Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

RNA-seq of hepatocytes obtained through step-wise differentiation of hIPSCs from a patient with A1AT deficiency and its point mutation-corrected isogenic hIPSC line. Comparison to primary hepatocytes from a healthy donor and an A1AT-deficient patient.

ABSTRACT: A1AT deficiency is an autosomal not recessive disorder caused by mutations in the SERPINA1 gene. Individuals with the Z variant retain polymerised protein in the endoplasmic reticulum of hepatocytes, predisposing them to liver disease. This study primarily aimed to uncover the molecular mechanisms that link protein misfolding to liver injury. To that end, RNA was extracted from hepatocytes differentiated from hIPSCs carrying the Z variant and mutation-corrected hIPSCs (control). The second objective of the study was to benchmark the gene expression profile of both hIPSC-derived hepatocytes types to primary hepatocytes of wild type and a Z variant A1AT genotype.

INSTRUMENT(S): Illumina MiSeq, Illumina HiSeq 2000

ORGANISM(S): Homo sapiens

SUBMITTER: Rute Tomaz

PROVIDER: E-MTAB-6781 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

hiPSC hepatocyte model demonstrates the role of unfolded protein response and inflammatory networks in α<sub>1</sub>-antitrypsin deficiency.

Segeritz Charis-Patricia CP Rashid Sheikh Tamir ST de Brito Miguel Cardoso MC Serra Maria Paola MP Ordonez Adriana A Morell Carola Maria CM Kaserman Joseph E JE Madrigal Pedro P Hannan Nicholas R F NRF Gatto Laurent L Tan Lu L Wilson Andrew A AA Lilley Kathryn K Marciniak Stefan J SJ Gooptu Bibek B Lomas David A DA Vallier Ludovic L

Journal of hepatology 20180605 4

<h4>Background & aims</h4>α<sub>1</sub>-Antitrypsin deficiency (A1ATD) is an autosomal recessive disorder caused by mutations in the SERPINA1 gene. Individuals with the Z variant (Gly342Lys) retain polymerised protein in the endoplasmic reticulum (ER) of their hepatocytes, predisposing them to liver disease. The concomitant lack of circulating A1AT also causes lung emphysema. Greater insight into the mechanisms that link protein misfolding to liver injury will facilitate the design of novel ther ...[more]

PMID: 29879455

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Project description:Cell-based models of many neurological and psychiatric diseases, established by reprogramming patient somatic cells into human induced pluripotent stem cells (hiPSCs), have now been reported. While numerous reports have demonstrated that neuronal cells differentiated from hiPSCs are electrophysiologically active mature neurons, the âageâ of these cells relative to cells in the human brain remains unresolved. Comparisons of gene expression profiles of hiPSC-derived neural progenitor cells (NPCs) and neurons to the Allen BrainSpan Atlas indicate that hiPSC neural cells most resemble first trimester neural tissue. Consequently, we posit that hiPSC-derived neural cells may most accurately be used to model the early developmental defects that contribute to disease predisposition rather than the late features of the disease. Though the characteristic symptoms of schizophrenia SZ generally appear late in adolescence, it is now thought to be a neurodevelopmental condition, often predated by a prodromal period that can appear in early childhood. Postmortem studies of SZ brain tissue typically describe defects in mature neurons, such as reduced neuronal size and spine density in the prefrontal cortex and hippocampus, but abnormalities of neuronal organization, particularly in the cortex, have also been reported. We postulated that defects in cortical organization in SZ might result from abnormal migration of neural cells. To test this hypothesis, we directly reprogrammed fibroblasts from SZ patients into hiPSCs and subsequently differentiated these disorder-specific hiPSCs into NPCs. SZ hiPSC differentiated into forebrain NPCs have altered expression of a number of cellular adhesion genes and WNT signaling. Methods: We compared global transcription of forebrain NPCs from six control and four SZ patients by RNAseq. Results: Multi-dimensional scaling (MDS) resolved most SZ and control hiPSC NPC samples; 848 genes were significantly differentially expressed (FDR<0.01) Conclusions: The WNT signaling pathway was enriched 2-fold (fisher exact test p-value = 0.031). 1-2 independent differentiations (biological replicates) for each of four control and four schizophrenia patients were analyzed; samples were generated in parallel to neuron RNAseq data.

Dataset Information

RNA-seq of hepatocytes obtained through step-wise differentiation of hIPSCs from a patient with A1AT deficiency and its point mutation-corrected isogenic hIPSC line. Comparison to primary hepatocytes from a healthy donor and an A1AT-deficient patient.

Publications

hiPSC hepatocyte model demonstrates the role of unfolded protein response and inflammatory networks in α<sub>1</sub>-antitrypsin deficiency.

Similar Datasets

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