Jukam D , Kapoor RR , Straight AF , Skotheim JM .

R01 HD085135 NICHD NIH HHS , F32 GM108295 NIGMS NIH HHS

	Graphical Abstract
	Figure 1. Xenopus hybrid and cybrid embryos have a 3-fold difference in DNA per cell (A) Experiment schematic. Xenopus laevis has ∼2× more DNA than Xenopus tropicalis. X. laevis eggs fertilized with X. tropicalis sperm generate hybrid embryos. UV irradiation destroys the genome in X. laevis eggs so that fertilization results in cybrid (cytoplasmic hybrid) embryos containing 3-fold less DNA per cell than hybrids. The X. laevis maternal environment and X. tropicalis genome template for RNA expression are identical in both conditions. (B) Representative interphase nuclei from hybrid and cybrid embryos, stained to visualize DNA (DAPI) and centromeres (antibodies against CENP-A). The interphase centromere number equals the chromosome number. Scale bar represents 5 μm. (C) Graph of chromosome counts in hybrid and cybrid. Each point represents one nucleus, and each cluster is a different embryo. The chromosome number decreases from ∼28 in hybrids to ∼10 in cybrids. The nucleus with 20 chromosomes in cybrid-embryo-1 was in mitosis with the expected double X. tropicalis chromosome complement. (D) Schematic depicting the developmental timeline of early Xenopus embryo development. Gray rectangles, cleavage cell division. The MBT (yellow) occurs at the ∼12th cell division (4,000-cell stage), corresponding to Nieuwkoop and Faber (NF) morphological stage 8.5. Dashed lines after divisions 12–14 indicate loss of cell division synchrony. Purple triangles indicate embryo collection time for the transcriptomic time series.
	Figure 2. Identification of zygotically expressed X. tropicalis genes in hybrids (A) Heatmap of defined zygotic X. tropicalis gene expression in hybrids across the MBT. Genes were hierarchically clustered across time points by their log2-normalized expression. Color value scale represents min (expression = 0, dark blue), mean (exp = 10), and max (exp = 20, dark orange) expression. Expression values in all figures are ERCC-spike-in normalized gene counts unless otherwise noted (see STAR Methods). (B) Scatterplot showing gene expression for X. tropicalis ZGA genes (red) and remaining genes (gray). Expression counts are compared before and after the MBT, at 5.5 (y axis) and 9.5 (x axis) h post-fertilization (hpf), respectively. Each point represents one gene. The first X. tropicalis transcript expressed, miR-427, is purple. Dashed diagonal line is X = Y. (C) Scatterplot of gene count centroids (mean X and mean Y) from each time point for the 595 ZGA genes, for all common time points from two biological replicates. Axes display log2-normalized counts. Dashed line is the linear fit. (D) Genome browser images of expression signal (spike-in normalized read counts; y axis) for 5 representative X. tropicalis ZGA genes, with replicates 2 and 3 merged. Intronic signal likely represents nascent transcription. The znf44 9.5 hpf y axis is scaled 6-fold higher to display the complete intron-exon signal (gray asterisk). The eef1a1o 9.5 hpf y axis is scaled to match earlier time points, and the expression signal is truncated. (E) Expression time course profiles for individual ZGA genes. Points are overlaid with a lowess fit (purple line) and standard error of the fit (purple shading). (F) Time course profiles for every defined ZGA gene in hybrids. A composite lowess fit (thick black line) and standard error of the fit (purple shading) to all genes are overlaid. Individual colors represent a single gene (N = 595).
	Figure 3. Embryos with less DNA have less zygotic gene expression specifically at the MBT (A) Scatterplot of expression values for all genes before the MBT at 5.5 hpf. In (A)–(C): 595 ZGA genes (red); all other genes (gray); ZGA gene density shown on right and top; X- and Y-axes show log2(counts) of spike-in normalized RNA-seq gene counts. (B) Hybrid versus cybrid gene expression values at the MBT, at 8.0 hpf. (C) Hybrid versus cybrid gene expression values after the MBT, at 9.5 hpf. (D) Cumulative distribution of log2(cybrid − hybrid) fold change values of each ZGA gene’s expression, before the MBT (5.5 hpf), at the MBT (8.0 hpf), and after the MBT (9.0 hpf). Negative values are consistent with delayed expression in cybrids relative to hybrids. Red line is defined X. tropicalis ZGA genes only; black line is X. laevis genes (two-sided Kolmogorov-Smirnov test: D = 0.32 [5.5 hpf]; D = 0.69 [8.0 hpf]; D = 0.22 [9.5 hpf]; p < 10−10 for all; N = 595). (E) Violin plot of fold changes for each ZGA gene’s expression in cybrid relative to hybrid embryos. Box inside shows mean 1st and 3rd quartiles. Hybrid embryos are the reference, so a decreased fold change indicates decreased expression in cybrids. Fold changes are population means of every ZGA gene’s log2-normalized fold change mean from 2 or 3 replicates (N = 595). (F) Schematic of fold change approach to compare transcriptomic time series data. (G) Distribution of log2-normalized fold changes of each ZGA gene’s expression in cybrid versus hybrid embryos, with genes binned according to expression level deciles. Expression level is per gene mean across all time points. Highest expression decile in purple, lowest in dark red (N = 595). (H) Violin plot of fold changes for each ZGA gene’s expression in cybrid relative to hybrid embryos using only the intron signal. Graph parameters identical to (E) (N = 1,899).
	Figure 4. Decreased DNA per cell leads to delayed ZGA gene activation (A) Smoothing spline fit (black line) of hybrid embryo RNA-seq time series for example ZGA gene. Black dots denote mean-normalized expression values at each time point. Blue dashed line denotes the estimated “activation point.” One replicate is shown as representative. Schematic below displays activation time approach to compare transcriptomic time series data. (B) Curve fit and estimated activation times for example ZGA genes in hybrid and cybrid embryos. Time difference between dashed lines (cybrid − hybrid) = activation time difference or ΔtAct. One replicate is shown as representative. (C) Violin plot of mean activation time for each gene over two replicates in hybrids and cybrids. Boxplot in center shows median and 1st and 3rd quartiles. ∗∗∗∗p << 10−10 (paired sample t test w/Bonferroni correction; N = 547). (D) Cumulative distribution of the activation time difference (h) between cybrids and hybrids (N = 547). (E) Relationship between ΔAct and maximum expression for each gene. Values were binned and smoothed over a 30-min sliding window. Light blue is standard error. Replicate 3 is shown as representative.
	Figure 5. DNA content regulates cell-cycle duration and transcription per genome accelerates through the MBT (A) Cybrid embryos display early cell cycle lengthening as compared to hybrid embryos. Boxplot shows mean inter-cleavage periods for single cells during embryogenesis. Values are taken from movie (see STAR Methods). Box edges are 25th and 75th percentiles; centerline is median. Whiskers include all non-outlier points; dots are outliers. NS, not significant or p > 0.01 between hybrids and cybrids; ∗p = 0.0012 for this sample; ∗∗∗p < 0.001; ∗∗∗∗p < 0.0001 between hybrids and cybrids in the same cell cycle (two-tailed t test with unequal variance). (B) Line plot showing estimated genome copy number for hybrids and cybrids. Data are calculated and extended from inter-cleavage division times in (A). Cybrid embryos contain more cells post-MBT due to having 1 to 2 additional rapid cleavage divisions. (C) Scatterplot comparing activation time, tAct, and genome template number normalized activation time, tAct-TPG, for each ZGA gene. Pearson correlation, r = 0.80 (replicate 2; N = 570) and r = 0.70 (replicate 3; N = 538). tAct-TPG values were calculated from the genome-normalized time series using the smoothing spline fit approach as in Figure 4 (see STAR Methods). Regression fit variation (light blue) is the bootstrap-inferred 95% confidence interval. (D) Comparison of genome-normalized activation times (tAct-TPG) between hybrids and cybrids. Replicate mean is for all genes shown. ∗∗∗∗p < 0.0001 (paired sample t test w/Bonferroni correction; N = 520). (E) Heatmap showing genome-normalized expression values for each gene, aligned at time points adjacent to the original activation time, tAct. Legend shows mean-normalized expression values. Inset schematic shows the position of numbered time points relative to tAct. (F) Violin plot showing slope of the genome-template normalized gene expression curves for time points before and after tAct. Note the mean slope changes from ∼0 to ∼1 mean-normalized transcripts per genome per hour, indicating an expression increase above that predicted from genome template number alone.
	Figure 6. Integrative model for N/C ratio control of ZGA timing at the MBT Model for ZGA timing. Maternal factors, histone acetylation, and diverse chromatin changes establish transcriptional competence of the embryonic genome and regulate transcriptional initiation of up to several hundred genes during cleavage stages prior to the mid-blastula transition.23,25 These standard transcriptional initiation processes are likely required throughout embryo development. A rapid increase in the DNA-to-cytoplasm (N/C) ratio initiates the MBT and regulates ZGA transcriptional timing for the vast majority of zygotic genes at this stage. These non-mutually exclusive layers of regulation integrate to control the precise initiation and stage-dependent expression level increase of each gene across early embryo development.
	Figure S1. RNA-seq time series, replicate, and exogenous spike-in RNA quality assessment. Related to Figure 1 and Figure 2. (A) Correlation matrix for replicates 2 and 3 at similar time points in hybrids. Pearson correlation for gene expression values is shown in each box. Color corresponds to Pearson correlation value as indicated in the legend below. To reduce zero-inflated correlation effects, we only considered a gene if it had >40 counts total across the time series in both replicates (mean expression >2.5 counts per time point). White dashed boxes correspond to most highly similar time points between replicates. (B) Scatterplot of gene expression values for all genes in hybrids for 2 replicates indicates high reproducibility. Time points shown include 6.5 hours post fertilization (hpf), 7.5 hpf, and 9.0 hpf. X- and Y-axes show log2(counts) of spike-in normalized RNA-seq gene counts. Dashed diagonal line is X=Y. Pearson correlation shown in inset of each plot. (C) Scatterplot of ERCC (External RNA Controls Consortium) spike-in RNA from two hybrid replicates at all time points shows high reproducibility for each of 38 unique spike-in RNA species used during normalization, as well as the spike-in population. Spike-in RNAs were used to normalize expression counts from all time points and conditions within each replicate (see STAR methods). Each color represents a spike-in RNA species, and each RNA includes the 8 high-quality time points found in both replicates. Black line denotes the linear fit to the data. X- and Y-axes show spike-in normalized RNA-seq counts. ERCC RNAs along the Y-axis (7/38) had low expression in one time point in one replicate that had lower sequencing read depth. Pearson correlation shown in lower right corner (r = 0.977). (D) Scatterplot of ERCC spike-in RNA from the hybrid (high ploidy) and cybrid (low ploidy) conditions reveals consistent expression in both conditions at all time points. Hybrid and Cybrid data are from matched samples from a single egg clutch. Each of 38 unique spike-in RNAs are represented by a single color. Black line denotes the linear fit to the data. Pearson correlation shown in lower right corner (r = 0.97). (E) Scatterplot of observed spike-in RNA counts and their expected abundance based on their known concentrations upon addition to samples. High correlations are present for all time points in both hybrids and cybrids shown for one replicate. Similar correlations were found for the second replicate (data not shown). Each blue dot represents one unique spike- in species. Black line denotes the linear fit to the data. Pearson correlation shown in upper left of each plot.
	Figure S2. Interspecies alignment quality assessment in hybrids. Related to Figure 2. (A) Bar plot showing proportion of read counts for X. laevis and X. tropicalis across time points. Color indicates species as in legend. (B) Scatter plot showing results of cross-species BLAST between the X. laevis and X. tropicalis transcriptomes (mRNA sequences). There were ~2400 interspecies gene pairs with at least one contiguous nucleotide stretch of >97% identity; each point is one gene pair; genes within a pair are not mutually exclusive, e.g., one X. laevis gene could be the top BLAST hit for multiple independent X. laevis genes. X-axis shows the length of contiguous nucleotides with >97% identity. Y-axis shows the proportion of each X. tropicalis mRNA covered by the contiguous nt region. The red lines indicate thresholds of 0.3 (Y-axis) and 75 nt (X-axis). All genes (n=22) with at least one stretch of 75 nt with >97% interspecies identity with a length over 30% of the total mRNA were not included in the final ZGA gene set (upper right portion of plot). (C) Genome browser images showing gene expression signal (spike-in normalized read counts) for X. laevis and X. tropicalis transcripts for cdk9 and srsf6. Signal tracks include merged data from replicates 2 and 3. Read count shown in Y-axis. Signal intensity was originally at base-pair resolution (unbinned) with mean signal over windows shown for clarity. Transcript structure at top in black (boxes = exons; line = introns). Note the lack of intronic signal in maternal X. laevis genes that are likely mature, spliced transcripts, and the presence of intronic signal in zygotic X. tropicalis genes (black arrow) that likely reflects nascent transcription. cdk9 (top) and srsf6 (bottom) shown as representative MZT genes. (D) Expression time-course profiles for cdk9 and srsf6, which have both maternal (X. laevis) and zygotic (X. tropicalis) mRNA expression in hybrids. The X. laevis genome had undergone a duplication and subsequent divergence that results in two subgenomes, short (S) and long (L). The subgenomes include paralogous transcripts for most mRNAs that have high, but not identical, sequence homology. The lack of cross-alignment in the earlier time points indicates that each RNA species (X. laevis L, X. laevis S, and X. tropicalis) can be distinguished. Gene expression was normalized using spike-ins. Points are overlaid with a lowess fit and the associated standard error of the fit. (E) Expression time-course profiles for maternal transcription factors critical for ZGA in XenopusS1. Vegt, sox3, pou5f3.3, and ets2 have both maternal (X. laevis) and zygotic (X. tropicalis) mRNA expression in hybrids. As in panel C, the lack of cross-alignment in the earlier time points indicates that sequencing reads arising from each species can be distinguished. Gene expression was normalized using spike-ins. Points are overlaid with a lowess fit and the associated standard error of the fit.
	Figure S3. Validation of defined zygotically active genes in hybrids. Related to Figure 2. (A) Gene Ontology (GO) term enrichment of the defined ZGA genes compared to the entire transcriptome. X-axis is -log(p-value), where the p-value was calculated using a hypergeometric test. Fold enrichment of each GO-term in ZGA genes vs. the transcriptome is represented by color as displayed in the legend at right. (B) Venn diagram shows overlap between our hybrid X. tropicalis ZGA gene set and wild- type X. tropicalis ZGA genes defined in published data sets. Only genes annotated with common names were used to directly compare genes from different genome assemblies and annotations, v7 S2,S3 and v9 (this work).
	Figure S4. Zygotically activated genes are delayed in embryos with less DNA. Related to Figure 3. (A) Distribution of fold-changes for each ZGA gene’s expression in cybrid relative to hybrid embryos in the replicate 1 time series. Hybrid embryos are the reference, so a decreased fold-change indicates decreased expression in cybrids. For each time point, fold-changes shown are the means of log2-normalized fold-change for all genes from replicate 1. In (A-C), the box shows the mean and 1st and 3rd quartiles. In (A-C) the gray shaded box denotes timing of the MBT. N=595 genes. (B) Distribution of fold-changes for each ZGA gene’s expression in the replicate 2 time series. Fold-changes are means of log2-normalized fold-change for all genes in replicate 2 as in (A). (C) Distribution of fold-changes for each ZGA gene’s expression in the replicate 2 time series. Fold-changes are the means of log2-normalized fold-change for all genes from replicate 3 as in (A). (D) Histograms of fold-changes for defined ZGA genes in all 3 replicates at time points across the MBT (7.5 hpf, top; 8.0 hpf, middle, 8.5 hpf, bottom). Hybrid embryos are the reference; a decreased fold-change indicates decreased expression in cybrids. For each time point, fold-changes are means of each ZGA gene’s log2-normalized fold-change across 3 replicates (for time points 7.5 hpf and 8.5 hpf) or 2 replicates (for 8.0 hpf). (E) Venn diagram shows overlap between our mRNA X. tropicalis ZGA gene set analyzed in the main figures (light blue, N=595) and expanded X. tropicalis ZGA gene sets derived from total gene signal (purple, N=2045) or intronic signal (yellow, N=1899). The total number of unique defined ZGA genes between the total gene signal set and the mRNA set is N=2289 (2045+244). (F) Distribution of fold-changes for intron-derived ZGA gene expression in cybrid relative to hybrid embryos in all three replicate time-series. Fold-change, boxplot parameters, and gray shading are as described in (A-C) (N=1899 genes). (G) Distribution of log2-normalized fold-changes of each intron-derived ZGA gene’s expression in cybrid vs hybrid embryos. Genes are binned according to expression level deciles. Expression level is each gene’s mean level across all time points. Highest expression decile in purple, lowest in dark red (N=1899 genes). (H) Violin plot displaying the distribution of fold-changes for each ZGA gene’s expression in cybrid relative to hybrid embryos, using expression counts across the full gene length. Box inside shows mean and 1st and 3rd quartiles. Hybrid embryos are the reference so a decreased fold-change indicates decreased expression in cybrids. Fold-changes are population means of every ZGA gene’s log2-normalized fold-change mean from 3 replicates. Each time point contains 2 or 3 replicates (N=2045).
	Figure S4. Zygotically activated genes are delayed in embryos with less DNA. Related to Figure 3. (A) Distribution of fold-changes for each ZGA gene’s expression in cybrid relative to hybrid embryos in the replicate 1 time series. Hybrid embryos are the reference, so a decreased fold-change indicates decreased expression in cybrids. For each time point, fold-changes shown are the means of log2-normalized fold-change for all genes from replicate 1. In (A-C), the box shows the mean and 1st and 3rd quartiles. In (A-C) the gray shaded box denotes timing of the MBT. N=595 genes. (B) Distribution of fold-changes for each ZGA gene’s expression in the replicate 2 time series. Fold-changes are means of log2-normalized fold-change for all genes in replicate 2 as in (A). (C) Distribution of fold-changes for each ZGA gene’s expression in the replicate 2 time series. Fold-changes are the means of log2-normalized fold-change for all genes from replicate 3 as in (A). (D) Histograms of fold-changes for defined ZGA genes in all 3 replicates at time points across the MBT (7.5 hpf, top; 8.0 hpf, middle, 8.5 hpf, bottom). Hybrid embryos are the reference; a decreased fold-change indicates decreased expression in cybrids. For each time point, fold-changes are means of each ZGA gene’s log2-normalized fold-change across 3 replicates (for time points 7.5 hpf and 8.5 hpf) or 2 replicates (for 8.0 hpf). (E) Venn diagram shows overlap between our mRNA X. tropicalis ZGA gene set analyzed in the main figures (light blue, N=595) and expanded X. tropicalis ZGA gene sets derived from total gene signal (purple, N=2045) or intronic signal (yellow, N=1899). The total number of unique defined ZGA genes between the total gene signal set and the mRNA set is N=2289 (2045+244). (F) Distribution of fold-changes for intron-derived ZGA gene expression in cybrid relative to hybrid embryos in all three replicate time-series. Fold-change, boxplot parameters, and gray shading are as described in (A-C) (N=1899 genes). (G) Distribution of log2-normalized fold-changes of each intron-derived ZGA gene’s expression in cybrid vs hybrid embryos. Genes are binned according to expression level deciles. Expression level is each gene’s mean level across all time points. Highest expression decile in purple, lowest in dark red (N=1899 genes). (H) Violin plot displaying the distribution of fold-changes for each ZGA gene’s expression in cybrid relative to hybrid embryos, using expression counts across the full gene length. Box inside shows mean and 1st and 3rd quartiles. Hybrid embryos are the reference so a decreased fold-change indicates decreased expression in cybrids. Fold-changes are population means of every ZGA gene’s log2-normalized fold-change mean from 3 replicates. Each time point contains 2 or 3 replicates (N=2045).
	Figure S6. Decreased DNA per cell leads to delayed zygotic gene activation for intron- derived and genome-normalized expression. Related to Figure 4 and Figure 5. (A) (Left panel) Scatterplot of activation times for intron-derived ZGA genes compared to mRNA-derived ZGA genes in replicate 2 hybrids, for genes found in both sets (N=238). (Right panel) Scatterplot of activation times for intron-derived ZGA genes compared to mRNA-derived ZGA genes in replicate 3, for genes found in both sets (N=185). In panels (A- B), the blue line is a linear fit and variation (light blue) is the bootstrapped-inferred 95% confidence interval. Pearson correlation in upper left inset. (B) Scatterplot of activation times for intron-derived ZGA genes comparing replicate 2 hybrids to replicate 3 hybrids (N=1564). (C) Cumulative distribution of the activation time difference (hrs) between cybrids and hybrids, for intron-derived high confidence X. tropicalis ZGA genes (N=1500). Dashed black line indicates X=0 (no difference). (D) Violin plot showing mean activation times for each gene over two replicates in hybrid and cybrid embryos for intron-derived ZGA genes. Box plot in center shows median, 1st and 3rd quartiles. **** indicates p-value << 10-10 (paired sample t-test w/Bonferroni correction) (N=1500). (E) Display of the distribution of the sign of ∆tAct across both replicates for intron-derived ZGA genes. A positive sign indicates that cybrid gene expression was less than that of hybrids (i.e., delayed). Percent of ZGA genes indicated by color as shown in legend (N=1491/1500 genes with a non-zero ∆tAct ). (F) Cumulative distribution of the genome-normalized activation time difference (hrs), ∆tAct- TPG, between cybrids and hybrids for intron-derived ZGA genes (N=1459). (G) Violin plot showing mean activation times for each gene over two replicates in hybrid and cybrid embryos for intron-derived ZGA genes. Box plot in center shows median, 1st and 3rd quartiles. **** indicates p-value << 10-10 (paired sample t-test w/Bonferroni correction) (N=1459).

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