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| Status |
Public on Mar 29, 2024 |
| Title |
Variant-to-function analysis of the childhood obesity chr12q13 locus implicates rs7132908 as a causal variant within the 3’ UTR of FAIM2 (snATAC-Seq) |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
The ch12q13 obesity locus is among the most significant childhood obesity loci identified in genome-wide association studies. This locus resides in a non-coding region within FAIM2; thus, the underlying causal variant(s) presumably influence disease susceptibility via an influence on cis-regulation within the genomic region. We implicated rs7132908 as a putative causal variant at this locus leveraging a combination of our inhouse 3D genomic data, public domain datasets, and several computational approaches. Using a luciferase reporter assay in human primary astrocytes, we observed allele-specific cis-regulatory activity of the immediate region harboring rs7132908. Motivated by this finding, we went on to generate isogenic human embryonic stem cell lines homozygous for either rs7132908 allele with CRISPR-Cas9 homology-directed repair to assess changes in gene expression due to genotype and chromatin accessibility throughout a differentiation to hypothalamic neurons, a key cell type known to regulate feeding behavior. We observed that the rs7132908 obesity risk allele influenced the expression of FAIM2 along with other genes, decreased the proportion of neurons produced during differentiation, up-regulated cell death gene sets, and conversely down-regulated neuron differentiation gene sets. We have therefore functionally validated rs7132908 as a causal obesity variant which temporally regulates nearby effector genes at the ch12q13 locus and influences neurodevelopment and survival.
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| Overall design |
To investigate the cis-regulatory effects of rs7132908 genotype on chromatin accessibility, we established H9 ESC lines homozygous for the rs7132908 obesity risk A allele with CRISPR-Cas9 homology-directed repair while the parent line is homozygous for the non-risk G allele. We performed single-nucleus ATAC-seq on hypothalamic cells derived from these ESCs after 40 days of differentiation. We identified cell types found in our data using paired single-nucleus RNA-seq profiles and then detected significantly differentially accessible peaks due to rs7132908 genotype in each cell type. We also identified transcription factor motifs significantly enriched in each differentially accessible peak.
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| Contributor(s) |
Littleton SH, Trang KB, Grant SF |
| Citation(s) |
38697123 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| F31 HD105404 |
Investigating the role of the FAIM2 locus in predisposition to childhood obesity |
UNIVERSITY OF PENNSYLVANIA |
Sheridan Hope Littleton |
| R01 HD056465 |
Genome Wide Association Study for Childhood Obesity |
CHILDREN'S HOSPITAL OF PHILADELPHIA |
Struan F A Grant |
| UM1 DK126194 |
Functional Interrogation of T2D-associated genes in human stem cell-derived models and mice |
UNIVERSITY OF PENNSYLVANIA |
Struan F A Grant |
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| Submission date |
Aug 23, 2023 |
| Last update date |
May 03, 2024 |
| Contact name |
Sheridan Hope Littleton |
| E-mail(s) |
sl2225@cam.ac.uk
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| Organization name |
University of Pennsylvania
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| Department |
Genetics
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| Lab |
Struan F.A. Grant
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| Street address |
3615 Civic Center Blvd
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| City |
Philadelphia |
| State/province |
PA |
| ZIP/Postal code |
19104 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (8)
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| GSM7731445 |
snATAC-Seq Hypothalamic Cells, rs7132908 GG, Differentiation 1, Replicate 1 |
| GSM7731446 |
snATAC-Seq Hypothalamic Cells, rs7132908 GG, Differentiation 1, Replicate 2 |
| GSM7731447 |
snATAC-Seq Hypothalamic Cells, rs7132908 GG, Differentiation 1, Replicate 3 |
| GSM7731448 |
snATAC-Seq Hypothalamic Cells, rs7132908 GG, Differentiation 3, Replicate 1 |
| GSM7731449 |
snATAC-Seq Hypothalamic Cells, rs7132908 AA, Differentiation 1, Replicate 1 |
| GSM7731450 |
snATAC-Seq Hypothalamic Cells, rs7132908 AA, Differentiation 2, Replicate 1 |
| GSM7731451 |
snATAC-Seq Hypothalamic Cells, rs7132908 AA, Differentiation 4, Replicate 1 |
| GSM7731452 |
snATAC-Seq Hypothalamic Cells, rs7132908 AA, Differentiation 4, Replicate 2 |
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| This SubSeries is part of SuperSeries: |
| GSE241691 |
Variant-to-function analysis of the childhood obesity chr12q13 locus implicates rs7132908 as a causal variant within the 3’ UTR of FAIM2 |
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| Relations |
| BioProject |
PRJNA1008745 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE241593_barcodes.tsv.gz |
16.2 Mb |
(ftp)(http) |
TSV |
| GSE241593_features.tsv.gz |
6.0 Mb |
(ftp)(http) |
TSV |
| GSE241593_matrix.mtx.gz |
5.7 Gb |
(ftp)(http) |
MTX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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