Elucidation of HHEX in pancreatic endoderm differentiation using a human iPSC differentiation model

Ito, Ryo; Kimura, Azuma; Hirose, Yurie; Hatano, Yu; Mima, Atsushi; Mae, Shin-Ichi; Keidai, Yamato; Nakamura, Toshihiro; Fujikura, Junji; Nishi, Yoshimi; Ohta, Akira; Toyoda, Tarō; Inagaki, Nobuya; Osafune, Kenji

doi:10.1038/s41598-023-35875-1

Cited by 4 publications

(4 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S3 ). We compared another PDX1 -prone differentiation protocol with the same differentiation duration ( 24 ). While CDX2 expression remained relatively lower than the protocol used in this study, a similar decrease in PDX1 and CDX2 expressions due to the RFX6 deficit was nevertheless observed (Fig.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Human RFX6 regulates endoderm patterning at the primitive gut tube stage

Nakamura,

Fujikura,

Ito

et al. 2023

PNAS Nexus

Self Cite

View full text Add to dashboard Cite

Transcriptional factor RFX6 is known to be a causal gene of Mitchell-Riley syndrome (MRS), an autosomal recessive neonatal diabetes associated with pancreatic hypoplasia and intestinal atresia/malformation. The morphological defects are limited to posterior foregut and mid-hindgut endodermal lineages and do not occur in the anterior foregut lineage; the mechanism remains to be fully elucidated. We generated RFX6 +/eGFP heterozygous-knock-in and RFX6 eGFP/eGFP homozygous knock-in/knock-out human induced pluripotent stem cell (hiPSC) lines and performed in vitro endoderm differentiation to clarify the role of RFX6 in early endoderm development. RFX6 expression is found to surge at the primitive gut tube (PGT) stage in comparison with that in the undifferentiated or definitive endoderm stage. At the PGT stage, the expression of PDX1 and CDX2, posterior foregut and mid-hindgut master regulators, respectively, are decreased by the RFX6 deficit. PDX1+ and CDX2+ cells were mostly GFP+ in RFX6 +/eGFP hiPSCs, but their cell number was markedly decreased in RFX6 eGFP/eGFP hiPSCs. The expression of SOX2, an anterior foregut marker, was not affected by the RFX6 deficit. In addition, we found a putative RFX6-binding X-box motif using CAGE-seq and the motif-containing sequences in the enhancer regions of PDX1 and CDX2 bound to RFX6 in vitro. Thus, RFX6 regulates the ParaHox genes PDX1 and CDX2 but does not affect SOX2 in early endodermal differentiation, suggesting that defects in early-stage endoderm patterning account for the morphological pathology of MRS.

show abstract

Section: Resultsmentioning

confidence: 99%

“…We also used another PDX1 -prone differentiation protocol to validate the consistency of the major results (Fig. S4 ) ( 24 ).…”

Section: Methodsmentioning

confidence: 94%

Human RFX6 regulates endoderm patterning at the primitive gut tube stage

Nakamura,

Fujikura,

Ito

et al. 2023

PNAS Nexus

Self Cite

View full text Add to dashboard Cite

show abstract

“…The ONECUT3 gene is situated on human chromosome 19p13.3 and codes for the protein transcription factor ONECUT3. ONECUT3, a homolog of ONECUT1, is crucial in zebra sh for early-stage bile duct development, neuronal differentiation, endodermal differentiation of the human pancreas, and hearing development in Drosophila 18, [30][31][32][33] . Our study has presented novel evidence regarding the role of ONECUT3 in the aerobic glycolysis of colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

Transcription factor ONECUT3 regulates HDAC6/HIF-1α activity to promote the Warburg effect and tumor growth in colorectal cancer

Xue,

Wang

et al. 2024

Preprint

View full text Add to dashboard Cite

The Warburg effect, also known as aerobic glycolysis, plays a crucial role in the onset and progression of colorectal cancer, although its mechanism remains unclear. Bioinformatics analysis of public databases and verification of clinical specimens revealed that the transcription factor ONECUT3 is a key regulator related to the Warburg effect in colorectal cancer. Functionally, genetic silencing of ONECUT3 reverses the Warburg effect and blunts tumor growth. Importantly, ONECUT3 promotes tumor growth in a glycolysis-dependent manner. Mechanistically, ONECUT3 does not directly alter the expression of hypoxia-inducible factor 1α (HIF-1α), but rather inhibits the acetylation of HIF-1α via histone deacetylase 6 (HDAC6). This inhibition leads to increased transcriptional activity of HIF-1α, ultimately upregulating various glycolysis-related genes downstream of HIF-1α, thereby promoting the Warburg effect in colorectal cancer and facilitating tumor growth. Our study provides evidence for the mechanism of the Warburg effect in colorectal cancer, suggesting that ONECUT3 could be a potential new target for colorectal cancer treatment.

show abstract

“…The pancreas and liver originate from a shared pool of progenitors, and HHEX plays a crucial role in development by serving as a gatekeeper for pancreatic lineage specification by collaborating with pancreatic transcription factors and endodermal transcription factors like FOXA2 and GATA4 [28]. HHEX participates in the development of the pancreatic endoderm by controlling the expression of genes associated with pancreatic development, including NKX6.1, PTF1A, ONECUT1, and ONECUT3 [29]. Notably, HHEX was not detected in the pancreatic β-cells and α-cells of adult humans and mice, while it was exhibited in adult pancreatic δ-cells and regulated somatostatin secretion [30].…”

Section: Hhexmentioning

confidence: 99%

Mechanisms and Physiological Roles of Polymorphisms in Gestational Diabetes Mellitus

Suthon,

Tangjittipokin

2024

IJMS

View full text Add to dashboard Cite

Gestational diabetes mellitus (GDM) is a significant pregnancy complication linked to perinatal complications and an elevated risk of future metabolic disorders for both mothers and their children. GDM is diagnosed when women without prior diabetes develop chronic hyperglycemia due to β-cell dysfunction during gestation. Global research focuses on the association between GDM and single nucleotide polymorphisms (SNPs) and aims to enhance our understanding of GDM’s pathogenesis, predict its risk, and guide patient management. This review offers a summary of various SNPs linked to a heightened risk of GDM and explores their biological mechanisms within the tissues implicated in the development of the condition.

show abstract

Elucidation of HHEX in pancreatic endoderm differentiation using a human iPSC differentiation model

Cited by 4 publications

References 45 publications

Human RFX6 regulates endoderm patterning at the primitive gut tube stage

Human RFX6 regulates endoderm patterning at the primitive gut tube stage

Transcription factor ONECUT3 regulates HDAC6/HIF-1α activity to promote the Warburg effect and tumor growth in colorectal cancer

Mechanisms and Physiological Roles of Polymorphisms in Gestational Diabetes Mellitus

Contact Info

Product

Resources

About