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Human NPY/AgRP hypothalamic cell lines for study of obesity susceptibility

ABSTRACT: Recent data suggests that common genetic risk for metabolic disorders such as obesity may be human-specific and exert effects through the central nervous system. To overcome the limitation of human tissue access for study, we have generated induced human pluripotent stem cell (hiPSC)- derived neuronal cultures which recapture many features of hypothalamic neurons within the arcuate nucleus. Here we have comprehensively characterized this model across development and benchmarked these neurons to in vivo events. We also demonstrate their utility in study of obesity risk variants. The dynamic transcriptome across neuronal maturation was examined using microarray and RNAseq methods at 9 time points. K-means clustering of the longitudinal data was conducted to identify co-regulation and miRNA control of biological processes. The transcriptomes were compared to those of 103 samples from 13 brain regions reported in the Genotype-Tissue Expression database (GTEx) using principal components analysis. Genes with proximity to body mass index (BMI)-associated genetic variants were mapped to the developmentally expressed genesets, and enrichment significance was assessed with Fisher’s exact test. The human neuronal cultures have a transcriptional and physiological profile of NPY/AgRP hypothalamic neurons. The neuronal transcriptomes were highly correlated with adult hypothalamus as compared to any other brain region from the GTEx. Also, roughly 25% of the transcripts showed changes in expression across maturation stages and potential co-regulation of biological processes that mirror neuronal development in vivo. These developmentally expressed genes were significantly enriched for genes in proximity to BMI-associated variants.

ORGANISM(S): Homo sapiens

PROVIDER: GSE78789 | GEO | 2018/02/22

REPOSITORIES: GEO

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Project description:Human epidemiologic and animal model data indicate that early environmental influences can persistently alter an individual’s risk of obesity. Environmental effects on hypothalamic developmental epigenetics provide a strong candidate mechanism to explain such ‘developmental programming’ of obesity. To advance our understanding of these processes, it is essential to determine to what extent the diversity of hypothalamic cell types is regulated by epigenetic differences, and when these are established. By performing genome-scale DNA methylation profiling in hypothalamic neurons and non-neuronal cells at postnatal day 0 (P0) and P21, we found that most of the DNA methylation differences distinguishing these two cell types are established postnatally. We found dramatic neuron-specific increases in DNA methylation from P0 to P21. Gene ontology analyses indicated that cell-type specific P0 to P21 methylation changes are key regulators of hypothalamic development. Quantitative bisulfite pyrosequencing verified our methylation profiling results in 16 of 16 selected regions. Expression differences were associated with DNA methylation in several genes analyzed. Our data indicate that future studies of hypothalamic epigenetics in developmental programming of obesity will gain far greater sensitivity and insight by examining outcomes at the cell-type specific level. Moreover, our results provide new evidence that early postnatal life is a critical period for murine hypothalamic developmental epigenetics. Hypothalami were dissected from inbred male C57 mice at postnatal day 0 (P0) and P21. Non-neuronal and neuronal nuclei were separated via fluorescence-activated sorting based on staining for the neuron-specific nuclear surface marker NeuN; each sample for sorting was comprised of 2 age-matched hypothalami. Genome-scale DNA methylation profiling was performed by methylation specific amplification coupled with next generation sequencing (MSA-seq) as decribed below (5 independent samples per age).

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Human NPY/AgRP hypothalamic cell lines for study of obesity susceptibility

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