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. 2007 Mar;39(3):403-8.
doi: 10.1038/ng1983. Epub 2007 Feb 11.

X chromosome repression by localization of the C. elegans dosage compensation machinery to sites of transcription initiation

Sevinc Ercan  1 , Paul G Giresi, Christina M Whittle, Xinmin Zhang, Roland D Green, Jason D Lieb
Affiliations

X chromosome repression by localization of the C. elegans dosage compensation machinery to sites of transcription initiation

Sevinc Ercan et al. Nat Genet. 2007 Mar.

Abstract

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 males. 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). We observed strong foci of DCC binding on X, surrounded by broader regions of localization. Binding foci, but not adjacent regions of localization, were distinguished by clusters of a 10-bp DNA motif, suggesting a recruitment-and-spreading mechanism for X recognition. The DCC was preferentially bound upstream of genes, suggesting modulation of transcriptional initiation and polymerase-coupled spreading. Stronger DCC binding upstream of genes with high transcriptional activity indicated a mechanism for tuning DCC activity at specific loci. These data aid in understanding how proteins involved in higher-order chromosome dynamics can regulate transcription at individual loci.

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Figures

Figure 1
Figure 1. High-resolution localization of the DCC authenticates binding at putative recruitment elements and reveals new targets
(A) Raw log2 ratios (ChIP/Input) from each of three SDC-3 ChIP replicates plotted along 25 kb of the X chromosome, with gene annotations below. Arrows indicate direction of transcription. A previously identified recruitment element on X (rex-1) downstream of dpy-23 is indicated in pink. (B) Same as (a), but a DPY-27 ChIP (C) Same as (a), but a no antibody control ChIP. (D) SDC-3 localization at the her-1 locus. Introns are indicated by thin lines connecting exons. (E) Same as (d), but for DPY-27. Lower levels of DPY-27 localization are observed at her-1, consistent with the lower requirement indicated by genetic data. (F) Sequence-specific ChIP analysis of rex-1, two newly identified DCC binding foci on X (near B0302.2 and R11.4) and a reference region on chromosome I (K07G5.3).
Figure 2
Figure 2. SDC-3 and DPY-27 bind specifically to the X with distinct modes of distribution
(A) Median z scores of enrichment (calculated from ChIP/Input signals) following ChIP using antibodies to SDC-3, DPY-27 and a no antibody control, plotted along a 5 MB region from the left end of X. (B) Same as (a), plotted along a 5 MB region of chromosome II. (C-E) Histograms of the distribution of z-score ChIP enrichment values of individual probes for autosomes and X chromosomes. (C) SDC-3 ChIP, (D) DPY-27 ChIP and (E) a no antibody control ChIP.
Figure 3
Figure 3. A distinct class of DCC localization foci along X
(A) The distribution of maximum amplitudes (z-score) for SDC-3 ChIP peaks. Peaks classified as “Foci” are indicated by brackets (> 2 standard deviations from mean of the distribution). (B) Same as (a) for DPY-27. (C) Distribution of SDC-3 foci and DPY-27 foci along X. (D) Peaks classified as foci were aligned by their maxima, and the rate of signal decline was measured by sliding a window (width of 3 probes, step size of 1 probe) away from the maximum in both directions.
Figure 4
Figure 4. A stereotypic 10 bp DNA sequence motif is enriched in foci of DCC binding
(A) DNA sequence motifs derived from foci of SDC-3 and DPY-27 binding, depicted by sequence logos. (B) DCC binding and motif occurrence at rex-1. Median z scores are plotted with respect to the chromosome coordinates for SDC-3, DPY-27, and no antibody control ChIPs. Locations of the 10-bp motifs are depicted with red tick marks, with longer marks indicating better matches to the consensus motif (MatrixScan p ≤ 10−5) than shorter marks (MatrixScan p ≤ 10−4). The location and sequence of a 33-bp fragment of rex-1 competent for DCC recruitment is shown below. In this fragment, the motif we identify spans two previously characterized motifs (7-bp A and 8-bp B), which were derived from four rex sites. The ChIP data suggest the previously reported “B” motif (TGTAATTG) plays a weak role, if any, in DCC recruitment on natural chromosomal substrates (Supplementary Figure 5). (C) DCC binding and motif occurrence near xol-1. Longer marks indicate better matches to the consensus motif (MatrixScan p ≤ 10−6) than shorter marks (MatrixScan p ≤ 10−5).
Figure 5
Figure 5. The DCC preferentially binds upstream of genes and is positively correlated with transcriptional activity
(A) Data was centered (coordinate 0) according to the predicted translation start sites of each X-linked gene, and the average z score of the probes in a sliding window (width 3 probes, step size 1 probe) was plotted, taking into account the direction of transcription. Translation start sites were used as a proxy for transcription start sites because they are much better-annotated. (B) Translation start sites of X-linked genes located at the start (solid, 56 genes) or inside (hatched, 69 genes) of an operon were centered. As in panel A, DCC binding is plotted as a function of distance from translation start site. (C) A moving average of DCC ChIP enrichment (performed in embryos) plotted as a function of embryonic transcript level of the downstream gene. The positive correlation between embryonic DCC binding and embryonic transcription persisted when RNA measurements from a second publication were utilized (Supplementary Figure 4C). (D) As in panel C, except adult RNA levels are used. Additionally, as expected, DCC binding was not correlated with male- or hermaphrodite-specific expression (Supplementary Figure 4D).
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Comment in

  • Think globally, act locally.
    Reinke V. Reinke V. Nat Genet. 2007 Mar;39(3):287-9. doi: 10.1038/ng0307-287. Nat Genet. 2007. PMID: 17325676 No abstract available.

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