“…Regulation of POU5F1/OCT4 transcription by HNF1A is an especially exciting finding, connecting HNF1A with a previously unidentified role in regulating stemness. Our study identifies a recently described LTR promoter region (Malakootian et al, 2017), upstream from the canonical POU5F1/OCT4 promoter, as a likely region of direct transcriptional regulation of POU5F1/OCT4 by HNF1A, supported by both ChIP and reporter assays (Figure 6—figure supplement 1B,D). As this promoter region, is not conserved between humans and rodents, it is possible the interaction between HNF1A and POU5F1/OCT4 is an acquisition of human evolution and may explain why POU5F1/OCT4 has not previously been identified as an HNF1A target.…”
Section: Discussionsupporting
confidence: 65%
“…10.7554/eLife.33947.024Figure 6—figure supplement 1.HNF1A binds directly to and activates transcription from the POU5F1/OCT4 upstream LTR region.( A ) Schematic representation of the POU5F1/OCT4 locus, including the canonical exon 1 ( E1 ), distal enhancer region (DE), and the cryptic exon E0 and upstream LTR regions reported in Malakootian et al (2017). Putative HNF1A half-sites (HS) are indicated by purple triangles.…”
Section: Resultsmentioning
confidence: 99%
“…Statistical difference was determined by one-way ANOVA with Tukey’s multiple comparisons test, and comparisons to enrichment of MYOD by HNF1A are shown. ( C ) Schematic representation of Cypridina luciferase (CLuc) reporter constructs, including the cloning vector, a reporter containing the LTR from Malakootian et al (2017) expanded to include the third HNF1A half-site, and a containing the fulllenght canonical POU5F1/OCT4 promoter region. Relative positions of HNF1A half-sites (HS) and the distal enhancer (DE) are indicated.…”
Section: Resultsmentioning
confidence: 99%
“…( A ) Schematic representation of the POU5F1/OCT4 locus, including the canonical exon 1 ( E1 ), distal enhancer region (DE), and the cryptic exon E0 and upstream LTR regions reported in Malakootian et al (2017). Putative HNF1A half-sites (HS) are indicated by purple triangles.…”
Section: Resultsmentioning
confidence: 99%
“…Previously published HNF1A chromatin immunoprecipitation sequencing (ChIP-seq) data performed in HepG2 cells by The Encyclopedia of DNA Elements (ENCODE) project (Consortium and ENCODE Project Consortium, 2012) identified a region of enrichment of HNF1A upstream of the POU5F1/PSORS1C3 gene loci proximal to recently identified retrotransposon long terminal repeat (LTR)-rich region that can serve as a promoter for both genes (Malakootian et al, 2017). Additionally, enrichment of this LTR region by TATA-binding protein (TBP) and acetylated lysine 27 histone H3 supports the involvement of this region in the transcription of POU5F1/OCT4 .…”
The biological properties of pancreatic cancer stem cells (PCSCs) remain incompletely defined and the central regulators are unknown. By bioinformatic analysis of a human PCSC-enriched gene signature, we identified the transcription factor HNF1A as a putative central regulator of PCSC function. Levels of HNF1A and its target genes were found to be elevated in PCSCs and tumorspheres, and depletion of HNF1A resulted in growth inhibition, apoptosis, impaired tumorsphere formation, decreased PCSC marker expression, and downregulation of POU5F1/OCT4 expression. Conversely, HNF1A overexpression increased PCSC marker expression and tumorsphere formation in pancreatic cancer cells and drove pancreatic ductal adenocarcinoma (PDA) cell growth. Importantly, depletion of HNF1A in xenografts impaired tumor growth and depleted PCSC marker-positive cells in vivo. Finally, we established an HNF1A-dependent gene signature in PDA cells that significantly correlated with reduced survivability in patients. These findings identify HNF1A as a central transcriptional regulator of PCSC properties and novel oncogene in PDA.
“…Regulation of POU5F1/OCT4 transcription by HNF1A is an especially exciting finding, connecting HNF1A with a previously unidentified role in regulating stemness. Our study identifies a recently described LTR promoter region (Malakootian et al, 2017), upstream from the canonical POU5F1/OCT4 promoter, as a likely region of direct transcriptional regulation of POU5F1/OCT4 by HNF1A, supported by both ChIP and reporter assays (Figure 6—figure supplement 1B,D). As this promoter region, is not conserved between humans and rodents, it is possible the interaction between HNF1A and POU5F1/OCT4 is an acquisition of human evolution and may explain why POU5F1/OCT4 has not previously been identified as an HNF1A target.…”
Section: Discussionsupporting
confidence: 65%
“…10.7554/eLife.33947.024Figure 6—figure supplement 1.HNF1A binds directly to and activates transcription from the POU5F1/OCT4 upstream LTR region.( A ) Schematic representation of the POU5F1/OCT4 locus, including the canonical exon 1 ( E1 ), distal enhancer region (DE), and the cryptic exon E0 and upstream LTR regions reported in Malakootian et al (2017). Putative HNF1A half-sites (HS) are indicated by purple triangles.…”
Section: Resultsmentioning
confidence: 99%
“…Statistical difference was determined by one-way ANOVA with Tukey’s multiple comparisons test, and comparisons to enrichment of MYOD by HNF1A are shown. ( C ) Schematic representation of Cypridina luciferase (CLuc) reporter constructs, including the cloning vector, a reporter containing the LTR from Malakootian et al (2017) expanded to include the third HNF1A half-site, and a containing the fulllenght canonical POU5F1/OCT4 promoter region. Relative positions of HNF1A half-sites (HS) and the distal enhancer (DE) are indicated.…”
Section: Resultsmentioning
confidence: 99%
“…( A ) Schematic representation of the POU5F1/OCT4 locus, including the canonical exon 1 ( E1 ), distal enhancer region (DE), and the cryptic exon E0 and upstream LTR regions reported in Malakootian et al (2017). Putative HNF1A half-sites (HS) are indicated by purple triangles.…”
Section: Resultsmentioning
confidence: 99%
“…Previously published HNF1A chromatin immunoprecipitation sequencing (ChIP-seq) data performed in HepG2 cells by The Encyclopedia of DNA Elements (ENCODE) project (Consortium and ENCODE Project Consortium, 2012) identified a region of enrichment of HNF1A upstream of the POU5F1/PSORS1C3 gene loci proximal to recently identified retrotransposon long terminal repeat (LTR)-rich region that can serve as a promoter for both genes (Malakootian et al, 2017). Additionally, enrichment of this LTR region by TATA-binding protein (TBP) and acetylated lysine 27 histone H3 supports the involvement of this region in the transcription of POU5F1/OCT4 .…”
The biological properties of pancreatic cancer stem cells (PCSCs) remain incompletely defined and the central regulators are unknown. By bioinformatic analysis of a human PCSC-enriched gene signature, we identified the transcription factor HNF1A as a putative central regulator of PCSC function. Levels of HNF1A and its target genes were found to be elevated in PCSCs and tumorspheres, and depletion of HNF1A resulted in growth inhibition, apoptosis, impaired tumorsphere formation, decreased PCSC marker expression, and downregulation of POU5F1/OCT4 expression. Conversely, HNF1A overexpression increased PCSC marker expression and tumorsphere formation in pancreatic cancer cells and drove pancreatic ductal adenocarcinoma (PDA) cell growth. Importantly, depletion of HNF1A in xenografts impaired tumor growth and depleted PCSC marker-positive cells in vivo. Finally, we established an HNF1A-dependent gene signature in PDA cells that significantly correlated with reduced survivability in patients. These findings identify HNF1A as a central transcriptional regulator of PCSC properties and novel oncogene in PDA.
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