SLEEP Advances, Journal Year: 2024, Volume and Issue: 5(1)
Published: Jan. 1, 2024
Model organisms such as
Language: Английский
Trends in Genetics, Journal Year: 2024, Volume and Issue: 40(10), P. 834 - 852
Published: June 12, 2024
Circadian rhythms, ~24 h cycles of physiological and behavioral processes, can be synchronized by external signals (e.g., light) persist even in their absence. Consequently, dysregulation circadian rhythms adversely affects the well-being organism. This timekeeping system is generated sustained a genetically encoded endogenous mechanism composed interlocking transcriptional/translational feedback loops that generate rhythmic expression core clock genes. Genome-wide association studies (GWAS) forward genetic show SNPs genes influence gene regulation correlate with risk developing various conditions. We discuss variations are associated phenotypes, implications for human health, stress need thorough this domain regulation.
Language: Английский
Citations
6
Diabetologia, Journal Year: 2024, Volume and Issue: unknown
Published: Sept. 6, 2024
Language: Английский
Citations
5
eLife, Journal Year: 2025, Volume and Issue: 13
Published: Jan. 15, 2025
The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts revealed 19 independent signals trait; however, mechanism action these loci remains to be elucidated. To molecularly characterize loci, we sought determine underlying causal variants corresponding effector genes within diverse cellular contexts. Integrating GWAS summary statistics existing 3D genomic datasets 57 human cell types, consisting high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq, RNA-seq, applied stratified LD score regression calculated proportion SNP heritability attributable type-specific features, revealing pancreatic alpha enrichment as most statistically significant. Subsequent chromatin contact-based fine-mapping was carried out significant their linkage disequilibrium proxies implicate genes, yielded abundant number candidate target at BDNF , ADCY3 TMEM18, FTO skeletal muscle myotubes beta-cell line, EndoC-BH1. One novel implicated gene, ALKAL2 – an inflammation-responsive gene nerve nociceptors observed key TMEM18 locus across multiple immune types. Interestingly, this observation also supported through colocalization analysis using expression quantitative trait (eQTL) derived from Genotype-Tissue Expression (GTEx) dataset, supporting inflammatory neurologic component pathogenesis obesity. Our comprehensive appraisal generated myriad different types provides insights into pediatric pathogenesis.
Language: Английский
Citations
0
The American Journal of Human Genetics, Journal Year: 2025, Volume and Issue: unknown
Published: April 1, 2025
Language: Английский
Citations
0
bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown
Published: March 20, 2024
Over 1,100 independent signals have been identified with genome-wide association studies (GWAS) for bone mineral density (BMD), a key risk factor mortality-increasing fragility fractures; however, the effector gene(s) most remain unknown. Informed by variant-to-gene mapping strategy implicating 89 non-coding elements predicted to regulate osteoblast gene expression at BMD GWAS loci, we executed single-cell CRISPRi screen in human fetal 1.19 cells (hFOBs). The relevance of hFOBs was supported heritability enrichment from cross-cell type stratified LD-score regression involving 98 cell types grouped into 15 tissues. 24 genes showed perturbation screen, four (
Language: Английский
Citations
3
Annual Review of Genomics and Human Genetics, Journal Year: 2024, Volume and Issue: 25(1), P. 259 - 285
Published: April 26, 2024
Healthy sleep is vital for humans to achieve optimal health and longevity. Poor disorders are strongly associated with increased morbidity mortality. However, the importance of good continues be underrecognized. Mechanisms regulating its functions in remain mostly unclear even after decades dedicated research. Advancements gene sequencing techniques computational methodologies have paved way various genetic analysis approaches, which provided some insights into human genetics. This review summarizes our current knowledge basis underlying traits disorders. We also highlight use animal models validate findings from studies discuss potential molecular mechanisms signaling pathways involved regulation sleep.
Language: Английский
Citations
3
Cancer Research, Journal Year: 2023, Volume and Issue: 83(20), P. 3462 - 3477
Published: Aug. 16, 2023
Abstract Long noncoding RNAs (lncRNA) play an important role in gene regulation and contribute to tumorigenesis. While pan-cancer studies of lncRNA expression have been performed for adult malignancies, the landscape across pediatric cancers remains largely uncharted. Here, we curated RNA sequencing data 1,044 leukemia extracranial solid tumors integrated paired tumor whole genome epigenetic relevant cell line models explore expression, regulation, association with cancer. A total 2,657 lncRNAs were robustly expressed six cancers, including 1,142 exhibiting histotype-elevated expression. DNA copy number alterations contributed dysregulation at a proportion comparable protein coding genes. Application multidimensional framework identify prioritize impacting networks revealed that dysregulated cancer are associated proliferation, metabolism, damage hallmarks. Analysis upstream via type–specific transcription factors further implicated distinct developmental lncRNAs. Integration these analyses prioritized experimental validation, silencing TBX2-AS1, top-prioritized neuroblastoma-specific lncRNA, resulted significant growth inhibition neuroblastoma cells, confirming computational predictions. Taken together, provide comprehensive characterization function pave way future mechanistic studies. Significance: Comprehensive leads identification highly childhood annotation showing histotype-specific elevated prediction regulatory networks.
Language: Английский
Citations
7
SLEEP, Journal Year: 2024, Volume and Issue: 47(7)
Published: April 4, 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 reside in non-coding regions are therefore presumed to impact cis-regulatory elements. Our previously reported ‘variant-to-gene mapping’ effort human induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs), combined with validation both Drosophila zebrafish, implicated phosphatidyl inositol glycan (PIG)-Q as a functionally relevant gene at insomnia “WDR90” GWAS locus. However, importantly that did characterize variant. Specifically, our previous 3D genomic datasets nominated shortlist three neighboring single nucleotide polymorphisms (SNPs) strong linkage disequilibrium within an intronic enhancer region WDR90 contacted open PIG-Q promoter. We sought investigate influence these SNPs collectively then individually on modulation pinpoint “regulatory” Starting gross level perturbation, deletion entire NPCs via CRISPR-Cas9 editing subsequent RNA sequencing revealed expression changes specific transcripts. Results from individual luciferase reporter assays each SNP iPSCs rs3752495 risk allele (RA) ~2.5-fold increase expression. Importantly, also exhibited allele-specific effect, RA increasing by ~2-fold versus non-RA. In conclusion, variant-to-function approach vitro implicate variant embedded while modulating distally located PIG-Q.
Language: Английский
Citations
2
Neurobiology of Sleep and Circadian Rhythms, Journal Year: 2023, Volume and Issue: 14, P. 100096 - 100096
Published: May 1, 2023
Sleep fulfills critical functions in neurodevelopment, such as promoting synaptic plasticity, neuronal wiring, and brain connectivity which are phenomena Autism Spectrum Disorder (ASD) pathophysiology. disturbance, specifically insomnia, accompanies ASD is associated with more severe core symptoms (e.g., social impairment). It possible that focusing on identifying effective ways to treat sleep problems can help alleviate other ASD-related symptoms. A body of evidence indicates shared mechanisms neurobiological substrates between investigation these may inform therapeutic effects improving at both behavioral molecular levels. In this study, we tested if behavior were different a zebrafish model the arid1b gene mutated compared controls. This was selected for study expert curations conducted Simons Foundation Research Institute (SFARI) Gene database define it 'high confidence' (i.e., clearly implicated) encoding chromatin remodeling protein. Homozygous mutants displayed increased arousability light their heterozygous wild type counterparts, based testing mechano-acoustic stimulus presenting vibration frequencies increasing intensity detect depth. addition, decreased preference observed homozygous mutant zebrafish. The phenotypes reported our line findings from mouse models human studies demonstrate utility vertebrate system high throughput phenotyping changes relevant ASD. Furthermore, importance including assessments arousal threshold when studying using vivo models.
Language: Английский
Citations
6
Frontiers in Molecular Neuroscience, Journal Year: 2022, Volume and Issue: 15
Published: April 7, 2022
Sleep disorders and chronic sleep disturbances are common associated with cardio-metabolic diseases neuropsychiatric disorders. Several genetic pathways neuronal mechanisms that regulate have been described in animal models, but the genes underlying human variation largely unknown. Identifying these is essential order to develop effective therapies for their comorbidities. To address this unmet health problem, genome-wide association studies (GWAS) identified numerous variants traits However, most cases, it unclear which gene responsible a phenotype variant. As result, necessary experimentally validate candidate by GWAS using an model. Rodents ill-suited endeavor due poor amenability high-throughput assays high costs generating, maintaining, testing large numbers of mutant lines. Zebrafish (
Language: Английский
Citations
8