An atrial fibrillation-associated regulatory region modulates cardiac Tbx5 levels and arrhythmia susceptibility DOI Creative Commons
Fernanda M. Bosada, Karel van Duijvenboden,

Alexandra E. Giovou

et al.

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Jan. 30, 2023

Heart development and rhythm control are highly Tbx5 dosage-sensitive. TBX5 haploinsufficiency causes congenital conduction disorders, whereas increased expression levels of in human heart samples has been associated with atrial fibrillation (AF). We deleted the conserved mouse orthologues two independent AF-associated genomic regions locus, one intronic (RE(int)) downstream (RE(down)) . In both lines, we observed a modest (30%) increase postnatal atria. To gain insight into effects slight dosage vivo, investigated transcriptional, epigenetic electrophysiological properties lines. Increased was induction genes involved development, ion transport conduction, susceptibility to arrhythmias, action potential duration cardiomyocytes. identified an variant RE(int) that increases its transcriptional activity. Expression transcription factor Prrx1 induced RE(int)KO found some functional changes atria caused by were normalized when reducing cardiac mice, indicating interaction between these AF genes. conclude dose-dependent factors, common regulatory variants, significantly impact on gene network disease susceptibility.

Language: Английский

The lens epithelium as a major determinant in the development, maintenance, and regeneration of the crystalline lens DOI
Zhenzhen Liu, Shan Huang, Yingfeng Zheng

et al.

Progress in Retinal and Eye Research, Journal Year: 2022, Volume and Issue: 92, P. 101112 - 101112

Published: Aug. 31, 2022

Language: Английский

Citations

55
Variant-to-gene mapping followed by cross-species genetic screening identifies GPI-anchor biosynthesis as a regulator of sleep DOI Creative Commons
Justin Palermo, Alessandra Chesi, Amber Zimmerman

et al.

Science Advances, Journal Year: 2023, Volume and Issue: 9(1)

Published: Jan. 6, 2023

Genome-wide association studies (GWAS) in humans have identified loci robustly associated with several heritable diseases or traits, yet little is known about the functional roles of underlying causal variants regulating sleep duration quality. We applied an ATAC-seq/promoter focused Capture C strategy human iPSC-derived neural progenitors to carry out a "variant-to-gene" mapping campaign that 88 candidate effector genes connected relevant GWAS signals. To functionally validate role implicated regulation, we performed neuron-specific RNA interference screen fruit fly,

Language: Английский

Citations

30
Proteogenomic links to human metabolic diseases DOI
Mine Koprulu, Julia Carrasco-Zanini, Eleanor Wheeler

et al.

Nature Metabolism, Journal Year: 2023, Volume and Issue: 5(3), P. 516 - 528

Published: Feb. 23, 2023

Language: Английский

Citations

27
Deep mutational scanning: A versatile tool in systematically mapping genotypes to phenotypes DOI Creative Commons

Huijin Wei,

Xianghua Li

Frontiers in Genetics, Journal Year: 2023, Volume and Issue: 14

Published: Jan. 12, 2023

Unveiling how genetic variations lead to phenotypic is one of the key questions in evolutionary biology, genetics, and biomedical research. Deep mutational scanning (DMS) technology has allowed mapping tens thousands efficiently economically. Since its first systematic introduction about a decade ago, we have witnessed use deep many research areas leading scientific breakthroughs. Also, methods each step become much more versatile thanks oligo-synthesizing technology, high-throughput phenotyping sequencing technology. However, specific possible pros cons, some limitations still await further technological development. Here, discuss recent accomplishments achieved through describe widely used scanning. We also compare these different analyze their advantages disadvantages, providing insight into design study that best suits aims readers' projects.

Language: Английский

Citations

26
Understanding the genetic complexity of puberty timing across the allele frequency spectrum DOI Creative Commons
Katherine A. Kentistou, Lena R. Kaisinger, Stasa Stankovic

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(7), P. 1397 - 1411

Published: July 1, 2024

Abstract Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women the top bottom 1% polygenic risk exhibited ~11 ~14-fold higher risks delayed precocious puberty, respectively. identified several genes harboring rare loss-of-function variants ~200,000 including ZNF483 , which abolished impact risk. Variant-to-gene mapping approaches mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, uncharacterized G-protein-coupled receptor, GPR83 amplified signaling MC3R a key nutritional sensor. Shared menopause involved DNA damage response suggest that ovarian reserve might signal centrally to trigger puberty. also highlight body size-dependent mechanisms potentially link reproductive life disease.

Language: Английский

Citations

14
Genetically transitional disease: conceptual understanding and applicability to rheumatic disease DOI
Timothy B. Niewold, Ivona Aksentijevich,

Peter D. Gorevic

et al.

Nature Reviews Rheumatology, Journal Year: 2024, Volume and Issue: 20(5), P. 301 - 310

Published: Feb. 28, 2024

Language: Английский

Citations

11
Rapid and quantitative functional interrogation of human enhancer variant activity in live mice DOI Creative Commons
Ethan W. Hollingsworth, Taryn Audrey Liu, Joshua A. Alcantara

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 6, 2025

Abstract Functional analysis of non-coding variants associated with congenital disorders remains challenging due to the lack efficient in vivo models. Here we introduce dual-enSERT, a robust Cas9-based two-color fluorescent reporter system which enables rapid, quantitative comparison enhancer allele activities live mice less than two weeks. We use this technology examine and measure gain- loss-of-function effects previously linked limb polydactyly, autism spectrum disorder, craniofacial malformation. By combining dual-enSERT single-cell transcriptomics, characterise gene expression cells where is normally ectopically active, revealing candidate pathways that may lead misregulation. Finally, demonstrate widespread utility by testing fifteen uncharacterised rare common neurodevelopmental disorders. In doing so identify reproducibly alter activity OTX2 MIR9-2 brain enhancers, implicating them autism. Dual-enSERT thus allows researchers go from identifying comparative embryos under

Language: Английский

Citations

1
The systemic lupus erythematosus-associated NCF190H allele synergizes with viral infection to cause mouse lupus but also limits virus spread DOI Creative Commons
Yanpeng Li, Ana Coelho, Zhilei Li

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 13, 2025

Abstract Studying how single nucleotide polymorphisms (SNPs) crosstalk with non-autologous factors to cause complex autoimmune diseases is challenging. An amino acid replacement in the neutrophil cytosolic factor 1 ( NCF1 -339/ R90H ) leading lower reactive oxygen species induction has been reported as major SNP for systemic lupus erythematosus (SLE). Here we show that infection murine norovirus (MNV) contributes of Ncf1 90H mice. Mutant upregulates IFN-α/JAK1/STAT1 pathway macrophages and anti-MNV-antibody production. In parallel, MNV mice Toll-like receptor 7 macrophages, plasmacytoid dendritic cells B220 + splenocytes, thereby promoting germinal center formation lupus-associated autoantibodies These compounded effects lead protection against but also glomeruloneph ritis proteinuria arthritis absence chemical inducers such pristane. Our data thus suggest this SLE-associated SNP, , synergizes induce development mouse lupus.

Language: Английский

Citations

1
High-throughput screening of human genetic variants by pooled prime editing DOI Creative Commons
Michael Herger, Christina M. Kajba, Megan Buckley

et al.

Cell Genomics, Journal Year: 2025, Volume and Issue: unknown, P. 100814 - 100814

Published: March 1, 2025

Language: Английский

Citations

1
Learning from natural variation across the proteomes of single cells DOI Creative Commons
Nikolai Slavov

PLoS Biology, Journal Year: 2022, Volume and Issue: 20(1), P. e3001512 - e3001512

Published: Jan. 5, 2022

Biological functions arise from protein interactions, which are reflected in the natural variation of proteome configurations across individual cells. Emerging single-cell proteomics methods may decode this and empower inference biological mechanisms with minimal assumptions.

Language: Английский

Citations

32