Chromatin dynamics reveal circadian control of human in vitro islet maturation [ChIP-seq]
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ABSTRACT:
PROVIDER: PRJNA589907 | ENA |
REPOSITORIES: ENA
Dataset's files
primary
| Action | DRS | |||
|---|---|---|---|---|
| SRR10466342_1.fastq.gz | Fastqsanger.gz | |||
| SRR10466342_2.fastq.gz | Fastqsanger.gz | |||
| SRR10466343_1.fastq.gz | Fastqsanger.gz | |||
| SRR10466343_2.fastq.gz | Fastqsanger.gz | |||
| SRR10466344_1.fastq.gz | Fastqsanger.gz |
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Project description:Stem cell-derived tissues could transform disease research and therapy, yet most methods generate functionally immature products. We investigate how human stem cells differentiate into pancreatic islets in vitro by profiling DNA methylation, chromatin accessibility, and histone modification changes. We find that enhancer potential is reset upon lineage commitment, and show how pervasive epigenetic priming steers endocrine cell fates. Modeling islet differentiation and maturation regulatory circuits reveals genes critical for generating endocrine cells and identifies circadian control as limiting for in vitro islet function. Entrainment to circadian feeding/fasting cycles triggers islet metabolic maturation by inducing cyclic synthesis of energy metabolism and insulin secretion effectors, including antiphasic insulin and glucagon pulses. Following entrainment, stem cell-derived islets gain persistent chromatin changes and rhythmic insulin responses with a raised glucose threshold, a hallmark of functional maturity, and function within days of transplantation. Thus, stem cell-derived tissues are amenable to functional improvement by circadian modulation. Overall design: Whole-genome bisulfite sequencing of purified live cells at defined developmental stages from stem cells to mature pancreatic islet α/β cells
2019-11-16 | GSE140501 | GEO
Project description:Stem cell-derived tissues could transform disease research and therapy, yet most methods generate functionally immature products. We investigate how human stem cells differentiate into pancreatic islets in vitro by profiling DNA methylation, chromatin accessibility, and histone modification changes. We find that enhancer potential is reset upon lineage commitment, and show how pervasive epigenetic priming steers endocrine cell fates. Modeling islet differentiation and maturation regulatory circuits reveals genes critical for generating endocrine cells and identifies circadian control as limiting for in vitro islet function. Entrainment to circadian feeding/fasting cycles triggers islet metabolic maturation by inducing cyclic synthesis of energy metabolism and insulin secretion effectors, including antiphasic insulin and glucagon pulses. Following entrainment, stem cell-derived islets gain persistent chromatin changes and rhythmic insulin responses with a raised glucose threshold, a hallmark of functional maturity, and function within days of transplantation. Thus, stem cell-derived tissues are amenable to functional improvement by circadian modulation. Overall design: RNA-seq of purified live cells or whole islet/SC-islet preparations from directional cDNA libraries generated from total RNA depleted for rRNA and sequenced on a HiSeq 2500 instrument.
2019-11-02 | GSE139816 | GEO
Project description:Stem cell-derived tissues could transform disease research and therapy, yet most methods generate functionally immature products. We investigate how human stem cells differentiate into pancreatic islets in vitro by profiling DNA methylation, chromatin accessibility, and histone modification changes. We find that enhancer potential is reset upon lineage commitment, and show how pervasive epigenetic priming steers endocrine cell fates. Modeling islet differentiation and maturation regulatory circuits reveals genes critical for generating endocrine cells and identifies circadian control as limiting for in vitro islet function. Entrainment to circadian feeding/fasting cycles triggers islet metabolic maturation by inducing cyclic synthesis of energy metabolism and insulin secretion effectors, including antiphasic insulin and glucagon pulses. Following entrainment, stem cell-derived islets gain persistent chromatin changes and rhythmic insulin responses with a raised glucose threshold, a hallmark of functional maturity, and function within days of transplantation. Thus, stem cell-derived tissues are amenable to functional improvement by circadian modulation. Overall design: ChIP-sequencing of purified fixed cells at defined developmental stages from stem cells to mature pancreatic islet α/β cells
2019-11-16 | GSE140500 | GEO
Project description:Stem cell-derived tissues could transform disease research and therapy, yet most methods generate functionally immature products. We investigate how human stem cells differentiate into pancreatic islets in vitro by profiling DNA methylation, chromatin accessibility, and histone modification changes. We find that enhancer potential is reset upon lineage commitment, and show how pervasive epigenetic priming steers endocrine cell fates. Modeling islet differentiation and maturation regulatory circuits reveals genes critical for generating endocrine cells and identifies circadian control as limiting for in vitro islet function. Entrainment to circadian feeding/fasting cycles triggers islet metabolic maturation by inducing cyclic synthesis of energy metabolism and insulin secretion effectors, including antiphasic insulin and glucagon pulses. Following entrainment, stem cell-derived islets gain persistent chromatin changes and rhythmic insulin responses with a raised glucose threshold, a hallmark of functional maturity, and function within days of transplantation. Thus, stem cell-derived tissues are amenable to functional improvement by circadian modulation. Overall design: ATAC-sequencing of purified live cells at defined developmental stages from stem cells to mature pancreatic islet α/β cells
2019-11-16 | GSE140499 | GEO
Project description:Chromatin dynamics reveal circadian control of human in vitro islet maturation
| PRJNA587096 | ENA
Project description:Chromatin dynamics reveal circadian control of human in vitro islet maturation [WGBS]
| PRJNA589906 | ENA
Project description:Chromatin dynamics reveal circadian control of human in vitro islet maturation [RNA-seq]
| PRJNA587101 | ENA
Project description:Chromatin dynamics reveal circadian control of human in vitro islet maturation [ATAC-seq]
| PRJNA589908 | ENA
Project description:Development of cell replacement therapies in diabetes requires understanding of the molecular underpinnings of ?-cell maturation. The circadian clock regulates diverse cellular functions important for regulation of ?-cell function and turnover. However, postnatal ontogenesis of the islet circadian clock and its potential role in ?-cell maturation remain unknown. To address this, we studied wild-type Sprague-Dawley as well as Period1 luciferase transgenic (Per1:LUC) rats to determine circadian clock function, clock protein expression, and diurnal insulin secretion during islet development and maturation process. We additionally studied ?-cell-specific Bmal1-deficient mice to elucidate a potential role of this key circadian transcription factor in ?-cell functional and transcriptional maturation. We report that emergence of the islet circadian clock 1) occurs during the early postnatal period, 2) depends on the establishment of global behavioral circadian rhythms, and 3) leads to the induction of diurnal insulin secretion and gene expression. Islet cell maturation was also characterized by induction in the expression of circadian transcription factor BMAL1, deletion of which altered postnatal development of glucose-stimulated insulin secretion and the associated transcriptional network. Postnatal development of the islet circadian clock contributes to early-life ?-cell maturation and should be considered for optimal design of future ?-cell replacement strategies in diabetes.
2018-01-01 | S-EPMC5910002 | BioStudies
Project description:AIMS/HYPOTHESIS: Following on from the emerging importance of the pancreas circadian clock on islet function and the development of type 2 diabetes in rodent models, we aimed to examine circadian gene expression in human islets. The oscillator properties were assessed in intact islets as well as in beta cells. METHODS: We established a system for long-term bioluminescence recording in cultured human islets, employing lentivector gene delivery of the core clock gene Bmal1 (also known as Arntl)-luciferase reporter. Beta cells were stably labelled using a rat insulin2 promoter fluorescent construct. Single-islet/cell oscillation profiles were measured by combined bioluminescence-fluorescence time-lapse microscopy. RESULTS: Human islets synchronised in vitro exhibited self-sustained circadian oscillations of Bmal1-luciferase expression at both the population and single-islet levels, with period lengths of 23.6 and 23.9 h, respectively. Endogenous BMAL1 and CRY1 transcript expression was circadian in synchronised islets over 48 h, and antiphasic to REV-ERB? (also known as NR1D1), PER1, PER2, PER3 and DBP transcript circadian profiles. HNF1A and PDX1 exhibited weak circadian oscillations, in phase with the REV-ERB? transcript. Dispersed islet cells were strongly oscillating as well, at population and single-cell levels. Importantly, beta and non-beta cells revealed oscillatory profiles that were well synchronised with each other. CONCLUSIONS/INTERPRETATION: We provide for the first time compelling evidence for high-amplitude cell-autonomous circadian oscillators displayed in human pancreatic islets and in dispersed human islet cells. Moreover, these clocks are synchronised between beta and non-beta cells in primary human islet cell cultures.
1000-01-01 | S-EPMC3563957 | BioStudies