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Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant common complex traits (ATAC-Seq)

ABSTRACT: To investigate the role of the hypothalamus in complex traits, we generated ATAC-seq, RNA-seq, and Promoter Focused Capture C to gain insight into the gene regulatory arcitecture contacting promoters in an embryonic stem cell dervived model of hypothalamic neuron differentiation

ORGANISM(S): Homo sapiens

PROVIDER: GSE152090 | GEO | 2021/10/01

REPOSITORIES: GEO

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Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant common complex traits (RNA-Seq)

Project description:To investigate the role of the hypothalamus in influencing complex traits, we generated ATAC-seq, RNA-seq, and Promoter Focused Capture C to gain insight into the gene regulatory arcitecture contacting promoters in an embryonic stem cell dervived model of hypothalamic neuron differentiation

2021-10-01 | GSE152097 | GEO

Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant common complex traits (Capture C)

Project description:To investigate the role of the hypothalamus in complex traits, we generated ATAC-seq, RNA-seq, and Promoter Focused Capture C to gain insight into the gene regulatory arcitecture contacting promoters in an embryonic stem cell dervived model of hypothalamic neuron differentiation

2021-10-01 | GSE152092 | GEO

Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant complex traits.

Project description:The hypothalamus regulates metabolic homeostasis by influencing behavior and endocrine systems. Given its role governing key traits, such as body weight and reproductive timing, understanding the genetic regulation of hypothalamic development and function could yield insights into disease pathogenesis. However, given its inaccessibility, studying human hypothalamic gene regulation has proven challenging. To address this gap, we generate a high-resolution chromatin architecture atlas of an established embryonic stem cell derived hypothalamic-like neuron model across three stages of in vitro differentiation. We profile accessible chromatin and identify physical contacts between gene promoters and putative cis-regulatory elements to characterize global regulatory landscape changes during hypothalamic differentiation. Next, we integrate these data with GWAS loci for various complex traits, identifying multiple candidate effector genes. Our results reveal common target genes for these traits, potentially affecting core developmental pathways. Our atlas will enable future efforts to determine hypothalamic mechanisms influencing disease susceptibility.

| S-EPMC8604959 | biostudies-literature

A genomic atlas of mouse hypothalamic development

Project description:The hypothalamus is a central regulator of many behaviors essential for survival such as temperature regulation, food intake and circadian rhythms. However, the molecular pathways that mediate hypothalamic development are largely unknown. To identify genes expressed in developing mouse hypothalamus, microarray analysis at 12 different developmental time points was performed. Developmental in situ hybridization was conducted for 1,045 genes dynamically expressed by microarray analysis. In this way, we identified markers that stably labeled each major hypothalamic nucleus over the entire course of neurogenesis, and thus constructed a detailed molecular atlas of the developing hypothalamus. As proof of concept for the utility of this data, we used these markers to analyze the phenotype of mice where Sonic Hedgehog (Shh) was selectively deleted from hypothalamic neuroepithelium, demonstrating an essential role for Shh in anterior hypothalamic patterning. Our results serve as a resource for functional investigations of hypothalamic development, connectivity, physiology, and dysfunction. Affymetrix MOE430 microarrays were used to analyze the expression patterns of mouse hypothalamic and preoptic area tissues. The results were compared across the variables of Strain, Sex and Age.

2010-05-27 | E-GEOD-21278 | biostudies-arrayexpress

Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant common complex traits

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-10-01 | GSE152098 | GEO

A genomic atlas of mouse hypothalamic development

2010-05-04 | GSE21278 | GEO

Repeated hypoglycemia in diabetic mice induce hypothalamic mitochondrial and synaptic activity deregulations characteristic of neurodegenerative diseases

Project description:Repeated exposures to insulin-induced hypoglycemia in diabetic patients progressively impair the counter-regulatory response (CRR) that restores normoglycemia. This defect is characterized by reduced secretion of glucagon and other counter-regulatory hormones. Evidence indicates that glucose responsive neurons located in the hypothalamus, orchestrate the CRR. Here, we aimed at identifying the changes in hypothalamic gene and protein expression that underlie impaired CRR. High fat diet fed and low dose streptozocin-treated C57BL6N mice were exposed to one (acute hypoglycemia, AH) or multiple (recurrent hypoglycemia, RH) insulin-induced hypoglycemic episodes. Single nuclei RNA sequencing (snRNAseq) data were obtained from the hypothalamus and cortex of AH and RH mice. Proteomic data were also obtained from hypothalamic synaptosomal fractions. The present study shows that repeated moderate hypoglycemia in diabetic mice lead, in the hypothalamus, to multiple cellular physiology changes, affecting all cell types and their interactions, which show striking features of neurodegenerative diseases. It also shows that repeated hypoglycemic episodes affect very differently the hypothalamus and the cortex.

2023-11-13 | PXD040183 | Pride

Hypothalamic Proteomics analysis of lipopolysaccharide (LPS)-induced depressed mice

Project description:Hypothalamic dysfunction is a key pathological factor in inflammation-associated depression. In the present study, isobaric tags for relative-absolute quantitation (iTRAQ) combined with mass spectrometry were employed to detect the proteomes in the hypothalamus of the lipopolysaccharide (LPS)-induced depression mouse. A total of 187 proteins were differentially expressed compared with the control group. The results indicated altered molecules were clustered into Ephrin receptor signalling; glutamatergic transmission, and inflammation-related signalling. Ephrin type-B receptor 2 (EPHB2), a transmembrane receptor protein in Ephrin receptor signalling, was significantly elevated and interacted with the accumulated NMDAR subunit GluN2A in the hypothalamus. Additionally, molecules involved in synaptic plasticity regulation, such as hypothalamic postsynaptic density protein-95 (PSD-95), p-AKT and brain-derived neurotrophic factor (BDNF), were significantly altered in the LPS-induced depressed group. It might be an underlying pathogenesis that the EPHB2-GluN2A-AKT cascade regulates synaptic plasticity in depression. EPHB2 can be a potential therapeutic target in the correction of glutamatergic transmission dysfunction. In summary, our findings point to the previously undiscovered molecular underpinnings of the pathophysiology in the hypothalamus of inflammation-associated depression and offer potential targets to develop antidepressants.

2020-01-09 | PXD016040 | Pride

Single cell RNA-Seq identifies mechanisms controlling hypothalamic patterning and differentiation

Project description:The hypothalamus is a central regulator of many innate behaviors that are essential for survival, but the molecular mechanisms controlling hypothalamic patterning and cell fate specification remain poorly understood. To identify genes that control hypothalamic development, we have used single-cell RNA sequencing (scRNA-Seq) to profile mouse hypothalamic gene expression across 11 developmental time points between embryonic day 10 and postnatal day 45. This identified genes that delineated clear developmental trajectories for all major hypothalamic cell types and readily distinguished major regional subdivisions of the developing hypothalamus. We show that this approach can rapidly and comprehensively characterize mutants that control hypothalamic patterning and, in doing so, identify multiple genes that simultaneously repress posterior hypothalamic identity while promoting prethalamic identity. This argues in favor of a modified columnar organization of hypothalamus and prethalamus. These data serve as a resource for further studies of hypothalamic development, physiology, and dysfunction.

2020-08-09 | GSE132355 | GEO

Hypothalamic oxidative stress provokes leptin and insulin resistance [hypothlamus]

Project description:The relationship between loss of hypothalamic function and onset of diabetes mellitus remains elusive. Therefore, we generated a targeted oxidative-stress murine model utilizing conditional knockout of selenocysteine-tRNA (Trsp) using rat insulin promoter-driven-Cre (RIP-Cre). These Trsp-knockout (TrspRIPKO) mice exhibit deletion of Trsp in both hypothalamic cells and pancreatic β-cells leading to increased hypothalamic oxidative stress and severe insulin resistance. Leptin signals were suppressed and numbers of proopiomelanocortin-positive neurons in the hypothalamus were decreased. In contrast, a Trsp-knockout mouse (TrspIns1KO) expressing Cre specifically in pancreatic β-cells, but not in the hypothalamus, did not display insulin and leptin resistance, demonstrating a critical role of the hypothalamus in the onset of diabetes mellitus. Nrf2 (NF-E2-related-factor-2) regulates antioxidant gene expression. Gene-driven increase in Nrf2 signaling suppressed hypothalamic oxidative stress and improved insulin and leptin resistance in TrspRIPKO mice. Thus, Nrf2 harbors the potential to prevent the onset of diabetic mellitus by reducing hypothalamic oxidative damage.

2017-02-06 | GSE92235 | GEO

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