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Article ; Online: Technologies, strategies, and cautions when deconvoluting genome-wide association signals: FTO in focus.

Pahl, Matthew C / Grant, Struan F A / Leibel, Rudolph L / Stratigopoulos, George

Obesity reviews : an official journal of the International Association for the Study of Obesity

2023 Volume 24, Issue 5, Page(s) e13558

Abstract: Genome-wide association studies have revealed a plethora of genetic variants that correlate with polygenic conditions. However, causal molecular mechanisms have proven challenging to fully define. Without such information, the associations are not ... ...

Abstract	Genome-wide association studies have revealed a plethora of genetic variants that correlate with polygenic conditions. However, causal molecular mechanisms have proven challenging to fully define. Without such information, the associations are not physiologically useful or clinically actionable. By reviewing studies of the FTO locus in the genetic etiology of obesity, we wish to highlight advances in the field fueled by the evolution of technical and analytic strategies in assessing the molecular bases for genetic associations. Particular attention is drawn to extrapolating experimental findings from animal models and cell types to humans, as well as technical aspects used to identify long-range DNA interactions and their biological relevance with regard to the associated trait. A unifying model is proposed by which independent obesogenic pathways regulated by multiple FTO variants and genes are integrated at the primary cilium, a cellular antenna where signaling molecules that control energy balance convene.
MeSH term(s)	Humans ; Animals ; Genome-Wide Association Study ; Obesity/genetics ; Phenotype ; Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics ; Polymorphism, Single Nucleotide
Chemical Substances	Alpha-Ketoglutarate-Dependent Dioxygenase FTO (EC 1.14.11.33) ; FTO protein, human (EC 1.14.11.33)
Language	English
Publishing date	2023-03-07
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2147980-X
ISSN	1467-789X ; 1467-7881
ISSN (online)	1467-789X
ISSN	1467-7881
DOI	10.1111/obr.13558
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Article ; Online: Technologies, strategies, and cautions when deconvoluting genome‐wide association signals: FTO in focus

Pahl, Matthew C. / Grant, Struan F. A. / Leibel, Rudolph L. / Stratigopoulos, George

Obesity Reviews. 2023 May, v. 24, no. 5 p.e13558-

2023

Abstract: Genome‐wide association studies have revealed a plethora of genetic variants that correlate with polygenic conditions. However, causal molecular mechanisms have proven challenging to fully define. Without such information, the associations are not ... ...

Abstract	Genome‐wide association studies have revealed a plethora of genetic variants that correlate with polygenic conditions. However, causal molecular mechanisms have proven challenging to fully define. Without such information, the associations are not physiologically useful or clinically actionable. By reviewing studies of the FTO locus in the genetic etiology of obesity, we wish to highlight advances in the field fueled by the evolution of technical and analytic strategies in assessing the molecular bases for genetic associations. Particular attention is drawn to extrapolating experimental findings from animal models and cell types to humans, as well as technical aspects used to identify long‐range DNA interactions and their biological relevance with regard to the associated trait. A unifying model is proposed by which independent obesogenic pathways regulated by multiple FTO variants and genes are integrated at the primary cilium, a cellular antenna where signaling molecules that control energy balance convene.
Keywords	DNA ; animals ; energy balance ; etiology ; evolution ; loci ; models ; obesity
Language	English
Dates of publication	2023-05
Publishing place	John Wiley & Sons, Ltd
Document type	Article ; Online
Note	REVIEW
ZDB-ID	2147980-X
ISSN	1467-789X ; 1467-7881
ISSN (online)	1467-789X
ISSN	1467-7881
DOI	10.1111/obr.13558
Database	NAL-Catalogue (AGRICOLA)

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Zs.A 5908: Show issues

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Article ; Online: Foxp3 depends on Ikaros for control of regulatory T cell gene expression and function.

Thomas, Rajan M / Pahl, Matthew C / Wang, Liqing / Grant, Struan F A / Hancock, Wayne W / Wells, Andrew D

eLife

2024 Volume 12

Abstract: Ikaros is a transcriptional factor required for conventional T cell development, differentiation, and anergy. While the related factors Helios and Eos have defined roles in regulatory T cells (Treg), a role for Ikaros has not been established. To ... ...

Abstract	Ikaros is a transcriptional factor required for conventional T cell development, differentiation, and anergy. While the related factors Helios and Eos have defined roles in regulatory T cells (Treg), a role for Ikaros has not been established. To determine the function of Ikaros in the Treg lineage, we generated mice with Treg-specific deletion of the Ikaros gene (
MeSH term(s)	Animals ; Ikaros Transcription Factor/metabolism ; Ikaros Transcription Factor/genetics ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism ; Forkhead Transcription Factors/metabolism ; Forkhead Transcription Factors/genetics ; Mice ; Gene Expression Regulation ; Mice, Knockout
Chemical Substances	Ikaros Transcription Factor (148971-36-2) ; Forkhead Transcription Factors ; Foxp3 protein, mouse ; Zfpn1a1 protein, mouse
Language	English
Publishing date	2024-04-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.91392
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Restriction enzyme selection dictates detection range sensitivity in chromatin conformation capture-based variant-to-gene mapping approaches.

Su, Chun / Pahl, Matthew C / Grant, Struan F A / Wells, Andrew D

Human genetics

2021 Volume 140, Issue 10, Page(s) 1441–1448

Abstract: Promoter-focused chromatin conformation techniques directly detect interactions between gene promoters and distal genomic sequences, providing structural information relevant to gene regulation without the excessive non-genic architectural data generated ...

Abstract	Promoter-focused chromatin conformation techniques directly detect interactions between gene promoters and distal genomic sequences, providing structural information relevant to gene regulation without the excessive non-genic architectural data generated by full-scale Hi-C. 3D promoter 'interactome' maps are crucial for understanding how epigenomic features such as histone modifications and open chromatin, or genetic variants identified in genome-wide association studies (GWAS), contribute to biological function. However, variation in sensitivity between such promoter-focused methods, principally due to restriction enzyme selection, has not been systematically assessed. Here, we performed a head-to-head comparison of promoter capture datasets using 4 cutters (DpnII or MboI) versus the 6 cutter HindIII from the same five cell types. While HindIII generally produces a higher signal-to-noise ratio for significant interactions in comparison to 4-cutters, we show that DpnII/MboI detects more proximal interactions and shows little overlap with the HindIII detection range. Promoter-interacting genomic regions mapped by 4-cutters are more enriched for regulatory features and disease-associated genetic variation than 6-cutters maps, suggesting that high-resolution maps better capture gene regulatory architectures than do lower resolution approaches.
MeSH term(s)	Chromatin/genetics ; Chromosome Mapping/methods ; DNA Restriction Enzymes/genetics ; Genetic Variation ; Genome-Wide Association Study/methods ; Humans ; Promoter Regions, Genetic
Chemical Substances	Chromatin ; DNA Restriction Enzymes (EC 3.1.21.-)
Language	English
Publishing date	2021-08-18
Publishing country	Germany
Document type	Comparative Study ; Journal Article
ZDB-ID	223009-4
ISSN	1432-1203 ; 0340-6717
ISSN (online)	1432-1203
ISSN	0340-6717
DOI	10.1007/s00439-021-02326-8
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 256: Show issues

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Article: Delta-dependent Notch activation closes the early neuroblast temporal program to promote lineage progression and neurogenesis termination in

Sood, Chhavi / Nahid, Md Ausrafuggaman / Branham, Kendall R / Pahl, Matthew C / Doyle, Susan E / Siegrist, Sarah E

bioRxiv : the preprint server for biology

2023

Abstract: Neuroblasts ... ...

Abstract	Neuroblasts in
Language	English
Publishing date	2023-09-15
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.28.534626
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Article ; Online: E93 Integrates Neuroblast Intrinsic State with Developmental Time to Terminate MB Neurogenesis via Autophagy.

Pahl, Matthew C / Doyle, Susan E / Siegrist, Sarah E

Current biology : CB

2019 Volume 29, Issue 5, Page(s) 750–762.e3

Abstract: Most neurogenesis occurs during development, driven by the cell divisions of neural stem cells (NSCs). We use Drosophila to understand how neurogenesis terminates once development is complete, a process critical for neural circuit formation. We ... ...

Abstract	Most neurogenesis occurs during development, driven by the cell divisions of neural stem cells (NSCs). We use Drosophila to understand how neurogenesis terminates once development is complete, a process critical for neural circuit formation. We identified E93, a steroid-hormone-induced transcription factor that downregulates phosphatidylinositol 3-kinase (PI3K) levels to activate autophagy for elimination of mushroom body (MB) neuroblasts. MB neuroblasts are a subset of Drosophila NSCs that generate neurons important for memory and learning. MB neurogenesis extends into adulthood when E93 is reduced and terminates prematurely when E93 is overexpressed. E93 is expressed in MB neuroblasts during later stages of pupal development only, which includes the time when MB neuroblasts normally terminate their divisions. Cell intrinsic Imp and Syp temporal factors regulate timing of E93 expression in MB neuroblasts, and extrinsic steroid hormone receptor (EcR) activation boosts E93 levels high for termination. Imp inhibits premature expression of E93 in a Syp-dependent manner, and Syp positively regulates E93 to promote neurogenesis termination. Imp and Syp together with E93 form a temporal cassette, which consequently links early developmental neurogenesis with termination. Altogether, E93 functions as a late-acting temporal factor integrating extrinsic hormonal cues linked to developmental timing with neuroblast intrinsic temporal cues to precisely time neurogenesis ending during development.
MeSH term(s)	Animals ; Autophagy ; Down-Regulation ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster/genetics ; Drosophila melanogaster/physiology ; Gene Expression Regulation, Developmental ; Mushroom Bodies/metabolism ; Neurogenesis/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	Drosophila Proteins ; Eip93F protein, Drosophila ; Transcription Factors
Language	English
Publishing date	2019-02-14
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2019.01.039
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Zs.A 3208: Show issues

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Article ; Online: Variant to gene mapping for carpal tunnel syndrome risk loci implicates skeletal muscle regulatory elements.

Pahl, Matthew C / Liu, Lin / Pippin, James A / Wagley, Yadav / Boehm, Keith / Hankenson, Kurt D / Wells, Andrew D / Yang, Wenli / Grant, Struan F A

EBioMedicine

2024 Volume 101, Page(s) 105038

Abstract: Background: Carpal tunnel syndrome (CTS) is a common disorder caused by compression of the median nerve in the wrist, resulting in pain and numbness throughout the hand and forearm. While multiple behavioural and physiological factors influence CTS risk, ...

Abstract	Background: Carpal tunnel syndrome (CTS) is a common disorder caused by compression of the median nerve in the wrist, resulting in pain and numbness throughout the hand and forearm. While multiple behavioural and physiological factors influence CTS risk, a growing body of evidence supports a strong genetic contribution. Recent genome-wide association study (GWAS) efforts have reported 53 independent signals associated with CTS. While GWAS can identify genetic loci conferring risk, it does not determine which cell types drive the genetic aetiology of the trait, which variants are "causal" at a given signal, and which effector genes correspond to these non-coding variants. These obstacles limit interpretation of potential disease mechanisms. Methods: We analysed CTS GWAS findings in the context of chromatin conformation between gene promoters and accessible chromatin regions across cellular models of bone, skeletal muscle, adipocytes and neurons. We identified proxy variants in high LD with the lead CTS sentinel SNPs residing in promoter connected open chromatin in the skeletal muscle and bone contexts. Findings: We detected significant enrichment for heritability in skeletal muscle myotubes, as well as a weaker correlation in human mesenchymal stem cell-derived osteoblasts. In myotubes, our approach implicated 117 genes contacting 60 proxy variants corresponding to 20 of the 53 GWAS signals. In the osteoblast context we implicated 30 genes contacting 24 proxy variants coinciding with 12 signals, of which 19 genes shared. We subsequently prioritized BZW2 as a candidate effector gene in CTS and implicated it as novel gene that perturbs myocyte differentiation in vitro. Interpretation: Taken together our results suggest that the CTS genetic component influences the size, integrity, and organization of multiple tissues surrounding the carpal tunnel, in particular muscle and bone, to predispose the nerve to being compressed in this disease setting. Funding: This work was supported by NIH Grant UM1 DK126194 (SFAG and WY), R01AG072705 (SFAG & KDH) and the Center for Spatial and Functional Genomics at CHOP (SFAG & ADW). SFAG is supported by the Daniel B. Burke Endowed Chair for Diabetes Research. WY is supported by the Perelman School of Medicine of the University of Pennsylvania.
MeSH term(s)	Humans ; Carpal Tunnel Syndrome/genetics ; Genome-Wide Association Study ; Muscle, Skeletal ; Chromosome Mapping ; Chromatin/genetics ; DNA-Binding Proteins/genetics
Chemical Substances	Chromatin ; BZW2 protein, human ; DNA-Binding Proteins
Language	English
Publishing date	2024-02-27
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2024.105038
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Article ; Online: Perturbation of the insomnia WDR90 GWAS locus pinpoints rs3752495 as a causal variant influencing distal expression of neighboring gene, PIG-Q.

Sonti, Shilpa / Littleton, Sheridan H / Pahl, Matthew C / Zimmerman, Amber J / Chesi, Alessandra / Palermo, Justin / Lasconi, Chiara / Brown, Elizabeth B / Pippin, James A / Wells, Andrew D / Doldur-Balli, Fusun / Pack, Allan I / Gehrman, Phillip R / Keene, Alex C / Grant, Struan F A

Sleep

2024

Abstract: Although genome wide association studies (GWAS) have identified loci for sleep-related traits, they do not directly uncover the underlying causal variants and corresponding effector genes. The majority of such variants reside in non-coding regions and ... ...

Abstract	Although genome wide association studies (GWAS) have identified loci for sleep-related traits, they do not directly uncover the underlying causal variants and corresponding effector genes. The majority of such variants reside in non-coding regions and are therefore presumed to impact cis-regulatory elements. Our previously reported 'variant-to-gene mapping' effort in human induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs), combined with validation in both Drosophila and zebrafish, implicated PIG-Q as a functionally relevant gene at the insomnia 'WDR90' GWAS locus. However, importantly that effort did not characterize the corresponding underlying causal variant. Specifically, our previous 3D genomic datasets nominated a shortlist of three neighboring single nucleotide polymorphisms (SNPs) in strong linkage disequilibrium within an intronic enhancer region of WDR90 that contacted the open PIG-Q promoter. We sought to investigate the influence of these SNPs collectively and then individually on PIG-Q modulation to pinpoint the causal "regulatory" variant. Starting with gross level perturbation, deletion of the entire region in NPCs via CRISPR-Cas9 editing and subsequent RNA sequencing revealed expression changes in specific PIG-Q transcripts. Results from individual luciferase reporter assays for each SNP in iPSCs revealed that the region with the rs3752495 risk allele induced a ~2.5-fold increase in luciferase expression. Importantly, rs3752495 also exhibited an allele specific effect, with the risk allele increasing the luciferase expression by ~2-fold versus the non-risk allele. In conclusion, our variant-to-function approach and in vitro validation implicates rs3752495 as a causal insomnia variant embedded within WDR90 while modulating the expression of the distally located PIG-Q.
Language	English
Publishing date	2024-04-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	424441-2
ISSN	1550-9109 ; 0161-8105
ISSN (online)	1550-9109
ISSN	0161-8105
DOI	10.1093/sleep/zsae085
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Article: GWAS-informed data integration and non-coding CRISPRi screen illuminate genetic etiology of bone mineral density.

Conery, Mitchell / Pippin, James A / Wagley, Yadav / Trang, Khanh / Pahl, Matthew C / Villani, David A / Favazzo, Lacey J / Ackert-Bicknell, Cheryl L / Zuscik, Michael J / Katsevich, Eugene / Wells, Andrew D / Zemel, Babette S / Voight, Benjamin F / Hankenson, Kurt D / Chesi, Alessandra / Grant, Struan F A

bioRxiv : the preprint server for biology

2024

Abstract: Over 1,100 independent signals have been identified with genome-wide association studies (GWAS) for bone mineral density (BMD), a key risk factor for mortality-increasing fragility fractures; however, the effector gene(s) for most remain unknown. ... ...

Abstract	Over 1,100 independent signals have been identified with genome-wide association studies (GWAS) for bone mineral density (BMD), a key risk factor for mortality-increasing fragility fractures; however, the effector gene(s) for most remain unknown. Informed by a variant-to-gene mapping strategy implicating 89 non-coding elements predicted to regulate osteoblast gene expression at BMD GWAS loci, we executed a single-cell CRISPRi screen in human fetal osteoblast 1.19 cells (hFOBs). The BMD relevance of hFOBs was supported by heritability enrichment from cross-cell type stratified LD-score regression involving 98 cell types grouped into 15 tissues. 24 genes showed perturbation in the screen, with four (
Language	English
Publishing date	2024-03-20
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.03.19.585778
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Article: Variant-to-function analysis of the childhood obesity chr12q13 locus implicates rs7132908 as a causal variant within the 3' UTR of

Littleton, Sheridan H / Trang, Khanh B / Volpe, Christina M / Cook, Kieona / DeBruyne, Nicole / Ann Maguire, Jean / Ann Weidekamp, Mary / Boehm, Keith / Chesi, Alessandra / Pippin, James A / Anderson, Stewart A / Wells, Andrew D / Pahl, Matthew C / Grant, Struan F A

bioRxiv : the preprint server for biology

2023

Abstract: 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 ... ...

Abstract	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
Language	English
Publishing date	2023-08-22
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.21.553157
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