Kramer Maxwell, Kranz Anna-Lena, Su Amanda, Winterkorn Lara H, Albritton Sarah Elizabeth, Ercan Sevinc
Department of Biology, Center for Genomics and Systems Biology, New York University, New York, New York, United States of America.
PLoS Genet. 2015 Dec 7;11(12):e1005698. doi: 10.1371/journal.pgen.1005698. eCollection 2015 Dec.
In Caenorhabditis elegans, the dosage compensation complex (DCC) specifically binds to and represses transcription from both X chromosomes in hermaphrodites. The DCC is composed of an X-specific condensin complex that interacts with several proteins. During embryogenesis, DCC starts localizing to the X chromosomes around the 40-cell stage, and is followed by X-enrichment of H4K20me1 between 100-cell to comma stage. Here, we analyzed dosage compensation of the X chromosome between sexes, and the roles of dpy-27 (condensin subunit), dpy-21 (non-condensin DCC member), set-1 (H4K20 monomethylase) and set-4 (H4K20 di-/tri-methylase) in X chromosome repression using mRNA-seq and ChIP-seq analyses across several developmental time points. We found that the DCC starts repressing the X chromosomes by the 40-cell stage, but X-linked transcript levels remain significantly higher in hermaphrodites compared to males through the comma stage of embryogenesis. Dpy-27 and dpy-21 are required for X chromosome repression throughout development, but particularly in early embryos dpy-27 and dpy-21 mutations produced distinct expression changes, suggesting a DCC independent role for dpy-21. We previously hypothesized that the DCC increases H4K20me1 by reducing set-4 activity on the X chromosomes. Accordingly, in the set-4 mutant, H4K20me1 increased more from the autosomes compared to the X, equalizing H4K20me1 level between X and autosomes. H4K20me1 increase on the autosomes led to a slight repression, resulting in a relative effect of X derepression. H4K20me1 depletion in the set-1 mutant showed greater X derepression compared to equalization of H4K20me1 levels between X and autosomes in the set-4 mutant, indicating that H4K20me1 level is important, but X to autosomal balance of H4K20me1 contributes slightly to X-repression. Thus H4K20me1 is not only a downstream effector of the DCC [corrected].In summary, X chromosome dosage compensation starts in early embryos as the DCC localizes to the X, and is strengthened in later embryogenesis by H4K20me1.
在秀丽隐杆线虫中,剂量补偿复合物(DCC)特异性结合并抑制雌雄同体两条X染色体的转录。DCC由一个与多种蛋白质相互作用的X染色体特异性凝聚素复合物组成。在胚胎发育过程中,DCC在40细胞期左右开始定位于X染色体,随后在100细胞期到逗号期之间H4K20me1在X染色体上富集。在这里,我们通过对多个发育时间点进行mRNA测序和ChIP测序分析,研究了X染色体在不同性别间的剂量补偿,以及dpy - 27(凝聚素亚基)、dpy - 21(非凝聚素DCC成员)、set - 1(H4K20单甲基化酶)和set - 4(H4K20二/三甲基化酶)在X染色体抑制中的作用。我们发现,DCC在40细胞期开始抑制X染色体,但在胚胎发育的逗号期之前,雌雄同体中X连锁转录本水平仍显著高于雄性。Dpy - 27和dpy - 21在整个发育过程中对于X染色体抑制都是必需的,但特别是在早期胚胎中,dpy - 27和dpy - 21突变产生了不同的表达变化,表明dpy - 21具有独立于DCC的作用。我们之前推测,DCC通过降低X染色体上set - 4的活性来增加H4K20me1。因此,在set - 4突变体中,与X染色体相比,常染色体上H4K20me1增加得更多,使X染色体和常染色体之间的H4K20me1水平达到平衡。常染色体上H4K20me1的增加导致了轻微的抑制,从而产生了X染色体去抑制的相对效应。与set - 4突变体中X染色体和常染色体之间H4K20me1水平的平衡相比,set - 1突变体中H4K20me1的缺失表现出更大程度的X染色体去抑制,这表明H4K20me1水平很重要,但X染色体与常染色体之间H4K20me1的平衡对X染色体抑制的贡献较小。因此,H4K20me1不仅是DCC的下游效应物[已修正]。总之,X染色体剂量补偿在早期胚胎中随着DCC定位于X染色体而开始,并在后期胚胎发育中通过H4K20me1得到加强。