomes. rex sites engage in DCC-dependent long-range interactions, with the most frequent interactions occurring between rex sites at DCC-dependent TAD boundaries. These results imply that the DCC reshapes the topology of X chromosomes by forming new TAD boundaries and reinforcing weak boundaries through interactions between its highest-affinity binding sites. As this model predicts, deletion of an endogenous rex site at a DCC-dependent TAD boundary using CRISPR/Cas9 greatly diminished the boundary. Thus, the DCC imposes a distinct higher-order structure onto X chromosomes while regulating gene expression chromosome-wide.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498965/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498965/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Crane, Emily -- Bian, Qian -- McCord, Rachel Patton -- Lajoie, Bryan R -- Wheeler, Bayly S -- Ralston, Edward J -- Uzawa, Satoru -- Dekker, Job -- Meyer, Barbara J -- R01 GM030702/GM/NIGMS NIH HHS/ -- R01 HG003143/HG/NHGRI NIH HHS/ -- S10RR029668/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jul 9;523(7559):240-4. doi: 10.1038/nature14450. Epub 2015 Jun 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California-Berkeley, Berkeley, California 94720-3204, USA. ; Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 368 Plantation Street, Worcester, Massachusetts 01605, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26030525" target="_blank"〉PubMed〈/a〉
Keywords:
Adenosine Triphosphatases/*metabolism
;
Animals
;
Caenorhabditis elegans/*genetics/*metabolism
;
Caenorhabditis elegans Proteins/genetics/*metabolism
;
DNA-Binding Proteins/*metabolism
;
Dosage Compensation, Genetic/genetics/*physiology
;
Female
;
Gene Expression Regulation
;
In Situ Hybridization, Fluorescence
;
Male
;
Multiprotein Complexes/*metabolism
;
Protein Binding
;
Sequence Analysis, RNA
;
X Chromosome/genetics/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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