Journal: Nature Communications

Article Title: TBL1X/TBL1XR1 govern β-cell identity through a PAX6-containing gene regulatory network

doi: 10.1038/s41467-026-72077-5

Figure Lengend Snippet: a Scheme for the generation of an inducible β-cell-specific TBL1X and TBL1XR1 knockout. b Random fed blood glucose levels over time in iTBL/RβKO ( n = 9) and control ( n = 9) mice on HFD. c Total pancreas insulin content normalized to protein levels in iTBL/RβKO and control mice 4 and 11 weeks after tamoxifen administration. n = 3 for 4w control and iTBL/RβKO mice, n = 6 for 11w control mice, n = 4 for 11w iTBL/RβKO mice. d , e Blood glucose ( d ) and plasma insulin ( e ) levels during an oral glucose tolerance test after 22 weeks of HFD. Corresponding area under the curve in iTBL/RβKO ( n = 8) and control ( n = 9) mice ( d , right). f , g Relative mRNA expression determined by qPCR in pancreatic islets of iTBL/RβKO and control mice of Tbl1x and Tbl1xr1 ( f ) and islet genes ( g ). Control mice Tbl1x , Tbl1xr1 , Ins1 , Ins2 , Nkx6.1 , Slc2a2 , Mafa , Pdx1 , Pax6 , Ucn3 : n = 9, control mice ChgA , Ngn3 , Ldha , Hk1 : n = 8, iTBL/RβKO mice Tbl1x , Ngn3 , Ldha , Hk1 : n = 7, iTBL/RβKO mice Tbl1xr1 , Ins1 , Ins2 , Slc2a2 , Mafa n = 6, iTBL/RβKO mice Nkx6.1 , Pdx1 , Pax6 , Ucn3 , ChgA : n = 5. h α/β-cell mass ratio of pancreatic islets from iTBL/RβKO ( n = 4) and control mice ( n = 4) on HFD, 24 weeks after knockout induction. i Representative immunofluorescent staining of insulin + (blue, β-cells) and glucagon + (red, α-cells) cells of paraffin-embedded pancreas from iTBL/RβKO and control mice on HFD, 24 weeks after knockout induction. Each point represents one mouse. Data are represented as mean ± SEM. The following statistical tests were applied: two-sided student’s t test ( d – Area under the curve, f – h ) and 2-way ANOVA with Šidák’s multiple comparison post hoc test ( b – d – time course, e ). Source data are provided as a Source Data file.

Article Snippet: The following TaqMan probes were used: Tbp - Mm01277042_m1, Tbl1x - Mm01222202_m1, Tbl1xr1 - Mm01283877_m1, Ins1 - Mm01259683_g1, Ins2 - Mm00731595_gH, Nkx6.1 - Mm00454961_m1, Slc2a2 - Mm00454961_m1, Mafa - Mm00845206_s1, Pdx1 - Mm00435565_m1, Pax6 - Mm00443081_m1, Ucn3 - Mm00453206_s1, ChgA - Mm00514341_m1, Ngn3 - Mm00437606_s1, Ldha - Mm01612132_g1, Hk1 - Mm00439344_m1, TBP - Hs00427620_m1, TBL1X - Hs00959540_m1, TBL1XR1 - Hs00226564_m1.

Techniques: Knock-Out, Control, Clinical Proteomics, Expressing, Staining, Comparison

Journal: bioRxiv

Article Title: Workload-induced changes to cell state contribute to β-cell failure in diabetes

doi: 10.64898/2026.05.13.725004

Figure Lengend Snippet: (a) Schematic of alleles and treatments used to inactivate Lsd1 in db/db mice. TM, tamoxifen; wks, weeks. (b) Time course of ad libitum-fed blood glucose levels in TM-treated mice of the indicated genotypes. db/+ Lsd1 fl/+β : n = 7 mice, db/db Lsd1 fl/+β : n = 8 mice, db/db Lsd1 Δβ : n = 11 mice, db/+ Lsd1 Δβ : n = 14 mice. * p <0.05, ** p <0.01, *** p <0.001 between db/db Lsd1 fl/+β and db/db Lsd1 Δβ mice. (c) Glucose tolerance tests in TM-treated mice of the indicated genotypes. db/+ Lsd1 fl/+β : n = 6 mice, db/db Lsd1 Δβ : n = 11 mice, db/db Lsd1 fl/+β : n = 13 mice. * p <0.05, ** p <0.01 between db/db Lsd1 fl/+β and db/db Lsd1 Δβ mice. (d) Serum insulin and blood glucose (glc) levels in mice of the indicated genotypes following a 6-hour fast or 10 min following intraperitoneal injection of glucose. db/+ Lsd1 fl/+β fast and 10’ glucose: n = 4 mice, db/db Lsd1 Δβ 10’ glucose: n = 5 mice, all other groups: n = 6 mice. (e and f) Static insulin secretion assays for islets from the indicated genotypes of mice stimulated with the indicated glucose (glc) concentrations (in mM) with or without 10 nM of exendin-4 (Ex4) or GIP at 7 wks (e) and 9 wks (f) of age. db/+ Lsd1 fl/+β 16.8 mM glc + Ex4 or GIP wk 7: n = 4 pools of 10 islets each, db/+ Lsd1 Δβ 16.8 mM glc + Ex4 or GIP wk 7 and db/db Lsd1 fl/+β 16.8 mM glc + Ex4 wk 7: n = 5 islet pools, db/+ Lsd1 fl/+β 16.8 mM glc wk 7: n = 10 islet pools, db/+ Lsd1 fl/+β 2.8 mM glc wk 9 and db/db Lsd1 fl/+β 16.8 mM glc wk 9: n = 11 islet pools, db/db Lsd1 fl/+β 2.8 mM glc wk 9, db/db Lsd1 Δβ 2.8 mM glc or 16.8 mM glc wk 9, db/+ Lsd1 fl/+β 16.8 mM glc wk 9, and all genotypes 16.8 mM glc + Ex4 wk 9: n = 12 islet pools, all other groups: n = 6 islet pools. (g and h) Islet insulin content for islets from the indicated genotypes of mice. db/+ Lsd1 Δβ wk 7: n = 12 pools of 10 islets each, db/+ Lsd1 fl/+β wk 7: n = 17 islet pools, db/+ Lsd1 Δβ wk 9: n = 23 islet pools, all other groups: n = 24 islet pools. (i) Schematic of S961 administration via transplanted minipumps (20 nmol/week). Veh, vehicle. (j) Time course of ad libitum-fed blood glucose levels in TM-treated Lsd1 fl/+ ; Pdx1-CreER mice ( Lsd1 fl/+ β ) and TM-treated Lsd1 fl/fl ; Pdx1-CreER mice ( Lsd1 Δβ ) administered S961 or vehicle. Lsd1 fl/+ β veh: n = 3, Lsd1 Δβ veh: n = 5, Lsd1 fl/+ β S961: n = 7, Lsd1 Δβ S961, n = 9. NS, not significant between S961-treated Lsd1 fl/+ β and Lsd1 Δβ mice. * p <0.05 between Lsd1 fl/+ β and Lsd1 Δβ mice (k and l) Blood glucose levels (k) and serum insulin levels (l) after a 6-hour fast in Lsd1 fl/+ β and Lsd1 Δβ treated with S961 or vehicle for the indicated weeks. Lsd1 fl/+ β veh: n = 3, Lsd1 Δβ veh: n = 5, Lsd1 fl/+ β S961: n = 7, Lsd1 Δβ S961, n = 9. Significance was determined by one-way ANOVA followed by Student’s t-test with Welch’s correction for unequal variance as necessary followed by Dunnett’s multiple comparisons test (g and h) or by two-way ANOVA for treatment or genotype interaction with time or stimulation condition followed by Sidak’s (b, c, j) or Benjamini, Krieger and Yekutieli multiple comparisons test (d - f, k, l). * p <0.05, ** p <0.01, *** p <0.001; NS, not significant.

Article Snippet: The following strains were used in this study: Lsd1 flox , Pdx1-creER , and db/db (Jackson labs strain 000642).

Techniques: Injection

Journal: medRxiv

Article Title: Characterization of a pancreatic cancer GWAS signal suggests PDX1 buffers stress in the exocrine pancreas

doi: 10.64898/2026.04.13.26350790

Figure Lengend Snippet: (A) A Manhattan plot of the PanScan (phases I, II, III) and PanC4 meta-analyzed PDAC GWAS results at the chr13q12.2 PDX1 / PLUT locus. SNPs are colored according to their r 2 with the lead variant, rs2297316. (B) Plot of posterior probabilities for SNP inclusion in the 95% credible set of causal variants for the GWAS signal. SNPs are colored according to their r 2 with the lead variant, rs2297316. (C) Genome browser view of the PDX1 / PLUT region overlaying credible set SNPs with pancreatic epigenomic annotations, indicating SNPs with potential regulatory potential. Vertical red lines demonstrate overlap of rs2297316 and rs9581943 with putatively active regulatory regions.

Article Snippet: Gene expression levels were quantified by qRT-PCR using TaqMan (Thermo Fisher Scientific) assays: PDX1 (Hs00236830_m1), PLUT (Hs04940031_m1), CDX2 (Hs01078080_m1), HPRT (Hs99999909_m1).

Techniques: Variant Assay

Journal: medRxiv

Article Title: Characterization of a pancreatic cancer GWAS signal suggests PDX1 buffers stress in the exocrine pancreas

doi: 10.64898/2026.04.13.26350790

Figure Lengend Snippet: (A-B) Violin plots demonstrating GTEx v8 pancreas eQTL associations between rs9581943 genotype and PDX1 (A) or PLUT (B) normalized expression. Numbers under each genotype indicate the sample count. (C-D) LocusCompare plots demonstrate the degree of colocalization between the PDAC GWAS signal and the PDX1 (C) or PLUT (D) cis-eQTL signals (GTEx v8 pancreas). Posterior probability ( PP ) of a shared causal variant between signals was calculated with the coloc R package. SNPs are colored according to their r 2 with rs9581943. (E-F) Violin plots demonstrating the associations between rs9581943 genotype in CRISPR/Cas9-edited Panc 05.04 clones and PDX1 (E) or PLUT (F) normalized expression.

Article Snippet: Gene expression levels were quantified by qRT-PCR using TaqMan (Thermo Fisher Scientific) assays: PDX1 (Hs00236830_m1), PLUT (Hs04940031_m1), CDX2 (Hs01078080_m1), HPRT (Hs99999909_m1).

Techniques: Expressing, Variant Assay, CRISPR, Clone Assay

Journal: medRxiv

Article Title: Characterization of a pancreatic cancer GWAS signal suggests PDX1 buffers stress in the exocrine pancreas

doi: 10.64898/2026.04.13.26350790

Figure Lengend Snippet: Key results from analyses of the Tosti et al. 2021 integrated neonatal, adult, and chronic pancreatitis snRNA-seq datasets. (A) UMAP plots of exocrine pancreatic cells colored by exocrine cell subtype, PDX1 expression, or residualized PDX1 regulatory activity. (B-D) Forest plots of significantly enriched/depleted gene sets (FDR < 0.05) from the GO: Biological Processes (B) , MSigDB Hallmark (C) , and KEGG (D) gene set collections. Dot size scales with -log 10 (FDR) and dot shading corresponds to normalized enrichment score (NES). (E) Forest plot of global associations across all exocrine cells between residualized PDX1 activity and relevant gene module scores, where dot size scales with -log 10 (FDR). (F) Heatmap summarizing exocrine cell subtype-stratified associations between residualized PDX1 activity and relevant gene module scores. Grid shading indicates PDX1 activity coefficient effect size and *, **, and *** indicate FDR < 0.05, 0.01, and 0.001, respectively. (G) Stacked exocrine cell subtype composition plots over smoothed residualized PDX1 activity curves versus scaled pseudotime for each of three representative lineages inferred with the Slingshot R package.

Article Snippet: Gene expression levels were quantified by qRT-PCR using TaqMan (Thermo Fisher Scientific) assays: PDX1 (Hs00236830_m1), PLUT (Hs04940031_m1), CDX2 (Hs01078080_m1), HPRT (Hs99999909_m1).

Techniques: Expressing, Activity Assay

Journal: medRxiv

Article Title: Characterization of a pancreatic cancer GWAS signal suggests PDX1 buffers stress in the exocrine pancreas

doi: 10.64898/2026.04.13.26350790

Figure Lengend Snippet: Key results from analyses of the Chan-Seng-Yue et al. 2020 integrated pancreatic tumors scRNA-seq dataset. (A) UMAP plots of pancreatic tumors cells colored by pancreatic tumor cell transcriptional subtype, PDX1 expression, or PDX1 regulatory activity. (B) Violin plot of PDX1 regulatory activity stratified by pancreatic tumor cell transcriptional subtype. (C-E) Forest plots of top 10 significantly (FDR < 0.05) enriched or depleted gene sets from the GO: Biological Processes (C) , MSigDB Hallmark (D) , and KEGG (E) gene set collections. Dot size scales with-log 10 (FDR) and dot shading corresponds to normalized enrichment score (NES).

Article Snippet: Gene expression levels were quantified by qRT-PCR using TaqMan (Thermo Fisher Scientific) assays: PDX1 (Hs00236830_m1), PLUT (Hs04940031_m1), CDX2 (Hs01078080_m1), HPRT (Hs99999909_m1).

Techniques: Expressing, Activity Assay

Journal: medRxiv

Article Title: Characterization of a pancreatic cancer GWAS signal suggests PDX1 buffers stress in the exocrine pancreas

doi: 10.64898/2026.04.13.26350790

Figure Lengend Snippet: (A) A Manhattan plot of the PanScan (phases I, II, III) and PanC4 meta-analyzed PDAC GWAS results at the chr13q12.2 PDX1 / PLUT locus. SNPs are colored according to their r 2 with the lead variant, rs2297316. (B) Plot of posterior probabilities for SNP inclusion in the 95% credible set of causal variants for the GWAS signal. SNPs are colored according to their r 2 with the lead variant, rs2297316. (C) Genome browser view of the PDX1 / PLUT region overlaying credible set SNPs with pancreatic epigenomic annotations, indicating SNPs with potential regulatory potential. Vertical red lines demonstrate overlap of rs2297316 and rs9581943 with putatively active regulatory regions.

Article Snippet: Gene expression levels were quantified by qRT-PCR using TaqMan (Thermo Fisher Scientific) assays: PDX1 (Hs00236830_m1), PLUT (Hs04940031_m1), CDX2 (Hs01078080_m1), HPRT (Hs99999909_m1).

Techniques: Variant Assay

Journal: medRxiv

Article Title: Characterization of a pancreatic cancer GWAS signal suggests PDX1 buffers stress in the exocrine pancreas

doi: 10.64898/2026.04.13.26350790

Figure Lengend Snippet: (A-B) Violin plots demonstrating GTEx v8 pancreas eQTL associations between rs9581943 genotype and PDX1 (A) or PLUT (B) normalized expression. Numbers under each genotype indicate the sample count. (C-D) LocusCompare plots demonstrate the degree of colocalization between the PDAC GWAS signal and the PDX1 (C) or PLUT (D) cis-eQTL signals (GTEx v8 pancreas). Posterior probability ( PP ) of a shared causal variant between signals was calculated with the coloc R package. SNPs are colored according to their r 2 with rs9581943. (E-F) Violin plots demonstrating the associations between rs9581943 genotype in CRISPR/Cas9-edited Panc 05.04 clones and PDX1 (E) or PLUT (F) normalized expression.

Article Snippet: Gene expression levels were quantified by qRT-PCR using TaqMan (Thermo Fisher Scientific) assays: PDX1 (Hs00236830_m1), PLUT (Hs04940031_m1), CDX2 (Hs01078080_m1), HPRT (Hs99999909_m1).

Techniques: Expressing, Variant Assay, CRISPR, Clone Assay

Journal: medRxiv

Article Title: Characterization of a pancreatic cancer GWAS signal suggests PDX1 buffers stress in the exocrine pancreas

doi: 10.64898/2026.04.13.26350790

Figure Lengend Snippet: Key results from analyses of the Tosti et al. 2021 integrated neonatal, adult, and chronic pancreatitis snRNA-seq datasets. (A) UMAP plots of exocrine pancreatic cells colored by exocrine cell subtype, PDX1 expression, or residualized PDX1 regulatory activity. (B-D) Forest plots of significantly enriched/depleted gene sets (FDR < 0.05) from the GO: Biological Processes (B) , MSigDB Hallmark (C) , and KEGG (D) gene set collections. Dot size scales with -log 10 (FDR) and dot shading corresponds to normalized enrichment score (NES). (E) Forest plot of global associations across all exocrine cells between residualized PDX1 activity and relevant gene module scores, where dot size scales with -log 10 (FDR). (F) Heatmap summarizing exocrine cell subtype-stratified associations between residualized PDX1 activity and relevant gene module scores. Grid shading indicates PDX1 activity coefficient effect size and *, **, and *** indicate FDR < 0.05, 0.01, and 0.001, respectively. (G) Stacked exocrine cell subtype composition plots over smoothed residualized PDX1 activity curves versus scaled pseudotime for each of three representative lineages inferred with the Slingshot R package.

Article Snippet: Gene expression levels were quantified by qRT-PCR using TaqMan (Thermo Fisher Scientific) assays: PDX1 (Hs00236830_m1), PLUT (Hs04940031_m1), CDX2 (Hs01078080_m1), HPRT (Hs99999909_m1).

Techniques: Expressing, Activity Assay

Journal: medRxiv

Article Title: Characterization of a pancreatic cancer GWAS signal suggests PDX1 buffers stress in the exocrine pancreas

doi: 10.64898/2026.04.13.26350790

Figure Lengend Snippet: Key results from analyses of the Chan-Seng-Yue et al. 2020 integrated pancreatic tumors scRNA-seq dataset. (A) UMAP plots of pancreatic tumors cells colored by pancreatic tumor cell transcriptional subtype, PDX1 expression, or PDX1 regulatory activity. (B) Violin plot of PDX1 regulatory activity stratified by pancreatic tumor cell transcriptional subtype. (C-E) Forest plots of top 10 significantly (FDR < 0.05) enriched or depleted gene sets from the GO: Biological Processes (C) , MSigDB Hallmark (D) , and KEGG (E) gene set collections. Dot size scales with-log 10 (FDR) and dot shading corresponds to normalized enrichment score (NES).

Article Snippet: Gene expression levels were quantified by qRT-PCR using TaqMan (Thermo Fisher Scientific) assays: PDX1 (Hs00236830_m1), PLUT (Hs04940031_m1), CDX2 (Hs01078080_m1), HPRT (Hs99999909_m1).

Techniques: Expressing, Activity Assay

Journal: Oncogene

Article Title: Role of SCAP in regulation of pancreatic homeostasis, pancreatitis, and tumorigenesis

doi: 10.1038/s41388-026-03784-y

Figure Lengend Snippet: A GSEA analysis of upregulated and downregulated Hallmark genesets in the Scap Δpanc compared to Scap f/f acinar cluster. B IPA upstream regulator analysis of predicted upregulated and downregulated signaling pathways in the Scap Δpanc acinar cluster compared to Scap f/f . C Enrichr analysis of Jensen DISEASES genesets associated with genes overexpressed in Scap Δpanc versus Scap f/f acinar cells. D GSEA analysis of upregulated and downregulated Hallmark genesets in the Scap Δpanc compared to Scap f/f exocrine cluster. E IPA analysis of predicted upregulated and downregulated signaling pathways associated with observed gene expression changes in the Scap Δpanc versus Scap f/f exocrine cluster. F A UMAP projection of Scap Δpanc (left) and Scap f/f (right) pancreatic exocrine and acinar cells. Point color—from blue (early pseudotime, least differentiated, expressing genes Pdx1 , Hnf1b , Sox9 , Ptf1a ) through yellow (intermediate) to red (late pseudotime, most differentiated, expressing genes Amy2a , Cpa1 , Prss1 , Krt19 )—reflects Monocle 3-inferred differentiation progression, showing that Scap Δpanc cells are restricted to the middle differentiation stages while Scap f/f cells had both earlier and later differentiation states. G A violin plot showing the quantification of the pseudotime distribution of Scap Δpanc and Scap f/f clusters. H A UMAP projection of pseudotime values split into three equally populated bins (Early, Middle, and Late) using quantile-based tertile cuts. I Bar chart of percentage of cells in Scap Δpanc and Scap f/f samples by pseudotime stage. J Graphical abstract describing how the loss of Scap impacts the pancreas. Created in BioRender. Lilly, A. (2026) https://BioRender.com/511uib5 . *** p ≤ 0.001, in all panels. Chi-square test used for quantification of percentage of cells by pseudotime stage.

Article Snippet: The analysis used Pdx1-Cre mice ([ ], Jax#014647, RRID:IMSR_JAX:014647) and Scap f/f mice ([ ], Jax#004162, RRID:IMSR_JAX:004162) obtained from Jackson laboratory (Bar Harbor, ME).

Techniques: Protein-Protein interactions, Gene Expression, Expressing