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20210720-Supp Figures Combinatorial transcription factor profiles predict mature and functional human islet α and β cells Shristi Shrestha*, Diane C. Saunders*, John T. Walker*, Joan Camunas-Soler, Xiao-Qing Dai, Rachana Haliyur, Radhika Aramandla, Greg Poffenberger, Nripesh Prasad, Rita Bottino, Roland Stein, Jean-Philippe Cartailler, Stephen C. J. Parker, Patrick E. MacDonald, Shawn E. Levy, Alvin C. Powers#, Marcela Brissova# * These authors contributed equally, # Corresponding authors Supplemental Information A Arda et al. 2016 B Blodgett et al. 2015 30 α 250 α 25 β β 200 20 * 15 150 * 10 100 * 5 50 Normalized expression (TPM) Normalized expression (RPKM) 0 0 ARX MAFA MAFB ARX MAFA MAFB ARX MAFA MAFB C (Tissue donor 6) donor (Tissue 20y D (Tissue donor 7) donor (Tissue 35y GCG (α cells) CPEP (β cells) Supplemental Figure 1. ARX is expressed specifically in human α cells and MAFA in β cells, while MAFB is expressed in both α and β cells. (A–B) Normalized expression of ARX, MAFA, and MAFB in previously published bulk RNA-sequencing (RNA-seq) datasets Arda et al. 2016 (10) (A) and Blodgett et al. 2015 (26) (B) from α cells (green) and β cells (blue). Bars in both panels show mean + SEM; symbols represent individual donors. Asterisks indicate significantly different (adjusted p-value <0.05) fold change (α vs. β). See also Figure 1B. (C–D) Immunohistochemical staining of pancreatic sections from nondiabetic adults (Table S4), showing specificity of ARX, MAFA, and MAFB (red) in α cells (GCG; green) and β cells (CPEP; blue). Arrowheads indicate cells negative (white) or positive (purple) for transcription factors; scale bars, 50 μm. See also Figure 1C. S1 A Islet cells Single cells Live cells Endocrine cells α and β cells -A -A -H Count SSC FSC FSC NTPDase3 39y (Islet prep 1) prep (Islet 39y -A -A -H Count FSC SSC FSC NTPDase3 14y (islet prep 2) prep (islet 14y FSC-A FSC-A Propidium Iodide HPi1 HPa3 FACS- WI-SC-α WI-SC-β FACS-SC-α SC-β B 4000 C GCG GC TMEM176B TMEM176A 3000 RGS4 Scaled FAP Expression FXYD3 F10 2 2000 FABP5 SLC7A2 1 INS Number of genes of Number MEG3 0 1000 HADH SAMD11 -1 GSN β α -α - - -β ADCYAP1 SC SC -SC - - -SC PRSS23 PCSK1 WI WI TIMP2 6,247 cells FACS7,193 cells FACS3,129 cells 11,512 cells NPTX2 D GCG E INS -β -α ALDH1A1 SC - SC - NKX6-1 TM4SF4 MAFB PDX1 IRX2 IAPP ARX MAFA XBP1 XBP1 DPP4 HERPUD1 HERPUD1 Log (expression) (expression) Log WI Log (expression) (expression) Log WI ATF4 DDIT3 ATF4 DDIT3 Log (expression) FACS-SC-α Log (expression) FACS-SC-β F G Supplemental Figure 2. Purified α and β cells analyzed by cell surface markers and those identified by unsupervised clustering. (A) Gating strategy for sorted α and β cells identified by cell surface markers. Cell debris were excluded by forward scatter (FSC) and side scatter (SSC), single cells were identified by voltage pulse geometry (FSC-A v. FSC-H), and non-viable cells were excluded using propidium iodide (PI). Endocrine cell subpopulations were then isolated based on positivity for HPi1 (pan- endocrine marker) and additional positivity for HPa3 (α cells) or NTPDase3 (β cells). Antibody information can be found in Table S3. (B) Number of genes detected was similar among α and β cells identified by cell surface markers and unsupervised clustering. See Figure 2A for schematic of experimental design. (C) Heatmap depicts expression of genes contributing to variability in PCA of Figure 2G. (D–E) Comparison of average log expression of genes across cells identified by unsupervised clustering or cell surface markers for α (D) and β cells (E). Genes highlighted are α cell-enriched (yellow), β cell-enriched (blue), or selected markers of cell stress (grey). (F–G) KEGG enrichment performed on genes common between scRNA-seq and bulk RNA-seq as well as on the 1,000 most highly expressed genes unique to bulk RNA-seq (F, α cells; G, β cells) using Metascape. See also Figure 2D and 2F. S2 G 16.7 G 1.7 G 16.7 G 1.7 G 16.7 + IBMX 100 + Epi 1 KCl 20 G 16.7 + IBMX 100 + Epi 1 KCl 20 A 6 250 G 5.6 G 5.6 G 5.6 G 5.6 G 5.6 G 5.6 G 5.6 G 5.6 G 5.6 G 5.6 5 200 4 150 3 100 2 Insulin secretion (pg/100 IEQs/min) (ng/100IEQs/min) Glucagon secretion 50 1 0 0 0 30 60 90 120 150 0 30 60 90 120 150 Time (min) Time (min) B 66 C Cell Type α cells β cells 59 α Acinar 50 β Ductal δ Endothelial 39 γ Stellate 14y Donor age (years) 39y 14 ε Immune 50y 59y 0 10 20 30 40 50 60 70 80 90 100 66y Frequency (%) D E F Supplemental Figure 3. Detailed characterization of endocrine cells from five nondiabetic human islet donors. (A) Insulin and glucagon secretion were assessed in islets isolated from n=5 donors (age range 14–66 years) stimulated with 5.6 mM glucose (G 5.6), 16.7 mM glucose (G 16.7), 16.7 mM glucose + 100 mM isobutylmethylxanthine (IBMX) (G 16.7 + IBMX 100), 1.7 mM glucose + 1 mM epinephrine (G 1.7 + Epi 1), and 20 mM potassium chloride (KCl 20). Insulin and glucagon secretion is normalized to overall islet cell volume (expressed as islet equivalents; IEQs). (B) Bar graph illustrating cell type distribution within each islet preparation as per cell types annotated in Figure 3A. (C) UMAP of only α or β cells, showing clustering by islet preparation. See also Figures 4A and 5A. (D) User-friendly web portal application for searching and viewing pancreatic cell types and their gene expression; available at https://powersbrissovalab.shinyapps.io/scRNAseq-Islets/. (E) Number of genes detected in cells expressing low (ln[UMI per 10,000 +1] <0.5) or high (ln[UMI per 10,000 +1] >0.5) levels of transcription factors ARX and MAFB in α cells (pink) and MAFA and MAFB in β cells (green); dotted line represents quality threshold of 500 genes. (F) PCA showing cell cycle genes among the four MAFA/MAFB β cell populations. S3 9 6 3 2 1 Log expression 0 RFX6 PDX1 PAX6 NKX6-1 NKX2-2 NEUROD1 MAFB MAFA ISL1 IRX2 # ^ # ^ $ ^ # ^ $ # ^ $ # ^ 9 6 3 2 1 Log expression 0 FOXA2 ARX TTR SLC38A4 PTPRT POU6F2 PLCE1 PCSK2 PAPPA2 LOXL4 ^ # ^ $ ^ $ # ^ $ ^ $ # ^ $ 9 6 3 2 1 Log expression 0 KLHL41 IGFBP2 GC FXYD3 DPP4 TMCO1 SCN3B KCTD12 KCNMA1 KCNK3 $ # $ # ^ ^ 9 6 3 2 1 Log expression 0 KCNK16 KCNJ8 KCNJ6 CACNB2 CACNA2D1 CACNA1D CACNA1C CACNA1A ABCC8 ACLY # ^ # ^ $ ^ # ^ # ^ 9 6 3 2 1 Log expression 0 PKM PDHA1 MDH2 GSTK1 GSTA4 GPX3 GPI G6PC2 ENO2 VTI1B # ^ # ^ $ # ^ ^ # ^ $ # 9 6 3 2 1 Log expression 0 VAMP2 SYT7 SYT5 SYT13 STXBP1 STX1A SNAP25 RIMS2 PCLO TSPAN7 # ^ ^ ^ 9 6 3 None ARX MAFB Both 2 # None differs from 1 all other groups ^ Both differs from Log expression 0 all other groups TSPAN1 RGS9 GYG1 FAM159B BMP5 HSPA5 HERPUD1 DDIT3 ATF4 $ ARX and # ^ $ # $ MAFB differ Supplemental Figure 4. Raw expression values for transcription factor, α cell-enriched, ion channel, glucose metabolism, vesicle trafficking, exocytosis, and stress genes in ARX/MAFB populations. Violin plots depict gene expression in α cell populations lacking ARX and MAFB (grey) and those expressing MAFB only (red), ARX only (blue), or co-expressing both MAFB and ARX (purple); n=24,248 total α cells. Data corresponds to dot plot in Figure 4C. Symbols underneath gene names indicate significance (p<0.05) from Tukey’s multiple comparisons test following 2-way ANOVA. S4 A Baron et al. 2,326 α cells, 4 donors (InDrop) Transcription factors α-enriched Ion channels Glucose metabolism Vesicle trafficking Exocytosis Stress Segerstolpe et al. 415 α cells, 5 donors (Smart-Seq2) Transcription factors α-enriched Ion channels Glucose metabolism Vesicle trafficking Exocytosis Stress Camunas et al. 511 α cells, 18 donors (Smart-Seq2) Transcription factors α-enriched Ion channels Glucose metabolism Vesicle trafficking Exocytosis Stress Current study 24,248 α cells, 5 donors (10x) Transcription factors α-enriched Ion channels Glucose metabolism Vesicle trafficking Exocytosis Stress 1.0 0 Expression 0.5 25 Cells expressing z-score 0.0 50 (% total cells) -0.5 75 100 -1.0 B DAPI ARX MAFB ARX MAFB GCG DAPI ARX MAFB ARX MAFB GCG 3 3 3 3 4 4 4 4 4 4 4 4 3 3 3 3 1 1 1 1 1 1 1 1 20y (Tissue donor 6) donor (Tissue 20y 35y (Tissue donor 7) donor (Tissue 35y 2 2 2 2 2 2 2 2 Supplemental Figure 5. Validation of α cell populations based on ARX and MAFB expression, as determined by previous scRNA-seq studies. (A) Dot plots showing the expression patterns of selected genes related to cell identify, ion flux, glucose metabolism, vesicle trafficking, and exocytotic machinery. α cell populations (rows) are identified by expression of neither ARX nor MAFB (None), ARX only (ARX), MAFB only (MAFB), and co-expression of ARX and MAFB (Both). Dot size indicates the percentage of cells with detectable transcripts; color indicates gene’s average scaled expression. Headers list study details from previously published datasets (Segerstolpe et al., 2016 [29]; Baron et al., 2016 [28]; Camunas-Soler et al., 2020 [18]) and final dot plot is as shown in Figure 4C for comparison. (B) Immunohistochemical staining of ARX (blue) and MAFB (red) in glucagon (GCG)- expressing α cells (green) of two nondiabetic adults (Table S4).
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