# a-c，來自內胚層、中胚層和外胚層器官的GO術語。

*biotech · news · 2026-05-27 · Nature*

## Key points

- MYF5、KLF1 和 MYBL2 調控子活性在胚胎發育中呈現階段及組織特異性富集。
- ETS1 和 NOTCH1 在心臟不同區域空間定位，有助於心肌小樑形態形成。
- ACE2 與 TMPRSS2 在胚胎腸道上皮細胞中展現空間共表達。
- 印記基因如 IGF2 在胚胎組織中呈現等位基因不平衡表達模式。

a-c, GO terms of organs derived from endoderm (a), mesoderm (b) and ectoderm (c). d, Heatmap showing the representative DEGs for hemopoiesis in liver and somite/sclerotome/bone. e, Spatial patterns of MYF5 regulon activity and target gene expressions from CS12 to CS23. f, Boxplot showing normalized MYF5 regulon activity among somite, myotome and skeletal muscle. n = 71,074 bins (whole embryo) and 8,621 bins (somite) examined in two biologically independent samples for somite, n = 200,205 bins (whole embryo) and 8,677 bins (myotome) examined in two biologically independent samples for myotome, n = 763,470 bins (whole embryo) and 38,679 bins (skeletal muscle) examined in four biologically independent samples for skeletal muscle. p < 1.0 × 10−100. g, Spatial patterns of KLF1 regulon activity and target gene expressions from CS18 to CS23. Boxplot showing normalized KLF1 regulon activity enriched in liver. n = 132,277 bins (whole embryo) and 11,540 bins (liver) examined over one biologically independent sample for CS18, n = 263,202 bins (whole embryo) and 16,945 bins (liver) examined in one biologically independent sample for CS19, n = 32,858 bins (whole embryo) and 2,343 bins (liver) examined in one biologically independent sample for CS20, n = 87,350 bins (whole embryo) and 3,530 bins (liver) examined in one biologically independent sample for CS23. p < 1.0 × 10−100. h, Spatial patterns of MYBL2 regulon activity and target genes expression at CS17, CS19, CS20 and CS23. Boxplot showing normalized MYBL2 regulon activity enriched in liver. n = 66,586 bins (whole embryo) and 2,800 bins (liver) examined in one biologically independent sample for CS17, n = 510,985 bins (whole embryo) and 30,785 bins (liver) examined in one biologically independent sample for CS19, n = 16,977 bins (whole embryo) and 1,219 bins (liver) examined in one biologically independent sample for CS20, n = 87,350 bins (whole embryo) and 3,530 bins (liver) examined in one biologically independent sample for CS23. p = 7.8 × 10−7 for CS17, p < 1.0 × 10−100 for CS19, CS20 and CS23. For f-h, center line denotes median value, whisker lengths are within 1.5 interquartile range of the 25th and 75th percentile box boundaries, and outlier points are not shown. Statistical significance was assessed using the two-tailed Mann-Whitney U test. ***p < 0.001. Source data a, H&E staining and schematic diagram of trabecular and compact layers of CS14-15 E3S3 heart. The bin50 spatial distribution of the ETS1 regulon activity, and, cell-segmented spatial distribution of ETS1 and NOTCH1 expression. CL, compact layer; TL, trabecular layer; A, atrium; V, ventricle; OFT, outflow tract; En, endocardium; AVC, atrioventricular canal. Results are representative of 7 sections (from four biologically independent samples) with similar outcomes. b, UMAP visualization of major cell types in the developing human heart between 9 and 16 post-conception weeks (PCW), based on a public single-cell RNA sequencing (scRNA-seq) dataset. P-RBC, platelet-red blood cells; WBC, white blood cells; LEC, lymphatic endothelial cells; BEC, blood endothelial cells; Fibro, fibroblasts; SMC, smooth muscle cells; ncCM, non-chambered cardiomyocytes; aCM, atrial cardiomyocytes; vCM, ventricular cardiomyocytes. c, UMAP visualization of the expression profiles of ETS1, NOTCH1, and CDH5 (pan-endothelial marker). d, Dotplot illustrating the expression profiles of ETS1, NOTCH1, and CDH5 using the scRNA-seq dataset. e, Stereo-seq data of the CS14-15 E3S3 heart, with segmented cells color-coded by the cell-type annotation of the 9 PCW cardiac scRNA-seq profile, mapped to their spatial positions using Tangram. f,g, Spatial distribution of endocardial cells (f) and ETS1 (g) within the squared regions highlighted in (e). h, Spatial localization of ETS1+ cells, color-coded by cell type. i, Dotplot depicting the expression profiles of ETS1 using cell-segmented Stereo-seq data. j, RNA-scope analysis showing the expression of ETS1, MYH7 (ventricular cardiomyocyte marker), and CDH5 in the human embryonic heart. The images are representative of 3 independent experiments. k, Regulatory network of ETS1, in which genes highlighted with orange circles represent genes for trabecular morphogenesis. The line width represents the weight of motif enrichment. l, Barplot exhibiting the representative GO enrichment terms of genes in (k). m, Dotplot illustrating specific signaling interactions between endocardium and trabecular ventricular cardiomyocytes across Carnegie stages (CS) 12–20. n, Stereo-seq data of the CS14-15 E3S3 heart, with segmented cells color-coded by the cell-type annotation of the 9 post-conception weeks (PCW) cardiac scRNA-seq profile19 mapped to their spatial positions using Tangram. The spatial distribution of NRG3, ERBB2, and ERBB4 is shown within the squared regions in the left panel. Results are representative of 7 sections (from three biologically independent samples) with similar outcomes. o, Heatmap depicting the cell type-specific expression of NRG3, ERBB2, and ERBB4 in the developing human heart between 9 and 16 PCW, based on a public dataset. P-RBC, platelet-red blood cells; WBC, white blood cells; LEC, lymphatic endothelial cells; BEC, blood endothelial cells; Fibro, fibroblasts; SMC, smooth muscle cells; ncCM, non-chambered cardiomyocytes; aCM, atrial cardiomyocytes; vCM, ventricular cardiomyocytes. p, UMAP visualization of major cell types, and, NRG3, ERBB2 and ERBB4 derived from this dataset. q,r, Spatial visualization for the downstream genes of SHOX2 (q) and RORA (r) in CS17 E1S3 heart. s, RNA-scope analysis showing the expression of KIAA1324L, RORA and the pacemaker cell marker HCN4. The images are representative of 3 independent experiments. a, Heatmap showing the expression of marker genes across the substructures of human embryonic nervous system, and the color bar represents scaled gene expression level. b, The proportion of bins assigned to brain substructures at each Carnegie stage. c, Heatmap showing the Spearman correlation of transcriptional profiles among brain substructures at each Carnegie stage. d, Heatmap illustrating the activities of pathways across brain substructures, accompanied by enriched terms within each cluster. Colors in b correspond to the substructure identity in d. e, Barplots showing the cell proportion of radial glial cells in each brain region. f, Barplots showing the cell proportion of neural progenitor cells, glial progenitor cells, oligodendrocytes, astrocytes, microglia and oligodendrocyte progenitor cells in each brain region. For panel e and f, the bar height indicates cell proportion in the Fb, Mb, Hb, and SpC, respectively, and, bar color denotes the compositional ratio within the finer brain substructures. g, Schematic representation of immunofluorescence localization patterns from Fig. 4b. RNA ISH image of DCX (green, immature neurons), GAD1 (red, inhibitory neurons) and NEUROD6 (purple, excitatory neurons) in CS12-13 and CS19 (same in Fig. 4, left), along with their specific locations and orientations within the embryo. h-m, Cross validation of the temporal sequence of neurogenesis with data from Zeng et al. 2023 Cell Stem Cell25. h-j, tSNE of all cells colored by stage (h), expression of excitatory neuron maker (i) and inhibitory neuron maker (j). The scale bar (i,j) represents normalized gene expression level. k. tSNE of all cells colored by cell types (left) and temporal dynamics of excitatory and inhibitory neuron ratios across different stages (right). l, Bubbleplot showing the proportion of cells with marker gene expression at different developmental stages. W, weeks post-conception. m, Spatial visualization of excitatory (NEUROD2, NEUROD6) and inhibitory (GAD1, GAD2) neurons in Zeng et al.’s spatial transcriptomics (CS12 S5), and the scale bar represents normalized gene expression level. a, Upset plot showing intersections of regulons at central nervous system at each stage. b, Spatial visualization of the HMGA2 regulon activity (top) and expression (bottom) in the brain and spinal cord, and the color bar represents regulatory activity score (top) and scaled gene expression level (bottom). c, RNA ISH image of HMGA2 and DCX in the developing brain. The images are representative of 3 independent experiments. d,e, Bubbleplot showing the expression of cell marker genes for different neural cells (d) and RGCs subpopulations (e). f, Spatial mapping of different RGCs subpopulations. g, The shift in proportions of RGCs subpopulations over different developmental stages. h, Expression of HMGA2 in different neural cells. i, Heatmap shows the normalized expression of gene sets S1 (exhibiting an inverse expression gradient) and S2 (a concordant gradient) relative to HMGA2 expression in human Pall VZ, and the color bar represents scaled gene expression level. j, Profile plot shows the averaged HMGA2 ChIP-seq signals of gene sets S1 and S2 (top). Barplot shows the averaged HMGA2 ChIP-seq signals of gene sets S1 and S2 (bottom). Data are presented as mean ± SEM (n = 4 biologically independent experiments). Initially, ANOVA was conducted to assess overall differences, followed by Tukey’s multiple comparison test for multiple comparisons to determine specific pairwise differences between the gene sets. k, HMGA2 binding patterns were grouped into four clusters using k-means clustering (k = 4). Profile plot shows the averaged HMGA2 ChIP-seq signals of 4 clusters (top). Heatmap shows the HMGA2 ChIP-seq signals ranging from 3,000 bp upstream of the TSS to 3,000 bp downstream of the TES (bottom). l, Differences in gene expression for each cluster between neocortical NPCs of Hmga2−/− mice and those of control mice. Data are presented as box plots, with the boxes representing the median and upper and lower quartiles and the whiskers indicating the range. Statistical significance was assessed using Kruskal-Wallis test followed by Dunn’s post hoc test with Bonferroni correction for multiple comparisons. m, The expression of the rostrocaudal axis expression of the gene set cluster3 in mouse (E15.5 E1S3) Pall VZ were grouped into 3 Sets using k-means clustering (k = 3). Data are presented as heatmap, and the color bar represents scaled gene expression level. n, GO enrichment analysis of the 3 Sets. The p-value was calculated by the one-tailed hypergeometric test to assess the statistical significance of the enrichment. o, Left panel, heatmap showing the regulon modules grouped by Hotspot at sections CS18 E1S1. Right panel, spatial visualization of modules in the brain. p, Left panel, heatmap showing the regulon modules grouped by Hotspot at sections CS19 E1S1. Right panel, spatial visualization of modules in the brain. q, Gene regulatory networks of module CS19_M1. Selected target genes and TFs in the DDG2P were shown. Source data a, Heatmap showing the normalized gene expression level of receptors in 15 representative anatomic regions from CS12-13 to CS23. The entry receptor of the virus in black and the important coreceptor in red. SpC, spinal cord; IE, inner ear; HD, hepatic diverticulum; LP, lung primordium; Epi, epidermis; PG, primitive gut; Pro, pronephron; Mes, mesonephron. b, RNA ISH images of CD147 in embryonic organs (CS23). c, RNA ISH images of PDGFRA and THY1 in embryonic organs (CS23). d, RNA ISH images of CD46, ASGR1 and NRP2 in embryonic organs (CS23). e, RNA ISH images of NTCP and EGFR in embryonic organs. The epidermis image was obtained from sample at Carnegie Stage 20 (CS20); all other images were from CS23 embryos. f, RNA ISH images of ACE2 and TMPRSS2 in embryonic gut (CS23). The images (b-f) are representative of 3 independent experiments. g, Spatial visualization of TMPRSS2 expression based on single-cell segmentation in gut at CS23. Results are representative of 8 sections (from two biologically independent samples) with similar outcomes. h, Scatterplot showing the co-expression pattern (red spots) of ACE2 and TMPRSS2 within the same cell in the gut epithelia based on Stereo-seq, snRNA data and human cell landscape89. a, The enrichment score of the causative genes implicated in developmental disorders. b, Bubbleplot showing the GO enrichment pathways of up-regulated genes in human liver compared with that of mouse from CS14-15 to CS23. c, Bubbleplot showing the GO enrichment pathways of up-regulated genes in human lung compared with that of mouse at CS19-20 and CS23. For panel b,c, the GO enrichment analysis was assessed by the one-sided GO over-representation test with Benjamini-Hochberg multiple comparison correction. d-f, Comparative heatmap of temporal expression profiles for UTGs (up-regulated genes) and DTGs (down-regulated genes) across human and mouse in the heart (d), liver (e) and brain (f). Selected genes from DDG2P are marked on the left. Top enriched GO terms are displayed on the right, with color-coded bars and text corresponding to functional gene clusters. g, Dynamic expression profiles of four representative genes (SUCLG1, NHP2, HNRNPK, CAMTA1) in human brain and their orthologous genes in mouse brain. a, The allelic expression analysis flowchart of spatial transcriptome from multiple chips. b-d, The imbalanced allelic expressions of 104 phased genes in tissues of CS20 E2 (b), CS14-15 E1 (c) and CS14-15 E3 (d) embryos. The known imprinted genes were highlighted in purple at the bottom of the chart. The pooled proportions of multiple sections are presented, with the size of each pie chart indicating the expressed bin rate within the corresponding tissue. e, The spatial allelic expression pattern (top) and common expression pattern (bottom) of MEST and MEG3. f, The spatial expression pattern of imprinted gene IGF2 in CS14-15 E3S4 and CS20 E2S2. g, The spatial imbalanced allelic expression pattern of RN7SKP255 in CS14-15 E1S4, accompanied by the validation in CS20 E2S2. h, Brain-specific imbalanced allelic expression of SCIRT and GFPT2 in CS20 E2S2. Representative sections (top) and pooled proportions for multiple sections; A1, blue; A2, red; color bar represents UMI count (f-h). i, The allelic expression of PEG3, RN7SKP255, SCRIPT (in brain), DUSP22 and LINC01535 in the spatial transcriptome data from 4 sections of CS20 E2. X-axis represents the proportion of the A2 allele. Red indicates a higher proportion of the A2 allele, while blue indicates a higher proportion of the A1 allele. Each dot corresponds to a chip. Statistical analysis was based on the comparations of the allele proportion differences (A1 vs. A2) for each gene. Two-tailed p values by paired Student’s t-test. j, Sanger sequencing of genomic DNA and cDNA of allelic imbalanced expression gene from CS20 E2. Source data

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