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

и другие.

eLife, Год журнала: 2023, Номер 12

Опубликована: Янв. 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.

Язык: 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

и другие.

Progress in Retinal and Eye Research, Год журнала: 2022, Номер 92, С. 101112 - 101112

Опубликована: Авг. 31, 2022

Язык: Английский

Процитировано

56
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

и другие.

Science Advances, Год журнала: 2023, Номер 9(1)

Опубликована: Янв. 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,

Язык: Английский

Процитировано

30
Deep mutational scanning: A versatile tool in systematically mapping genotypes to phenotypes DOI Creative Commons

Huijin Wei,

Xianghua Li

Frontiers in Genetics, Год журнала: 2023, Номер 14

Опубликована: Янв. 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.

Язык: Английский

Процитировано

27
Proteogenomic links to human metabolic diseases DOI
Mine Koprulu, Julia Carrasco-Zanini, Eleanor Wheeler

и другие.

Nature Metabolism, Год журнала: 2023, Номер 5(3), С. 516 - 528

Опубликована: Фев. 23, 2023

Язык: Английский

Процитировано

27
Understanding the genetic complexity of puberty timing across the allele frequency spectrum DOI Creative Commons
Katherine A. Kentistou, Lena R Kaisinger, Stasa Stankovic

и другие.

Nature Genetics, Год журнала: 2024, Номер 56(7), С. 1397 - 1411

Опубликована: Июль 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.

Язык: Английский

Процитировано

15
Genetically transitional disease: conceptual understanding and applicability to rheumatic disease DOI
Timothy B. Niewold, Ivona Aksentijevich,

Peter D. Gorevic

и другие.

Nature Reviews Rheumatology, Год журнала: 2024, Номер 20(5), С. 301 - 310

Опубликована: Фев. 28, 2024

Язык: Английский

Процитировано

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

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 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

Язык: Английский

Процитировано

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

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 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.

Язык: Английский

Процитировано

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

и другие.

Cell Genomics, Год журнала: 2025, Номер unknown, С. 100814 - 100814

Опубликована: Март 1, 2025

Язык: Английский

Процитировано

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

PLoS Biology, Год журнала: 2022, Номер 20(1), С. e3001512 - e3001512

Опубликована: Янв. 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.

Язык: Английский

Процитировано

33