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• W2958805183 abstract "Report9 July 2019free access Transparent process Progressive dosage compensation during Drosophila embryogenesis is reflected by gene arrangement Khairunnadiya Prayitno orcid.org/0000-0003-2900-7487 Molecular Biology Division, Biomedical Center, Ludwig-Maximilians-University, Munich, Germany Graduate School of Quantitative Biosciences Munich, Ludwig-Maximilians-University, Munich, Germany Search for more papers by this author Tamás Schauer Molecular Biology Division, Biomedical Center, Ludwig-Maximilians-University, Munich, Germany Bioinformatics Unit, Biomedical Center, Ludwig-Maximilians-University, Munich, Germany Search for more papers by this author Catherine Regnard Molecular Biology Division, Biomedical Center, Ludwig-Maximilians-University, Munich, Germany Search for more papers by this author Peter B Becker Corresponding Author [email protected] orcid.org/0000-0001-7186-0372 Molecular Biology Division, Biomedical Center, Ludwig-Maximilians-University, Munich, Germany Search for more papers by this author Khairunnadiya Prayitno orcid.org/0000-0003-2900-7487 Molecular Biology Division, Biomedical Center, Ludwig-Maximilians-University, Munich, Germany Graduate School of Quantitative Biosciences Munich, Ludwig-Maximilians-University, Munich, Germany Search for more papers by this author Tamás Schauer Molecular Biology Division, Biomedical Center, Ludwig-Maximilians-University, Munich, Germany Bioinformatics Unit, Biomedical Center, Ludwig-Maximilians-University, Munich, Germany Search for more papers by this author Catherine Regnard Molecular Biology Division, Biomedical Center, Ludwig-Maximilians-University, Munich, Germany Search for more papers by this author Peter B Becker Corresponding Author [email protected] orcid.org/0000-0001-7186-0372 Molecular Biology Division, Biomedical Center, Ludwig-Maximilians-University, Munich, Germany Search for more papers by this author Author Information Khairunnadiya Prayitno1,2,‡, Tamás Schauer1,3,‡, Catherine Regnard1 and Peter B Becker *,1 1Molecular Biology Division, Biomedical Center, Ludwig-Maximilians-University, Munich, Germany 2Graduate School of Quantitative Biosciences Munich, Ludwig-Maximilians-University, Munich, Germany 3Bioinformatics Unit, Biomedical Center, Ludwig-Maximilians-University, Munich, Germany ‡These authors contributed equally to this work *Corresponding author. Tel: +49 89 2180 75427; Fax: +49 89 2180 75425; E-mail: [email protected] EMBO Rep (2019)20:e48138https://doi.org/10.15252/embr.201948138 PDFDownload PDF of article text and main figures. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract In Drosophila melanogaster males, X-chromosome monosomy is compensated by chromosome-wide transcription activation. We found that complete dosage compensation during embryogenesis takes surprisingly long and is incomplete even after 10 h of development. Although the activating dosage compensation complex (DCC) associates with the X-chromosome and MOF acetylates histone H4 early, many genes are not compensated. Acetylation levels on gene bodies continue to increase for several hours after gastrulation in parallel with progressive compensation. Constitutive genes are compensated earlier than developmental genes. Remarkably, later compensation correlates with longer distances to DCC binding sites. This time–space relationship suggests that DCC action on target genes requires maturation of the active chromosome compartment. Synopsis Dosage compensation to overcome X chromosome monosomy in Drosophila is established progressively during embryo development. Gradual dissemination of the active H4K16ac mark from DCC binding sites suggests that maturation of the X chromosome compartment is required for this process. Although MSL2 and MOF already target the X chromosome early in development, only partial dosage compensation is detected in the transcriptome. The extent of H4K16 acetylation on active gene bodies increases with time and correlates with better dosage compensation. Genes closer to MSL2 binding sites, which are mostly constitutive genes, are compensated faster than those farther away, which are mostly developmental genes. Introduction Dosage compensation (DC) is a regulatory mechanism that evolved to ensure balanced sex-chromosomal gene expression in sexually dimorphic species. In Drosophila melanogaster, where males are denoted as XY and females as XX, this adjustment is achieved by an approximately twofold activation of transcription of X-chromosomal genes in male organisms. In cases where DC fails, male-specific lethality is observed 1. This coordinated and chromosome-wide process is carried out by the male-specific lethal (MSL) dosage compensation complex (DCC), which consists of five protein subunits, MSL1, MSL2, MSL3, maleless (MLE), and males absent on the first (MOF), as well as long non-coding RNA, RNA on the X (roX1/roX2) 12. This ribonucleoprotein complex decorates the single male X-chromosome exclusively to enhance chromatin accessibility and transcription 34. How DCC targets the male X-chromosome is of great interest and serves as an example for chromosome-wide regulation. Key to targeting of the X are genetically encoded DCC binding sites, which are termed chromosomal entry sites (CES; 56) or high-affinity sites (HAS; 78). DCC is targeted to the X through its DNA binding subunit, MSL2 910, which cooperates with the ubiquitous CLAMP protein for tight binding to so-called MSL response elements (MREs) 1112. According to the current model, DCC “spreads” from HAS to transcriptionally active genes in the nuclear vicinity 12. Active genes are marked epigenetically by histone H3 trimethylation at lysine 36 (H3K36me3), which is recognized by MSL3 via its chromo barrel domain 1314. Long-range DCC interactions are guided by the three-dimensional chromosome topology within the active compartment 1516. Upon binding and spreading of the complex on the X-chromosome, the crucial function of DCC is initiated: H4K16 acetylation by the acetyltransferase MOF. Enrichment of H4K16ac on the X-chromosome weakens packing of the chromatin fiber 17 and renders chromatin open for more efficient transcription 1819. The establishment of DC during early embryonic development hinges on the expression of the only male-specific protein of the complex, MSL2, which is repressed in females by the master regulator gene sex-lethal (Sxl) 12. In the presence of MSL2 and at least one of the two male-specific roX RNAs 2021, DCC assembles. Nuclear localization of MSL proteins has been first observed at blastoderm stage 6 and its enrichment in X-chromosomal compartment at stage 9 2223. The first wave of zygotic transcription starts at least an hour earlier, at stage 4 24, and seems to be partially compensated, presumably by a generic, DCC-independent mechanism 2526. In our current study, we integrate a transcriptome analysis (RNA-seq) of single embryos during the 12 h of development representing embryonic stages 4–15, with high-resolution chromatin immunoprecipitation profiling (ChIP-seq) of MSL2, MOF, H4K16ac, and H3K36me3 at two time windows that allow monitoring of the progress of dosage compensation. To our surprise, we find only partial dosage compensation of genes between stages 5–8, about 3–4 h into embryonic development, despite robust detection of DCC binding and H4K16ac deposition at this time. However, the extent of H4K16 acetylation on the bodies of active genes increases with time and correlates with full dosage compensation, illustrating that the distribution of the activating acetylation to target genes rate limits dosage compensation. Interestingly, constitutive genes on the X-chromosome that are compensated earlier tend to be located closer to HAS than developmental genes, which require more time for full compensation. Conceivably, this signifies evolution of HAS closer to genes that require robust dosage compensation early during development. Results and Discussion Dosage compensation of the X-chromosomal transcription progresses gradually during embryogenesis To track dosage compensation of the X-chromosome during embryogenesis, we sorted single D. melanogaster embryos to developmental stages based on morphological features 27 and determined their transcriptome by RNA-seq (Table EV1). Principal component analysis (PCA) on 54 single embryonic transcriptomes confirmed the precision and reproducibility of the sorting (Fig 1A). The first principal component (PC1) categorizes embryos into distinct consecutive clusters based on their developmental stage, whereas PC2 delineates the onset of zygotic transcription. Furthermore, through assessment of sex-specific gene expression (i.e., Sxl, msl-2, roX1, and roX2), we unequivocally assigned sex to each embryo and ascertained that both sexes are represented in each developmental stage cluster (Table EV1). Figure 1. Dosage compensation is progressively established during embryonic development Principal component analysis (PCA) of RNA-seq data derived from 54 single embryos in eight developmental stages. X-axis shows the first (PC1) and y-axis the second (PC2) principal component. The variance explained by each component is indicated in parenthesis. Morphological stages are differentially colored and described in Table EV1 27. Ratio of X-chromosomal over autosomal median transcript abundances (X/A) of preblastoderm (PB), female, and male embryos in seven developmental stages. Each data point is a single embryo. A ratio of one represents balanced transcript levels between the X-chromosome and autosomes (dotted horizontal line). Log2 fold change (log2FC) of RNA-seq between female (F) and male (M) embryos of expressed genes on X-chromosome (X, left, total = 1,515) and on autosomes (A, right, total = 7,451) in seven developmental stages. Log2 fold change (log2FC) of RNA-seq between female (F) and male (M) embryos of X-chromosomal genes which are constitutively (left, total = 303) or developmentally expressed (right, total = 303) in seven developmental stages. Data information: Horizontal lines indicate median value, box ranges denote interquartile range (IQR), and whiskers mark ±1.5x IQR. P-values (pval) are calculated by one-sample Wilcoxon signed-rank test to assess the median log2FC values against zero (balanced expression); ns: non-significant (P-value > 0.001). Download figure Download PowerPoint We determined transcript abundances as log2 transcript per million (TPM) and compared the X-chromosome (X) to autosomes (A) (Fig EV1A). This shows an increase in median transcript levels between stages 4 and 15 (between 1.5 and about 12 h of development, Table EV1). At any given time, median autosomal transcript levels are similar in both sexes, showing an equivalent rate of genome activation in both sexes (Fig EV1A). Plotting the ratio of X-chromosomal over autosomal median transcript levels, for which a ratio of one indicates balanced X and A levels, revealed that maternal transcripts are biased for X-chromosomal expression (Fig 1B). Upon zygotic genome activation (from stage 5 onwards), the X/A ratio drops in both, females and males. In females, the ratios approximate 1, indicating a near-balanced expression of all chromosomes. Interestingly, the arch-shaped profile suggests some fine-tuning of X to A balance even in females. In male embryos, the ratio of X/A expression drops dramatically at stages 5–6, revealing that the first zygotic transcription is not yet fully compensated. During the course of the next 10 h of embryonic development, the X/A ratio in males slowly approximates 1, reflecting the progression of dosage compensation. Click here to expand this figure. Figure EV1. Dosage compensation dynamics of the X-chromosomal transcriptome during embryonic development (related to Fig 1) Log2 TPM (transcript per million, RNA-seq) levels of X-chromosomal (X) and autosomal (A) genes in preblastoderm (PB), female (F), or male (M) embryos in eight developmental stages. Horizontal lines indicate median value, box ranges denote interquartile range (IQR), and whiskers mark ±1.5x IQR. The number of embryos used for each stage analysis can be found on Table EV1. Log2 TPM (RNA-seq) levels of genes which were used for k-means clustering to determine the sex of the embryos (top), genes which encode non-sex-specific DCC subunits (middle) and additional genes related to dosage compensation (bottom). Western blot showing protein levels of DCC subunits in stages 5–8 and 13–15. Heatmaps of log2 TPM (RNA-seq) values for X-chromosomal constitutive (left) and developmental (right) genes. Genes are grouped by the variance across all developmental stages; i.e., constitutive as 20% least and developmental as 20% most variable. Gene Ontology (GO) of gene groups is on Table EV2. Log2 fold change (log2FC) of RNA-seq between female and male embryos for autosomal genes (A) which are constitutively (top, total = 1,474) or developmentally expressed (bottom, total = 1,474) in seven developmental stages. Horizontal lines indicate median value, box ranges denote interquartile range (IQR), and whiskers mark ±1.5x IQR. Download figure Download PowerPoint To avoid any possible bias from analyzing different sets of X-chromosomal and autosomal genes and to measure dosage compensation on a gene-by-gene basis, we calculated log2 fold changes of transcript abundance between female (F) and male (M) embryos for each gene. Average value of 0 indicates equal transcript levels originating from the single male X and the two female X-chromosomes, and thus corresponds to full dosage compensation, whereas a value of 1 implies a total lack of dosage compensation (2-fold more female than male transcripts). Expectedly, autosomal transcript levels are comparable at all stages (Fig 1C). As previously shown, a log2 fold change of 1 is never observed for X-chromosomal transcripts, indicating some compensation happens early 25. We were surprised, however, to find high ratios of female over male X expression at stages 6–8, indicating that dosage compensation is incomplete even ~ 4 h into development. In the following hours, male X expression becomes gradually balanced (Fig 1C). Nonetheless, full compensation is not reached by the latest timepoint of our analysis (stage 15, ~ 12 h of development). The lag in compensation in early stages may be explained by insufficient DCC components; therefore, we compared transcript abundances of the MSL and SXL genes. Noticeable increase in SXL and MSL2 transcripts is seen upon maternal to zygotic transition with the expected sex-specific bias (Fig EV1B top). Since the expression of both is regulated translationally, it is not surprising to detect transcripts of MSL2 in female embryos, and, conversely, SXL transcripts in males. As reported before, roX1 is transcribed in both sexes up to stage 12, from which point onwards it is male-specific 2021. Furthermore, male-specific roX2 RNA transcription begins at stage 10 and loosely mirrors the profile of gradual male X compensation 20. Of note, mRNAs of all DCC subunits except for MSL2, namely MSL1, MSL3, MLE, and MOF, were found maternally contributed and stably expressed in both sexes (Fig EV1B). Utilizing a fly line in which sex sorting can be done, protein levels of DCC subunits were confirmed by Western blot (Fig EV1C). Constitutive genes are compensated early, developmental genes later As a first step toward discovering possible reasons for the observed heterogeneity of dosage compensation during embryogenesis, we defined within our RNA-seq dataset constitutive genes as the 20% least varied and developmental genes as the 20% most varied transcripts through all developmental stages, regardless of sex (Fig EV1D). To ensure that genes were appropriately classified, we analyzed the gene ontology (GO) terms for each category. Consistent with our definition, those genes characterized as constitutive function in cellular processes such as transcription and translation, and those termed developmental are involved in processes such as anatomical, tissue, and organ development (Table EV2). Interestingly, X-chromosomal genes defined as constitutive are fully compensated by stage 15 and genes classified as developmental are compensated slower (Fig 1D), whereas developmental and constitutive genes on autosomes are expressed equally in both sexes (Fig EV1E). We proceeded to explore the reasons for delayed dosage compensation of developmental genes. Chromatin binding of MSL2 precedes complete dosage compensation Previous immunofluorescence microscopy (IFM) analyses had identified the colocalization of MSL proteins on X-chromosomal territory at stage 9 22. Since we found dosage compensation incomplete at this stage, we revisited the IFM analysis. In line with earlier report, we failed to detect localized MSLs in embryos at blastoderm stage 5. This is likely due to a combination of low protein levels and the decondensation of chromosomes 28, leading to a distribution of signal below detection limits. Even in a stage 8 embryo, MSL staining in interphase nuclei is difficult to detect, perhaps indicating that coherent territories are not formed yet (Appendix Fig S1A). However, concentrated staining on mitotic chromosomes allows a clear identification of X-chromosomal staining at stage 8, and by stage 14, focal colocalization of MSL3 and MSL2 was seen in all nuclei (Appendix Fig S1A). Is the delayed dosage compensation due to incomplete DCC binding to the X or due to a functional deficit, such as inefficient distribution to active genes or low histone acetylation activity? Because IFM is limited in sensitivity and resolution, we resorted to chromatin immunoprecipitation (ChIP), monitoring MSL2 and MOF distribution along the chromosome as a proxy for DCC interactions and H4K16 acetylation on gene bodies as an indicator for DCC activity. We optimized a protocol to generate high-resolution chromatin interaction profiles combining micrococcal nuclease (MNase) digestion with ChIP followed by sequencing of enriched DNA (ChIP-seq). We chose MNase digestion for chromatin fragmentation instead of sonication to preserve the integrity of the DCC and allow crosslinking of the complex at both HAS and active gene bodies 8. Two time windows during embryogenesis were chosen based on our RNA-seq: the first encompassing stages 5–8, where dosage compensation is least measured in male, and the second covering stages 13–15, where compensation of the constitutive genes was achieved. Our embryo staging was verified by monitoring the H3K36me3 profiles of suitable developmental indicator genes through ChIP-qPCR (Appendix Fig S1B, see Table EV3 for primers). We also monitored the ChIP efficiency of specific antibodies through qPCR of known targets by measuring enrichment over X-chromosomal HAS for MSL2 and gene body enrichment of active X-linked genes for MOF and H4K16ac (Appendix Fig S1C). To characterize the direct DNA binding of MSL2, DNA fragments from paired-end sequencing runs were computationally subset to sizes between 10 and 130 bp, i.e., sub-nucleosomal length, since it has been previously shown that HAS are nucleosome-free 812. For clarity, we refer to those binding events as direct “DNA” binding (Fig 2A). Interestingly, we found robust MSL2 enrichment at PionX sites 10 and HAS 8 during both developmental time windows (Fig 2B). MSL2 binds its target sequences already at times when compensation is least established. Conceivably, the interactions with active genes, which are not genetically encoded but epigenetically determined by H3K36me3 binding, may be weak in stages 5–8. Crosslinking of MSL2 (directly or indirectly via MSL3) to chromatin can be used as a measure for these interactions. We therefore analyzed interaction of MSL2 with nucleosomes defined as DNA fragments of lengths between 130 and 220 bp and referred to them as “chromatin” binding henceforth (Fig 2A). We observed MSL2 interaction with the nucleosomes neighboring HAS, but also with chromatin within a region of up to ~ 4 kb surrounding HAS (Fig 2C). To expand the analysis genome-wide, we called peaks for each time window (Dataset EV1) and confirmed that ChIP enrichment is concordant across replicates (Fig EV2A). Figure 2. Binding of MSL2 to high-affinity sites is established in early embryonic stages Example genomic region of MSL2 MNase-ChIP-seq profiles in early (stages 5–8, orange) and late (stages 13–15, purple) mixed-sex embryos. DNA binding is defined as sub-nucleosomal fragments (10–130 bp), while chromatin binding as mono-nucleosomal fragments (130–220 bp). Called peaks/regions (Dataset EV1) are represented as boxes above the tracks and HAS below. Late-appearing regions are marked by a plus (+) sign. Graph represents pooled IP/input signal of three biological replicates. Average composite plots of sub-nucleosomal MSL2 MNase-ChIP-seq (DNA) centered at PionX (left) or HAS (right) in early and late mixed-sex embryos. Total number of PionX = 56 and HAS = 247. Graph represents average IP/input signal of three biological replicates. Shaded area indicates the 95% confidence interval across sites. Average composite plots of mono-nucleosomal MSL2 ChIP-seq (Chromatin) centered at PionX (left) or HAS (right) in early and late mixed-sex embryos. Download figure Download PowerPoint Click here to expand this figure. Figure EV2. Binding of MSL2 to high-affinity sites and formation of broad MSL2 regions are established in early embryonic stages (related to Fig 2) Pearson correlation heatmaps of MSL2 MNase-ChIP-seq profiles at DNA peaks (left) and chromatin regions (right) for three biological replicates at two timepoints. Relative chromosomal distribution of MSL2 DNA peaks as defined in Fig 3A and B. Peaks which do not overlap (top) or overlap MSL2 chromatin regions (mid) and MSL2 chromatin regions which do not overlap MSL2 DNA peaks (bottom) are shown on the left. Relative chromosomal distribution of HAS and chromosome sizes are shown on the right. Number of sites is indicated in parentheses. De novo motif analysis of MSL2 DNA peaks of the same categories in (B). The most significant motif is shown. Size distribution of MSL2 chromatin regions (n = 215 and 231, respectively) present in both early (stages 5–8) and late (stages 13–15) embryos. Horizontal lines indicate median value, box ranges denote interquartile range (IQR), and whiskers mark ±1.5x IQR. P-value (Wilcoxon rank sum test) is indicated. Log10 distance between the middle of an MSL2 chromatin region and its nearest functional MSL2 DNA peak. Left: early (n = 212) and right: late (n = 87) regions as defined in Fig 3C. Red line indicates median distance to the nearest peak. Download figure Download PowerPoint Systematic comparison of “DNA” and “chromatin” interactions revealed three classes. First, 139 MSL2 DNA binding events reside within regions of chromatin binding (Figs 2A, and 3A and B). These regions are highly enriched on the X (Fig EV2B) and often contain a DNA sequence motif very similar to the known MRE motif (Fig EV2C). Conceivably, many of these sites represent HAS that are known to often reside in introns 815. Second, we observed 202 isolated MSL2 DNA binding events that are not associated with neighboring chromatin interactions (Figs 2A, and 3A and B). Many of these sites reside on autosomes (Fig EV2B) and do not always contain the typical GAGA-rich sequences of MRE (Fig EV2C). The lack of nucleosome association implies the absence of the MSL3 “reader”. As these attributes suggest a non-functional binding of MSL2 to DNA, we omitted them from further analysis. Third, we found 199 chromatin binding regions that do not contain a detected DNA binding site (Figs 2A, and 3A and B). These regions may well reflect the longer-range interactions of a remote HAS with an active gene facilitated by chromosome conformation 16. To explore the developmental kinetics of MSL2 “chromatin” binding, we classified each region, averaging at 4 kb (Fig EV2D), according to whether MSL2 binds early (stages 5–8) and stays, or whether it associates with the region only late (stages 13–15; Figs 2A and 3C). Interestingly, the delayed chromatin binding of MSL2 correlates with a longer chromosomal distance to the nearest peak of MSL2 DNA binding (Fig EV2E). Figure 3. MSL2 binds broad chromatin regions in early embryonic stages Venn diagram showing the overlap of sub-nucleosomal MSL2 DNA peaks and mono-nucleosomal MSL2 chromatin regions. Average composite plots of MSL2 [Chromatin] profiles (stages 5–8, orange and stages 13–15, purple) centered at MSL2 DNA peaks which do not overlap (DNA) or overlap MSL2 chromatin regions (DNA + Chromatin), and MSL2 chromatin regions which do not overlap MSL2 DNA peaks (Chromatin). Graphs represent average IP/input signal of three biological replicates. Shaded area indicates the 95% confidence interval across sites. Average composite plots of MSL2 [Chromatin] profiles centered at MSL2 chromatin regions called in both early and late (left) or only in late stages (right). Graphs represent average IP/input signal of three biological replicates. Shaded area indicates the 95% confidence interval across regions. Total number of early = 212 and late = 87. Average composite plots of MOF [Chromatin] profiles centered at MSL2 chromatin regions called in both early and late (left) or only in late stages (right). Download figure Download PowerPoint MOF-dependent H4K16ac accumulates on X-chromosomal target genes during embryogenesis Contrary to our expectation, we had found robust DNA binding and widespread chromatin contacts of MSL2 already in embryonic stages 5–8, when dosage is least compensated. We wondered whether the developmental delay of compensation may be explained by incomplete DCC assembly and absence of the histone acetyltransferase (HAT) MOF or by a functional restraint of the complex, characterized by reduced HAT activity. To distinguish between those possibilities, we performed high-resolution MOF and H4K16ac ChIP-seq on the same soluble chromatin as previously (Appendix Fig S1C; Fig 4A) in three biological replicates (Fig EV3A). We detected robust binding of MOF at MSL2-bound PionX sites and HAS (Fig EV3B), with interesting differences. First, monitoring small ChIP fragments, we do not recover sharp peaks as for MSL2 (Fig EV3B), in agreement with the earlier finding that MOF does not contact DNA directly, but only via MSL2/MSL3 8. Second, while the breadth of the region of MOF crosslinking aligns nicely with MSL2 interactions and does not change as development proceeds (Figs 3D, and 4A and B, Dataset EV2), crosslinking intensifies both around HAS (Fig EV3B) and on gene bodies (Fig 4C). Increased crosslinking at HAS may indicate the ongoing assembly of functional DC complexes, whereas crosslinking at gene bodies may reflect the refinement of X-chromosome conformation (see below). Figure 4. MOF-dependent H4K16ac accumulates at X-chromosomal gene bodies during embryonic development Example genomic region of DNA binding by MSL2 (DNA), and chromatin binding of MSL2 (Chrom.), MOF, and H4K16ac MNase-ChIP-seq profiles in early (stages 5–8, orange) and late (stages 13–15, purple) mixed-sex embryos. Called peaks/regions (Datasets EV1 and EV2) are represented as boxes above the tracks. Graph represents pooled IP/input signal of three biological replicates. Size distribution of X-chromosomal MOF and H4K16ac regions, which are present in both early and late embryos. Horizontal lines indicate median value, box ranges denote interquartile range (IQR), and whiskers mark ±1.5x IQR. P-value (Wilcoxon rank sum test) is indicated. Total number of regions is 459, 443, 854, and 400, respectively. Average composite plots of MOF MNase-ChIP-seq centered at transcription start site (TSS) or transcription termination site (TTS) in early or late embryos for X-chromosomal genes (total = 1,515). Graph represents average IP/input signal of three biological replicates. Shaded area indicates the 95% confidence interval across sites. Average composite plots of H4K16ac MNase-ChIP-seq centered at TSS or TTS in early or late embryos for X-chromosomal genes (total = 1,515). Download figure Download PowerPoint Click here to expand this figure. Figure EV3. MOF interaction with chromatin during embryonic development leads to accumulation of H4K16ac on the X-chromosome (related to Fig 4) Pearson correlation heatmaps of MOF (left) and H4K16ac (right) MNase-ChIP-seq profiles at X-chromosomal genes for three biological replicates at two timepoints. Average composite plots of sub-nucleosomal (“DNA”, left) and mono-nucleosomal (Chromatin, right) MOF MNase-ChIP-seq centered at PionX or HAS in early (stages 5–8, orange) and late (stages 13–15, purple) mixed-sex embryos. Total number of PionX = 56 and HAS = 247. Graph represents average IP/input signal of three biological replicates. Shaded area indicates the 95% confidence interval across sites. Average composite plots of H4K16ac MNase-ChIP-seq profiles centered at MSL2 chromatin regions called in both early and late (left) or only in late stages (right). Graph represents average IP/input signal of three biological replicates. Shaded area indicates the 95% confidence interval across sites. Total number of early = 212 and late = 87. Average composite plots of MOF and H4K16ac MNase-ChIP-seq centered at TSS or TTS in early or late embryos for autosomal genes (total = 7,451). Graph represents average IP/input signal of three biological replicates. Shaded area indicates the 95% co" @default.
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• W2958805183 title "Progressive dosage compensation during<i>Drosophila</i>embryogenesis is reflected by gene arrangement" @default.
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