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n2:pmcid
PMC0
bibo:doi
10.1038%2Fncb3160
n8:contains
_:vb40243311 _:vb40243279 _:vb40243352
Subject Item
_:vb40243279
rdf:type
n8:Section
dc:title
results
n8:contains
_:vb40243288 _:vb40243289 _:vb40243290 _:vb40243291 _:vb40243292 _:vb40243293 _:vb40243294 _:vb40243295 _:vb40243280 _:vb40243281 _:vb40243282 _:vb40243283 _:vb40243284 _:vb40243285 _:vb40243286 _:vb40243287 _:vb40243304 _:vb40243305 _:vb40243306 _:vb40243307 _:vb40243308 _:vb40243309 _:vb40243310 _:vb40243296 _:vb40243297 _:vb40243298 _:vb40243299 _:vb40243300 _:vb40243301 _:vb40243302 _:vb40243303
Subject Item
_:vb40243280
rdf:type
n2:Context
rdf:value
structure formed by cells expressing markers of pancreatic MPCs (including PDX1, HNF1B, FOXA2, NKX6.1 and SOX9), without obvious signs of endocrine or acinar differentiation, and is surrounded by mesenchymal cells (Supplementary Fig. 1a)>>16<<. For simplicity, we refer to this pancreatic MPC-enriched tissue as in vivo MPCs.
n2:mentions
n3:23630303
Subject Item
_:vb40243281
rdf:type
n2:Context
rdf:value
human embryonic tissue is extremely limited and less amenable to perturbation studies, in parallel we used hESCs for in vitro differentiation of cells that express the same constellation of markers as in vivo MPCs (Supplementary Fig. 1a)>>17<<. We refer to these cells as in vitro MPCs.
n2:mentions
n3:23011350
Subject Item
_:vb40243282
rdf:type
n2:Context
rdf:value
Earlier studies have shown that hESCs-derived pancreatic progenitors express appropriate markers>>17<<-20. However, the extent to which they provide a suitable model to study global genome regulation of genuine pancreatic MPCs has not been tested.
n2:mentions
n3:23011350
Subject Item
_:vb40243283
rdf:type
n2:Context
rdf:value
1d, Supplementary Table 3), whose orthologs have also been listed as selectively expressed in mouse embryonic pancreatic buds (Supplementary Table 4)>>21<<,22, suggesting an evolutionary conserved signaling mechanism operating in early pancreas development.
n2:mentions
n3:24013505
Subject Item
_:vb40243284
rdf:type
n2:Context
rdf:value
1d, Supplementary Table 3), whose orthologs have also been listed as selectively expressed in mouse embryonic pancreatic buds (Supplementary Table 4)21,>>22<<, suggesting an evolutionary conserved signaling mechanism operating in early pancreas development.
n2:mentions
n3:23177622
Subject Item
_:vb40243285
rdf:type
n2:Context
rdf:value
To map active cis-regulatory elements in human pancreatic MPCs, we employed in vitro MPCs to profile H3K27ac, which marks active transcriptional enhancers23,>>24<<. We then selected all genomic regions that showed H3K27ac and H3K4me1 enrichment in chromatin from in vitro MPCs, and that were also enriched in H3K4me1 in human Carnegie Stage 16-18 pancreas (in vivo MPCs).
n2:mentions
n3:21106759
Subject Item
_:vb40243286
rdf:type
n2:Context
rdf:value
Notably, 47% showed no overlap with enhancers from adult human islets>>25<< (Fig. 2d).
n2:mentions
n3:24413736
Subject Item
_:vb40243287
rdf:type
n2:Context
rdf:value
Mouse and human genetics have revealed numerous TFs that are essential for the specification, growth and morphogenesis of pancreatic MPCs>>3<<,26, yet very little is known about how such factors promote these processes.
n2:mentions
n3:21337462
Subject Item
_:vb40243288
rdf:type
n2:Context
rdf:value
Mouse and human genetics have revealed numerous TFs that are essential for the specification, growth and morphogenesis of pancreatic MPCs3,>>26<<, yet very little is known about how such factors promote these processes.
n2:mentions
n3:18676806
Subject Item
_:vb40243289
rdf:type
n2:Context
rdf:value
The availability of large numbers of in vitro MPCs allowed us to perform ChIP-seq analysis to profile the occupancy sites of several TFs that are essential for early pancreas development, namely HNF1B>>10<<, ONECUT111, PDX18,9 and GATA65-7, in addition to FOXA212 (Supplementary Table 2).
n2:mentions
n3:15668393
Subject Item
_:vb40243290
rdf:type
n2:Context
rdf:value
The availability of large numbers of in vitro MPCs allowed us to perform ChIP-seq analysis to profile the occupancy sites of several TFs that are essential for early pancreas development, namely HNF1B10, ONECUT>>111<<, PDX18,9 and GATA65-7, in addition to FOXA212 (Supplementary Table 2).
n2:mentions
n3:10825208
Subject Item
_:vb40243291
rdf:type
n2:Context
rdf:value
The availability of large numbers of in vitro MPCs allowed us to perform ChIP-seq analysis to profile the occupancy sites of several TFs that are essential for early pancreas development, namely HNF1B10, ONECUT111, PDX>>18<<,9 and GATA65-7, in addition to FOXA212 (Supplementary Table 2).
n2:mentions
n3:8631275
Subject Item
_:vb40243292
rdf:type
n2:Context
rdf:value
The availability of large numbers of in vitro MPCs allowed us to perform ChIP-seq analysis to profile the occupancy sites of several TFs that are essential for early pancreas development, namely HNF1B10, ONECUT111, PDX18,>>9<< and GATA65-7, in addition to FOXA212 (Supplementary Table 2).
n2:mentions
n3:8988180
Subject Item
_:vb40243293
rdf:type
n2:Context
rdf:value
The availability of large numbers of in vitro MPCs allowed us to perform ChIP-seq analysis to profile the occupancy sites of several TFs that are essential for early pancreas development, namely HNF1B10, ONECUT111, PDX18,9 and GATA>>65<<-7, in addition to FOXA212 (Supplementary Table 2). Based on our computational predictions we also profiled TEAD1, a TEAD homolog that is highly expressed in MPCs from human embryonic pancreas (Supplementary Fig.
n2:mentions
n3:23006325 n3:23006330 n3:22158542
Subject Item
_:vb40243294
rdf:type
n2:Context
rdf:value
large numbers of in vitro MPCs allowed us to perform ChIP-seq analysis to profile the occupancy sites of several TFs that are essential for early pancreas development, namely HNF1B10, ONECUT111, PDX18,9 and GATA65-7, in addition to FOXA>>212<< (Supplementary Table 2). Based on our computational predictions we also profiled TEAD1, a TEAD homolog that is highly expressed in MPCs from human embryonic pancreas (Supplementary Fig.
n2:mentions
n3:19141476
Subject Item
_:vb40243295
rdf:type
n2:Context
rdf:value
Consistently, strong TEAD1 occupancy was not only observed at known targets from other cell types, such as CTGF or CYR>>6127<< (Supplementary Fig.
n2:mentions
n3:18579750
Subject Item
_:vb40243296
rdf:type
n2:Context
rdf:value
1c, Supplementary Table 4) and transcriptome analysis of mouse pancreas development>>21<<,22.
n2:mentions
n3:24013505
Subject Item
_:vb40243297
rdf:type
n2:Context
rdf:value
1c, Supplementary Table 4) and transcriptome analysis of mouse pancreas development21,>>22<<.
n2:mentions
n3:23177622
Subject Item
_:vb40243298
rdf:type
n2:Context
rdf:value
Amongst these, we examined a CRM in the locus encoding SOX9, an essential regulator of the self-renewal of mouse pancreatic MPCs that is mutated in humans with pancreas hypoplasia>>13<<,14 (Fig. 5c,d). This CRM showed pancreas-specific enhancer activity in zebrafish transgenics, whilst mutation of the TEAD recognition sequence abolished enhancer activity, providing further confirmation that TEAD1 binding is required for
n2:mentions
n3:12128229
Subject Item
_:vb40243299
rdf:type
n2:Context
rdf:value
Amongst these, we examined a CRM in the locus encoding SOX9, an essential regulator of the self-renewal of mouse pancreatic MPCs that is mutated in humans with pancreas hypoplasia13,>>14<< (Fig. 5c,d). This CRM showed pancreas-specific enhancer activity in zebrafish transgenics, whilst mutation of the TEAD recognition sequence abolished enhancer activity, providing further confirmation that TEAD1 binding is required for the
n2:mentions
n3:17267606
Subject Item
_:vb40243300
rdf:type
n2:Context
rdf:value
YAP is negatively regulated by Hippo signaling, which triggers YAP phosphorylation and nuclear exclusion>>27<<. We examined nuclear localization of YAP throughout differentiation, and found that YAP was highly expressed in the nucleus of hESCs, and subsequently showed low yet detectable immunoreactivity throughout intermediary stages of the in
n2:mentions
n3:18579750
Subject Item
_:vb40243301
rdf:type
n2:Context
rdf:value
6c-f,h), in keeping with recent descriptions in mice>>28<<. By contrast, YAP immunoreactivity was undetectable or delocalized to the cytoplasm in NGN3+ endocrine-committed progenitors, differentiated acinar cells or endocrine cells (Fig.
n2:mentions
n3:23071096
Subject Item
_:vb40243302
rdf:type
n2:Context
rdf:value
6e), similar to what has been observed in other cell types that exhibit nuclear YAP expression>>27<<. Thus, during embryonic pancreas development the coactivator YAP shows stage-specific nuclear localization in MPCs. This suggests a YAP-dependent function of TEAD1 during early pancreas development that is confined to MPCs, and is then
n2:mentions
n3:18579750
Subject Item
_:vb40243303
rdf:type
n2:Context
rdf:value
To study YAP-dependent TEAD function in pancreatic MPCs, we first used Verteporfin (VP), a chemical compound that disrupts the TEAD-YAP complex>>29<<. VP treatment of human in vitro MPCs and pancreatic bud explants dissected from E11.5 mouse embryos and grown ex-vivo caused decreased expression of a subset of genes associated with TEAD1-bound enhancers, including genes that are
n2:mentions
n3:22677547
Subject Item
_:vb40243304
rdf:type
n2:Context
rdf:value
embryos and grown ex-vivo caused decreased expression of a subset of genes associated with TEAD1-bound enhancers, including genes that are established critical regulators of progenitor cell growth in the embryonic pancreas, such as FGFR>>230<< and SOX914,31, as well as mediators of growth regulatory pathways, such as NOTCH1 and the known Hippo target CCND1 (encoding Cyclin D1)(Fig.
n2:mentions
n3:11891329
Subject Item
_:vb40243305
rdf:type
n2:Context
rdf:value
grown ex-vivo caused decreased expression of a subset of genes associated with TEAD1-bound enhancers, including genes that are established critical regulators of progenitor cell growth in the embryonic pancreas, such as FGFR230 and SOX>>914<<,31, as well as mediators of growth regulatory pathways, such as NOTCH1 and the known Hippo target CCND1 (encoding Cyclin D1)(Fig.
n2:mentions
n3:17267606
Subject Item
_:vb40243306
rdf:type
n2:Context
rdf:value
ex-vivo caused decreased expression of a subset of genes associated with TEAD1-bound enhancers, including genes that are established critical regulators of progenitor cell growth in the embryonic pancreas, such as FGFR230 and SOX914,>>31<<, as well as mediators of growth regulatory pathways, such as NOTCH1 and the known Hippo target CCND1 (encoding Cyclin D1)(Fig.
n2:mentions
n3:17563382
Subject Item
_:vb40243307
rdf:type
n2:Context
rdf:value
In agreement, zebrafish embryos expressing a TEAD protein fused to the transcriptional repressor domain of Engrailed>>32<<, phenocopied the morpholino inhibition of yap1 (Fig.
n2:mentions
n3:16207754
Subject Item
_:vb40243308
rdf:type
n2:Context
rdf:value
5c), and that SOX9 regulates mouse and human pancreatic MPC growth>>13<<,14,31, we hypothesize that the effects of TEAD and YAP on pancreatic progenitors are partially mediated through SOX9.
n2:mentions
n3:12128229
Subject Item
_:vb40243309
rdf:type
n2:Context
rdf:value
5c), and that SOX9 regulates mouse and human pancreatic MPC growth13,>>14<<,31, we hypothesize that the effects of TEAD and YAP on pancreatic progenitors are partially mediated through SOX9.
n2:mentions
n3:17267606
Subject Item
_:vb40243310
rdf:type
n2:Context
rdf:value
5c), and that SOX9 regulates mouse and human pancreatic MPC growth13,14,>>31<<, we hypothesize that the effects of TEAD and YAP on pancreatic progenitors are partially mediated through SOX9.
n2:mentions
n3:17563382
Subject Item
_:vb40243311
rdf:type
n8:Section
dc:title
methods
n8:contains
_:vb40243320 _:vb40243321 _:vb40243322 _:vb40243323 _:vb40243324 _:vb40243325 _:vb40243326 _:vb40243327 _:vb40243312 _:vb40243313 _:vb40243314 _:vb40243315 _:vb40243316 _:vb40243317 _:vb40243318 _:vb40243319 _:vb40243344 _:vb40243345 _:vb40243346 _:vb40243347 _:vb40243348 _:vb40243349 _:vb40243350 _:vb40243351 _:vb40243336 _:vb40243337 _:vb40243338 _:vb40243339 _:vb40243340 _:vb40243341 _:vb40243342 _:vb40243343 _:vb40243328 _:vb40243329 _:vb40243330 _:vb40243331 _:vb40243332 _:vb40243333 _:vb40243334 _:vb40243335
Subject Item
_:vb40243312
rdf:type
n2:Context
rdf:value
embryos were collected with informed consent with approval from the North West Regional Ethics Committee (08/H1010/28) following termination of pregnancy and staged immediately by stereomicroscopy according to the Carnegie classification>>48<<. The collection, use and storage of material followed guidelines from the UK Polkinghorne Committee, legislation of the Human Tissue Act 2004 and the Codes of Practice of the Human Tissue Authority, UK.
n2:mentions
n3:3661464
Subject Item
_:vb40243313
rdf:type
n2:Context
rdf:value
Differentiation of pancreatic MPCs has been described>>17<<. Briefly, definitive endoderm (DE) was induced by growing hESCs in CDM-PVA + Activin-A(100 ng/mL), BMP4(10 ng/mL), bFGF(20 ng/mL) and LY(10 μM)(AFBLy).
n2:mentions
n3:23011350
Subject Item
_:vb40243314
rdf:type
n2:Context
rdf:value
Immunolocalization was performed as described>>16<<,17,49,50. Antibodies are listed in Supplementary Table 23.
n2:mentions
n3:23630303
Subject Item
_:vb40243315
rdf:type
n2:Context
rdf:value
Immunolocalization was performed as described16,>>17<<,49,50. Antibodies are listed in Supplementary Table 23.
n2:mentions
n3:23011350
Subject Item
_:vb40243316
rdf:type
n2:Context
rdf:value
Immunolocalization was performed as described16,17,>>49<<,50. Antibodies are listed in Supplementary Table 23.
n2:mentions
n3:14570708
Subject Item
_:vb40243317
rdf:type
n2:Context
rdf:value
Immunolocalization was performed as described16,17,49,>>50<<. Antibodies are listed in Supplementary Table 23.
n2:mentions
n3:15072563
Subject Item
_:vb40243318
rdf:type
n2:Context
rdf:value
Pancreatic explants from E12.5 C57BL/6 mouse embryos and whole mount stainings were performed as described>>51<< with modifications.
n2:mentions
n3:22951988
Subject Item
_:vb40243319
rdf:type
n2:Context
rdf:value
or ~10 million cells from a pool of 3 pancreatic progenitor in vitro differentiation experiments, were pooled in 1 mL of lysis buffer containing protease inhibitor cocktail (Roche) and sonicated 10-15 cycles essentially as described>>25<<,52. We verified that a substantial portion of chromatin fragments were in the 200-600 bp range by gel electrophoresis.
n2:mentions
n3:24413736
Subject Item
_:vb40243320
rdf:type
n2:Context
rdf:value
or ~10 million cells from a pool of 3 pancreatic progenitor in vitro differentiation experiments, were pooled in 1 mL of lysis buffer containing protease inhibitor cocktail (Roche) and sonicated 10-15 cycles essentially as described25,>>52<<. We verified that a substantial portion of chromatin fragments were in the 200-600 bp range by gel electrophoresis.
n2:mentions
n3:20118932
Subject Item
_:vb40243321
rdf:type
n2:Context
rdf:value
ChIP was performed with 50-300 μL of sonicated chromatin as described>>25<<,53,54, with minor modifications.
n2:mentions
n3:24413736
Subject Item
_:vb40243322
rdf:type
n2:Context
rdf:value
ChIP was performed with 50-300 μL of sonicated chromatin as described25,>>53<<,54, with minor modifications.
n2:mentions
n3:18497863
Subject Item
_:vb40243323
rdf:type
n2:Context
rdf:value
ChIP was performed with 50-300 μL of sonicated chromatin as described25,53,>>54<<, with minor modifications.
n2:mentions
n3:20395405
Subject Item
_:vb40243324
rdf:type
n2:Context
rdf:value
pre-cleared with A/G sepharose beads (GE Healthcare) for 1 hour, incubated overnight at 4°C with 1-1.5μg antibodies (Supplementary Table 23), rotated 2 hours at 4°C with A/G sepharose beads, and then sequentially washed and processed>>25<<,53,54.
n2:mentions
n3:24413736
Subject Item
_:vb40243325
rdf:type
n2:Context
rdf:value
pre-cleared with A/G sepharose beads (GE Healthcare) for 1 hour, incubated overnight at 4°C with 1-1.5μg antibodies (Supplementary Table 23), rotated 2 hours at 4°C with A/G sepharose beads, and then sequentially washed and processed25,>>53<<,54.
n2:mentions
n3:18497863
Subject Item
_:vb40243326
rdf:type
n2:Context
rdf:value
with A/G sepharose beads (GE Healthcare) for 1 hour, incubated overnight at 4°C with 1-1.5μg antibodies (Supplementary Table 23), rotated 2 hours at 4°C with A/G sepharose beads, and then sequentially washed and processed25,53,>>54<<.
n2:mentions
n3:20395405
Subject Item
_:vb40243327
rdf:type
n2:Context
rdf:value
Reads were aligned to the NCBI36/hg18 genome using TopHat-v1.2.>>055<< with default parameters, allowing only 1 mismatch per read.
n2:mentions
n3:19289445
Subject Item
_:vb40243328
rdf:type
n2:Context
rdf:value
For comparison of RNA levels, we processed and calculated fragments per kilobase of exon per million fragments mapped (FPKM) values for each transcript as described>>56<<. For a global comparison of gene expression profiles (Supplementary Fig. 1c), we analyzed 44,699 UCSC gene variants expressed at >5 FPKM in at least one sample. Expression values were median-centered and scaled by the root mean square.
n2:mentions
n3:23040067
Subject Item
_:vb40243329
rdf:type
n2:Context
rdf:value
Transcript functional annotation was performed with DAVID>>57<<, using Gene Ontology (GO) biological process (FAT), Pathways (KEGG, Panther) and annotation clustering.
n2:mentions
n3:19131956
Subject Item
_:vb40243330
rdf:type
n2:Context
rdf:value
GO Biological Process terms were further processed with REVIGO>>46<< (0.9 allowed similarity; term size database–whole UniProt; semantic similarity measure–normalized Resnik; cluster definition default parameters) taking the most significant term in each GO cluster.
n2:mentions
n3:21789182
Subject Item
_:vb40243331
rdf:type
n2:Context
rdf:value
Hierarchical clustering was performed with Cluster>>358<< with similarity metric set to Correlation (uncentered) and average linkage as clustering method.
n2:mentions
n3:14871861
Subject Item
_:vb40243332
rdf:type
n2:Context
rdf:value
Hierarchical clustering was performed with Cluster358 with similarity metric set to Correlation (uncentered) and average linkage as clustering method. Heatmaps were visualized with Treeview>>59<<.
n2:mentions
n3:15180930
Subject Item
_:vb40243333
rdf:type
n2:Context
rdf:value
Clusters of CRMs were defined as described>>25<<, essentially as any group of ≥3 CRMs in which all adjacent CRMs were separated by less than the 25th-percentile of chromosome-specific randomized distances.
n2:mentions
n3:24413736
Subject Item
_:vb40243334
rdf:type
n2:Context
rdf:value
De novo motif discovery was performed with HOMER>>44<<. For enhancers we searched for either short (length=6,8,10,12) or long (length=14,16,18,20) motifs as described previously25, retaining non-redundant matrices (Pearson correlation <0.65) with P<10−50.
n2:mentions
n3:20513432
Subject Item
_:vb40243335
rdf:type
n2:Context
rdf:value
For enhancers we searched for either short (length=6,8,10,12) or long (length=14,16,18,20) motifs as described previously>>25<<, retaining non-redundant matrices (Pearson correlation <0.65) with P<10−50.
n2:mentions
n3:24413736
Subject Item
_:vb40243336
rdf:type
n2:Context
rdf:value
Motifs were annotated using HOMER>>44<<, TOMTOM60 and manual comparisons.
n2:mentions
n3:20513432
Subject Item
_:vb40243337
rdf:type
n2:Context
rdf:value
Motifs were annotated using HOMER44, TOMTOM>>60<< and manual comparisons.
n2:mentions
n3:17324271
Subject Item
_:vb40243338
rdf:type
n2:Context
rdf:value
control tissue fold-enrichment and P values (Chi-squared test), and then combined them in a unique P value for each motif combination with a Z-weighted method>>61<<. Supplementary Table 12 shows the top 50 most enriched combinations.
n2:mentions
n3:16135132
Subject Item
_:vb40243339
rdf:type
n2:Context
rdf:value
Mappable regions were defined as those not annotated as genome gaps and with score of 1 in the CRG Mappability 50 bp track of the UCSC browser>>62<<. Binding enrichment was calculated over the median of 1,000 permutations.
n2:mentions
n3:22276185
Subject Item
_:vb40243340
rdf:type
n2:Context
rdf:value
To mutate CRMs, we replaced a 3 bp sequence of the core of TEAD motifs, as this was previously shown to disrupt TEAD binding>>27<<, and confirmed by Sanger sequencing.
n2:mentions
n3:18579750
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_:vb40243341
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Pancreatic explants were carried out as described>>63<< with minor modifications. Dorsal pancreatic buds from E11.5 CD-1 mouse embryos were cultured in RPMI medium with 10% FBS for 16 hours (day 1) prior to Verteporfin (VP) 0.1 μM (Atomax) or DMSO (control) treatment 24 hours in RPMI 3% FBS.
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n3:15542912
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Oligonucleotide sequences are listed in Supplementary Table 15 and in reference>>17<<. qPCR reactions were normalized to PBGD and analyzed by two-tailed t test.
n2:mentions
n3:23011350
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Five nl of 2 mM morpholino targeting a splice junction of yap1 (yap1-Mo, 5′- AGCAACATTAACAACTCACTTTAGG -3′; previously reported>>64<<) were injected in yolk of 1- to 2-cell stage zebrafish embryos.
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n3:19439659
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The mRNA of mouse Tead2 fused with engrailed repressor domain (TEAD2-EnR) was synthesized using an existing vector>>57<<, and 200 pg was injected in the yolk of 1- to 2-cell stage zebrafish embryos.
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n3:19131956
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In situ hybridization for Sox9b>>65<< and insulin66 was performed as described67 and revealed with NBT/BCIP substrate in 46-71 embryos per condition.
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n3:11180959
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In situ hybridization for Sox9b65 and insulin>>66<< was performed as described67 and revealed with NBT/BCIP substrate in 46-71 embryos per condition.
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n3:10495291
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In situ hybridization for Sox9b65 and insulin66 was performed as described>>67<< and revealed with NBT/BCIP substrate in 46-71 embryos per condition.
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n3:8178366
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All these elements were previously reported>>68<< and were assembled in a tol2 transposon69.
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All these elements were previously reported68 and were assembled in a tol2 transposon>>69<<. Transgenesis was performed as described68 and embryos were grown to 24 and 48 hours post fertilization (hpf) at 28°C. GFP was documented using an epifluorescence stereomicroscope. Embryos positive for transposon integration were
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n3:11027340
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Transgenesis was performed as described>>68<< and embryos were grown to 24 and 48 hours post fertilization (hpf) at 28°C.
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Note that in zebrafish Nkx6.1 is expressed in pancreatic MPCs but not in endocrine cells, unlike mammalian embryos>>47<<. For each construct we counted embryos with GFP expression in Nkx6.1+ pancreatic cells (Supplementary Table 21).
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discussion
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This included clustered enhancers, which were linked to a core cell-specific transcriptional program, in analogy to earlier studies in diverse cellular lineages>>25<<,33. Our studies also show that pancreatic embryonic progenitor cells derived from hESCs mimic salient transcriptional and epigenomic features of pancreatic progenitors from human embryos, illustrating the power of pluripotent stem cell
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n3:24413736
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This included clustered enhancers, which were linked to a core cell-specific transcriptional program, in analogy to earlier studies in diverse cellular lineages25,>>33<<. Our studies also show that pancreatic embryonic progenitor cells derived from hESCs mimic salient transcriptional and epigenomic features of pancreatic progenitors from human embryos, illustrating the power of pluripotent stem cell
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n3:23582322
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In support for this claim, H3K4me1, PDX1 and FOXA2 binding data from in vitro MPCs enabled the identification of recessive mutations that map to a previously unannotated enhancer of PTF1A and cause isolated pancreas agenesis>>34<<. Sequence variation in MPC enhancers could hypothetically increase the susceptibility to type 2 diabetes mellitus by impacting pancreas development and thereby affecting the pancreatic beta cell mass. Finally, germ-line or somatic
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n3:24212882
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Finally, germ-line or somatic variants in MPC enhancers could also influence the development of pancreatic adenocarcinoma, which has been associated with dedifferentiation of adult exocrine cells>>35<<,36 and to YAP activation37,38.
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n3:16702400
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Finally, germ-line or somatic variants in MPC enhancers could also influence the development of pancreatic adenocarcinoma, which has been associated with dedifferentiation of adult exocrine cells35,>>36<< and to YAP activation37,38.
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n3:21730103
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Finally, germ-line or somatic variants in MPC enhancers could also influence the development of pancreatic adenocarcinoma, which has been associated with dedifferentiation of adult exocrine cells35,36 and to YAP activation>>37<<,38.
n2:mentions
n3:24954535
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Finally, germ-line or somatic variants in MPC enhancers could also influence the development of pancreatic adenocarcinoma, which has been associated with dedifferentiation of adult exocrine cells35,36 and to YAP activation37,>>38<<.
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the upstream Hippo kinases Mst1/2 leads to increased proliferation of adult acinar pancreatic cells, which acquire a duct-like morphology, exhibit increased nuclear localization of Yap and show ectopic expression of the TEAD target Sox>>928<<,40. These observations do not address whether Hippo signaling or TEAD are important for pancreatic progenitors, but they are consistent with failed suppression of a progenitor program in adult cells, and therefore support the predictions
n2:mentions
n3:23071096
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upstream Hippo kinases Mst1/2 leads to increased proliferation of adult acinar pancreatic cells, which acquire a duct-like morphology, exhibit increased nuclear localization of Yap and show ectopic expression of the TEAD target Sox928,>>40<<. These observations do not address whether Hippo signaling or TEAD are important for pancreatic progenitors, but they are consistent with failed suppression of a progenitor program in adult cells, and therefore support the predictions
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n3:23454691
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The reactivation of the YAP/TEAD-dependent MPC enhancer program in adult acinar cells could conceivably activate a progenitor-like cellular program during early stages of pancreatic carcinogenesis>>36<<,41, and/or contribute to YAP-dependent cancer progression37,38.
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n3:21730103
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The reactivation of the YAP/TEAD-dependent MPC enhancer program in adult acinar cells could conceivably activate a progenitor-like cellular program during early stages of pancreatic carcinogenesis36,>>41<<, and/or contribute to YAP-dependent cancer progression37,38.
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n3:16702400
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the YAP/TEAD-dependent MPC enhancer program in adult acinar cells could conceivably activate a progenitor-like cellular program during early stages of pancreatic carcinogenesis36,41, and/or contribute to YAP-dependent cancer progression>>37<<,38. This same genetic program could potentially be exploited to control growth and differentiation during the generation of artificial pancreatic cells.
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n3:24954535
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YAP/TEAD-dependent MPC enhancer program in adult acinar cells could conceivably activate a progenitor-like cellular program during early stages of pancreatic carcinogenesis36,41, and/or contribute to YAP-dependent cancer progression37,>>38<<. This same genetic program could potentially be exploited to control growth and differentiation during the generation of artificial pancreatic cells.
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