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The C. elegans dosage compensation complex mediates interphase X chromosome compaction.

Lau AC, Nabeshima K, Csankovszki G - Epigenetics Chromatin (2014)

Bottom Line: In addition, we show that SET-1, SET-4, and SIR-2.1, histone modifiers whose activity is regulated by the DCC, need to be present for the compaction of the X chromosome territory.These results support the idea that condensin I(DC), and the histone modifications regulated by the DCC, mediate interphase X chromosome compaction.Our results link condensin-mediated chromosome compaction, an activity connected to mitotic chromosome condensation, to chromosome-wide repression of gene expression in interphase.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109 Michigan.

ABSTRACT

Background: Dosage compensation is a specialized gene regulatory mechanism which equalizes X-linked gene expression between sexes. In Caenorhabditis elegans, dosage compensation is achieved by the activity of the dosage compensation complex (DCC). The DCC localizes to both X chromosomes in hermaphrodites to downregulate gene expression by half. The DCC contains a subcomplex (condensin I(DC)) similar to the evolutionarily conserved condensin complexes which play fundamental roles in chromosome dynamics during mitosis and meiosis. Therefore, mechanisms related to mitotic chromosome condensation have been long hypothesized to mediate dosage compensation. However experimental evidence was lacking.

Results: Using 3D FISH microscopy to measure the volumes of X and chromosome I territories and to measure distances between individual loci, we show that hermaphrodite worms deficient in DCC proteins have enlarged interphase X chromosomes when compared to wild type. By contrast, chromosome I is unaffected. Interestingly, hermaphrodite worms depleted of condensin I or II show no phenotype. Therefore X chromosome compaction is specific to condensin I(DC). In addition, we show that SET-1, SET-4, and SIR-2.1, histone modifiers whose activity is regulated by the DCC, need to be present for the compaction of the X chromosome territory.

Conclusion: These results support the idea that condensin I(DC), and the histone modifications regulated by the DCC, mediate interphase X chromosome compaction. Our results link condensin-mediated chromosome compaction, an activity connected to mitotic chromosome condensation, to chromosome-wide repression of gene expression in interphase.

No MeSH data available.


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Depletion of the DCC-meditated histone modifiers leads to the loss of X chromosome compaction. (A) Quantification of the percentage of nuclear volume occupied by X in wild type (n = 40), set-1(tm1821) (n = 40), set-4(n4600) (n = 40) and sir-2.1(ok434) (n = 40). Error bars indicate standard deviation. Asterisks indicate level of statistical significance by t-test analysis (three asterisks, P <0.001). (B) Quantification of the percentage of nuclear volume occupied by chromosome I in wild type (n = 40), set-1(tm1821) (n = 20), set-4(n4600) (n = 40), and sir-2.1(ok434) (n = 40). Error bars indicate standard deviation.
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Fig6: Depletion of the DCC-meditated histone modifiers leads to the loss of X chromosome compaction. (A) Quantification of the percentage of nuclear volume occupied by X in wild type (n = 40), set-1(tm1821) (n = 40), set-4(n4600) (n = 40) and sir-2.1(ok434) (n = 40). Error bars indicate standard deviation. Asterisks indicate level of statistical significance by t-test analysis (three asterisks, P <0.001). (B) Quantification of the percentage of nuclear volume occupied by chromosome I in wild type (n = 40), set-1(tm1821) (n = 20), set-4(n4600) (n = 40), and sir-2.1(ok434) (n = 40). Error bars indicate standard deviation.

Mentions: We, and others, previously showed that DCC activity leads to the enrichment of H4K20me1 on the X chromosome by the methyltransferases SET-1 and SET-4 [48, 49]. This activity then leads to the depletion of H4K16ac levels on X, via the deacetylase SIR-2.1 [49]. In order to determine whether these chromatin modifications contribute to compaction of the X, we examined set-1(tm1821), set-4(n4600), and sir-2.1(ok434) mutant worms. Mutations in set-1, set-4, or sir-2.1 led to the loss of X chromosome compaction seen in wild type worms (Figure 6A and Additional file 4: Figure S4). However, chromosome I showed no significant change in volume in these histone modifier mutants (Figure 6B and Additional file 4: Figure S4). Interestingly, the DCC localizes normally to the X in set-1(tm1821), set-4(n4600), and sir-2.1(ok434) worms [48, 49]. Therefore, DCC alone is not sufficient for the compaction of the X chromosome territory. We conclude that X chromosome compaction by the DCC requires the presence of these chromatin modifiers.Figure 6


The C. elegans dosage compensation complex mediates interphase X chromosome compaction.

Lau AC, Nabeshima K, Csankovszki G - Epigenetics Chromatin (2014)

Depletion of the DCC-meditated histone modifiers leads to the loss of X chromosome compaction. (A) Quantification of the percentage of nuclear volume occupied by X in wild type (n = 40), set-1(tm1821) (n = 40), set-4(n4600) (n = 40) and sir-2.1(ok434) (n = 40). Error bars indicate standard deviation. Asterisks indicate level of statistical significance by t-test analysis (three asterisks, P <0.001). (B) Quantification of the percentage of nuclear volume occupied by chromosome I in wild type (n = 40), set-1(tm1821) (n = 20), set-4(n4600) (n = 40), and sir-2.1(ok434) (n = 40). Error bars indicate standard deviation.
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Fig6: Depletion of the DCC-meditated histone modifiers leads to the loss of X chromosome compaction. (A) Quantification of the percentage of nuclear volume occupied by X in wild type (n = 40), set-1(tm1821) (n = 40), set-4(n4600) (n = 40) and sir-2.1(ok434) (n = 40). Error bars indicate standard deviation. Asterisks indicate level of statistical significance by t-test analysis (three asterisks, P <0.001). (B) Quantification of the percentage of nuclear volume occupied by chromosome I in wild type (n = 40), set-1(tm1821) (n = 20), set-4(n4600) (n = 40), and sir-2.1(ok434) (n = 40). Error bars indicate standard deviation.
Mentions: We, and others, previously showed that DCC activity leads to the enrichment of H4K20me1 on the X chromosome by the methyltransferases SET-1 and SET-4 [48, 49]. This activity then leads to the depletion of H4K16ac levels on X, via the deacetylase SIR-2.1 [49]. In order to determine whether these chromatin modifications contribute to compaction of the X, we examined set-1(tm1821), set-4(n4600), and sir-2.1(ok434) mutant worms. Mutations in set-1, set-4, or sir-2.1 led to the loss of X chromosome compaction seen in wild type worms (Figure 6A and Additional file 4: Figure S4). However, chromosome I showed no significant change in volume in these histone modifier mutants (Figure 6B and Additional file 4: Figure S4). Interestingly, the DCC localizes normally to the X in set-1(tm1821), set-4(n4600), and sir-2.1(ok434) worms [48, 49]. Therefore, DCC alone is not sufficient for the compaction of the X chromosome territory. We conclude that X chromosome compaction by the DCC requires the presence of these chromatin modifiers.Figure 6

Bottom Line: In addition, we show that SET-1, SET-4, and SIR-2.1, histone modifiers whose activity is regulated by the DCC, need to be present for the compaction of the X chromosome territory.These results support the idea that condensin I(DC), and the histone modifications regulated by the DCC, mediate interphase X chromosome compaction.Our results link condensin-mediated chromosome compaction, an activity connected to mitotic chromosome condensation, to chromosome-wide repression of gene expression in interphase.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109 Michigan.

ABSTRACT

Background: Dosage compensation is a specialized gene regulatory mechanism which equalizes X-linked gene expression between sexes. In Caenorhabditis elegans, dosage compensation is achieved by the activity of the dosage compensation complex (DCC). The DCC localizes to both X chromosomes in hermaphrodites to downregulate gene expression by half. The DCC contains a subcomplex (condensin I(DC)) similar to the evolutionarily conserved condensin complexes which play fundamental roles in chromosome dynamics during mitosis and meiosis. Therefore, mechanisms related to mitotic chromosome condensation have been long hypothesized to mediate dosage compensation. However experimental evidence was lacking.

Results: Using 3D FISH microscopy to measure the volumes of X and chromosome I territories and to measure distances between individual loci, we show that hermaphrodite worms deficient in DCC proteins have enlarged interphase X chromosomes when compared to wild type. By contrast, chromosome I is unaffected. Interestingly, hermaphrodite worms depleted of condensin I or II show no phenotype. Therefore X chromosome compaction is specific to condensin I(DC). In addition, we show that SET-1, SET-4, and SIR-2.1, histone modifiers whose activity is regulated by the DCC, need to be present for the compaction of the X chromosome territory.

Conclusion: These results support the idea that condensin I(DC), and the histone modifications regulated by the DCC, mediate interphase X chromosome compaction. Our results link condensin-mediated chromosome compaction, an activity connected to mitotic chromosome condensation, to chromosome-wide repression of gene expression in interphase.

No MeSH data available.


Related in: MedlinePlus