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

Pahl, Matthew C; Doege, Claudia A.; Hodge, Kenyaita M.; Littleton, Sheridan H.; Leonard, Michelle E.; Lu, Sumei; Rausch, Rick; Pippin, James A.; Bradfield, Jonathan P.; Hammond, Reza; Boehm, Keith D.; Berkowitz, Robert I.; Lasconi, Chiara; Su, Chun; Chesi, Alessandra; Johnson, Matthew E.; Wells, Andrew D.; Voight, Benjamin F.; Leibel, Rudolph L.; Cousminer, Diana L.; Grant, Struan F.A.

doi:10.1101/2020.07.06.146951

Cited by 8 publications

(24 citation statements)

References 55 publications

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“…We compared 2 cell models: hESC-derived HNs and colonoids by leveraging ATAC sequencing–defined open chromatin maps and high-resolution, genome-scale, promoter-focused Capture C atlases. 23 , 24 The HNs data sets were previously derived in our laboratory. 23 Colonoids were derived from rectal biopsy specimens of 3 donors without pathologic disease noted at the time of colonoscopy.…”

Section: Resultsmentioning

confidence: 99%

“…ATAC sequencing libraries were generated and analyzed as previously described. 23,24 Briefly, 100,000 colonoids were collected and pelleted at 550 rcf Q40 for 5 minutes at 4 C. The pellet was resuspended in mL chilled lysis buffer and then centrifuged again at 550 rcf for 10 minutes at 4 C. The pelleted DNA then was tagged using Tn5 Transposase (cat.…”

Section: Atac Sequencingmentioning

confidence: 99%

“…ATAC sequencing libraries for HNs were generated and analyzed previously in our laboratory. 23 Promoter-Focused Capture C…”

Section: Q41mentioning

confidence: 99%

“…24 Promoter-focused Capture-C libraries from HNs were generated and analyzed previously in our laboratory. 23…”

Section: Q43mentioning

confidence: 99%

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Variant-to-Gene-Mapping Analyses Reveal a Role for the Hypothalamus in Genetic Susceptibility to Inflammatory Bowel Disease

Lasconi¹,

Pahl²,

Cousminer³

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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IBD genetic risk profile Non IBD genetic risk profile Dysfunctional stress responses STRESS Flares Functional stress responses SUMMARY Inflammatory bowel disease is associated with stress and depression. These 2 comorbidities are influenced by the hypothalamus. Integrating our 3-dimensional genomic data with publicly available genome-wide association study data, our results implicate a subset of inflammatory bowel disease loci conferring their effect via the hypothalamus. Our findings warrant further investigation.

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Section: Resultsmentioning

confidence: 99%

Section: Atac Sequencingmentioning

confidence: 99%

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Variant-to-Gene-Mapping Analyses Reveal a Role for the Hypothalamus in Genetic Susceptibility to Inflammatory Bowel Disease

Lasconi¹,

Pahl²,

Cousminer³

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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“…We generated ATAC-seq and promoter-focused Capture C libraries from mesenchymal stem cell (MSC)-derived adipocytes and leveraged our existing comparable data from human ESC-derived hypothalamic neurons to query open chromatin maps for open sub-threshold SNPs that contact open gene promoters ( Pahl et al, 2020 ). The adipocytes were derived from mesenchymal stem cells.…”

Section: Resultsmentioning

confidence: 99%

Biological constraints on GWAS SNPs at suggestive significance thresholds reveal additional BMI loci

Hammond

Pahl

et al. 2021

eLife

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To uncover novel significant association signals (p<5×10−8), genome-wide association studies (GWAS) requires increasingly larger sample sizes to overcome statistical correction for multiple testing. As an alternative, we aimed to identify associations among suggestive signals (5 × 10−8≤p<5×10−4) in increasingly powered GWAS efforts using chromatin accessibility and direct contact with gene promoters as biological constraints. We conducted retrospective analyses of three GIANT BMI GWAS efforts using ATAC-seq and promoter-focused Capture C data from human adipocytes and embryonic stem cell (ESC)-derived hypothalamic-like neurons. This approach, with its extremely low false-positive rate, identified 15 loci at p<5×10−5 in the 2010 GWAS, of which 13 achieved genome-wide significance by 2018, including at NAV1, MTIF3, and ADCY3. Eighty percent of constrained 2015 loci achieved genome-wide significance in 2018. We observed similar results in waist-to-hip ratio analyses. In conclusion, biological constraints on sub-significant GWAS signals can reveal potentially true-positive loci for further investigation in existing data sets without increasing sample size.

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Variant-to-gene-mapping followed by cross-species genetic screening identifies GPI-anchor biosynthesis as novel regulator of sleep

Palermo

Chesi

Zimmerman

et al. 2021

Preprint

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Sleep is nearly ubiquitous throughout the animal kingdom, with deficiencies in sleep having been linked to a wide range of human disorders and diseases. While genome wide association studies (GWAS) in humans have been identified loci robustly associated with several heritable diseases or traits, little is known about the functional roles of the underlying causal variants in regulating sleep duration or quality. We applied an ATAC-seq/promoter focused Capture C methodology in iPSC-derived neural progenitors to carry out a variant-to-gene mapping campaign that identified 88 candidate sleep effector genes connected to relevant GWAS signals. To functionally validate the role of the implicated effector genes in sleep regulation, we performed a neuron-specific RNAi screen in the fruit fly, Drosophila melanogaster. This approach identified a number of genes that regulated sleep, including phosphatidylinositol N-acetylglucosaminyltransferase subunit Q (PIG-Q). This gene encodes an enzyme involved in the first step of glycosylphosphatidylinositol (GPI)-anchor biosynthesis. We show that flies deficient for PIG-Q have longer sleep during both the day and night due to an increase in the total number of sleep bouts. Subsequent systematic investigation of other PIG-family genes identified increased sleep in flies for multiple different genes within the PIG pathway. We then mutated the PIG-Q locus in zebrafish and identified similar increases in sleep to those observed in Drosophila, confirming deep homology of PIG-Q mediated sleep regulation. These results provide the first physical variant-to-gene mapping of human sleep genes, and reveals a novel and conserved role for GPI-anchor biosynthesis in sleep regulation.

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

Cited by 8 publications

References 55 publications

Variant-to-Gene-Mapping Analyses Reveal a Role for the Hypothalamus in Genetic Susceptibility to Inflammatory Bowel Disease

Variant-to-Gene-Mapping Analyses Reveal a Role for the Hypothalamus in Genetic Susceptibility to Inflammatory Bowel Disease

Biological constraints on GWAS SNPs at suggestive significance thresholds reveal additional BMI loci

Variant-to-gene-mapping followed by cross-species genetic screening identifies GPI-anchor biosynthesis as novel regulator of sleep

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