GEO Logo
   NCBI > GEO > Accession DisplayHelp Not logged in | LoginHelp
GEO help: Mouse over screen elements for information.
Series GSE125768 Query DataSets for GSE125768
Status Public on Jun 19, 2019
Title Point mutations in the PDX1 transactivation domain impair human β-cell development and function (ChIP-Seq)
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary Missense mutations in coding region of PDX1 predispose to type-2 diabetes mellitus as well as cause MODY through largely unexplored mechanisms. Here, we screened a large cohort of subjects with increased risk for diabetes and identified two subjects with impaired glucose tolerance carrying heterozygous missense mutations in the PDX1 coding region leading to single amino acid exchanges (P33T, C18R) in its transactivation domain. We generated iPSCs from patients with heterozygous PDX1P33T/+, PDX1C18R/+ mutations and engineered isogenic cell lines carrying homozygous PDX1P33T/P33T, PDX1C18R/C18R mutations and a heterozygous PDX1 loss-of-function mutation (PDX1+/-). Using an in vitro β-cell differentiation protocol, we demonstrated that both PDX1P33T/+, PDX1C18R/+ and PDX1P33T/P33T, PDX1C18R/C18R mutations impair β-cell differentiation and function. Furthermore, PDX1+/- and PDX1P33T/P33T mutations reduced differentiation efficiency of pancreatic progenitors (PPs), due to downregulation of PDX1-bound genes, including transcription factors MNX1 and PDX1 as well as insulin resistance gene CES1. Additionally, both PDX1P33T/+ and PDX1P33T/P33T mutations in PPs reduced the expression of PDX1-bound genes including the long-noncoding RNA, MEG3 and the imprinted gene NEURONATIN, both involved in insulin synthesis and secretion. Our results reveal mechanistic details of how diabetes-associated PDX1 point mutations impair human pancreatic endocrine lineage formation and β-cell function and contribute to pre-disposition for diabetes.
Overall design We performed ChIP-seq of PDX1 and H3K27ac on PDX1P33T/+ cells at PP stage
Contributor(s) Wang X, Sterr M, Ansarullah A, Burtscher I, Böttcher A, Beckenbauer J, Siehler J, Staiger H, Häring H, Lederer G, Meitinger T, Cernilogar F, Schotta G, Irmler M, Beckers J, Wright C, Bakhti M, Lickert H
Citation(s) 30930126
Submission date Jan 28, 2019
Last update date Jun 19, 2019
Contact name Heiko Lickert
Organization name Helmholtz Zentrum München German Research Center for Environmental Health
Department Institute of Diabetes and Regeneration Research
Street address Ingolstaedter Landstraße 1
City Neuherberg
ZIP/Postal code 85764
Country Germany
Platforms (1)
GPL18460 Illumina HiSeq 1500 (Homo sapiens)
Samples (5)
GSM3581644 P33T-PP_H3K27ac_Lane1_TAGCTT
GSM3581645 P33T-PP_H3K27ac_Lane2_TAGCTT
GSM3581646 P33T-PP_H3K27ac_Lane3_TAGCTT
This SubSeries is part of SuperSeries:
GSE125770 Point mutations in the PDX1 transactivation domain impair human β-cell development and function
BioProject PRJNA517474
SRA SRP182693

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE125768_P33T_PDX1_Multi-Condidtion_GEM_events.bed.gz 130.5 Kb (ftp)(http) BED
GSE125768_XM001-P33T_H3K27ac_HOMER_Peaks.bed.gz 530.1 Kb (ftp)(http) BED
SRA Run SelectorHelp
Raw data are available in SRA
Processed data are available on Series record

| NLM | NIH | GEO Help | Disclaimer | Accessibility |
NCBI Home NCBI Search NCBI SiteMap