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| Open AccessBenchmarking of methods for DNA methylome deconvolution
Determining the different cell types that contribute to a mixture of DNA is key for research and diagnostic applications. Here, authors comprehensively benchmark DNA methylation-based deconvolution methods, evaluating their performance and robustness to technical bias.
- Kobe De Ridder
- , Huiwen Che
- & Bernard Thienpont
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Article
| Open AccessMycobacterial biotin synthases require an auxiliary protein to convert dethiobiotin into biotin
Lipid biosynthesis in the pathogen M. tuberculosis depends on biotin for posttranslational modification of key enzymes. Here, Qu et al. identify an auxiliary protein that is required by M. tuberculosis to synthesize biotin.
- Di Qu
- , Peng Ge
- & Dirk Schnappinger
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Article
| Open AccessStructure and genome editing of type I-B CRISPR-Cas
Here the authors present two cryo-EM structures of the Synechocystis sp. PCC 6714 (Syn) type I-B Cascade, revealing the molecular mechanisms that underlie RNA-directed Cascade assembly, target DNA recognition and local conformational changes of the effector complex upon R-loop formation.
- Meiling Lu
- , Chenlin Yu
- & Yibei Xiao
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Article
| Open AccessTransfer learning enables identification of multiple types of RNA modifications using nanopore direct RNA sequencing
Simultaneous profiling of multiple RNA modifications is a promising yet understudied field of research. Here, authors develop a transferable deep learning framework capable of detecting multiple types of RNA modifications in single nanopore sequencing sample.
- You Wu
- , Wenna Shao
- & Xiang Yu
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Article
| Open AccessDeep mutational scanning reveals a correlation between degradation and toxicity of thousands of aspartoacylase variants
The details of how the protein folding and degradation systems collaborate to combat potentially toxic non-native proteins are unknown. Here the authors perform systematic studies of missense and nonsense variants of the cytosolic aspartoacylase, ASPA, where loss-of-function variants are linked to Canavan disease.
- Martin Grønbæk-Thygesen
- , Vasileios Voutsinos
- & Rasmus Hartmann-Petersen
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Article
| Open AccessCoordinated wound responses in a regenerative animal-algal holobiont
The term ‘holobiont’ refers to a multicellular organism and its microbial symbionts. Whether and how symbionts react to host injury and how cellular responses are integrated across species remain unexplored. Here, the authors report a deeply conserved animal regeneration regulatory program that links molecular networks across species in an animal-algal holobiont.
- Dania Nanes Sarfati
- , Yuan Xue
- & Bo Wang
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Article
| Open AccessMammographic density mediates the protective effect of early-life body size on breast cancer risk
Mammographic density is known to be linked to breast cancer risk. Here, the authors use Mendelian randomization to estimate the effects of childhood body size and age at menarche on density phenotypes and breast cancer risk.
- Marina Vabistsevits
- , George Davey Smith
- & Eleanor Sanderson
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Article
| Open AccessEnhancing genome editing in hPSCs through dual inhibition of DNA damage response and repair pathways
Precise genome editing is crucial. Here the authors demonstrate that dual inhibition of p53-mediated cell death and distinct activation of the DNA damage repair system upon DNA damage by cytosine base editor (CBE) or prime editor (PE) additively enhanced editing efficiency in hPSCs.
- Ju-Chan Park
- , Yun-Jeong Kim
- & Hyuk-Jin Cha
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Article
| Open AccessThe greenbeard gene tgrB1 regulates altruism and cheating in Dictyostelium discoideum
Greenbeards encode perceptible signals, signal recognition ability, and altruism towards others displaying the signal. This study shows that activation of the greenbeard receptor gene tgrB1 increases altruism and inactivation causes kin-specific cheating in the social amoeba Dictyostelium discoideum.
- Mariko Katoh-Kurasawa
- , Peter Lehmann
- & Gad Shaulsky
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Article
| Open AccessA time-resolved multi-omics atlas of transcriptional regulation in response to high-altitude hypoxia across whole-body tissues
The mechanisms underlying high-altitude acclimatization remain unclear. Here authors use the sheep model to reveal multi-tissue temporal dynamics of gene transcription and regulation during acclimatization, and provide resources for hypoxia-related studies.
- Ze Yan
- , Ji Yang
- & Meng-Hua Li
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Article
| Open AccessRegulation of Myc transcription by an enhancer cluster dedicated to pluripotency and early embryonic expression
MYC regulates numerous genes involved in cell growth and proliferation. Here, Li-Bao et al. study the DNA regions that regulate Myc transcription in early mouse embryos and pluripotent stem cells. They report a specific region with independent modules dedicated to discrete temporal and spatial phases of Myc expression.
- Lin Li-Bao
- , Covadonga Díaz-Díaz
- & Miguel Torres
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Article
| Open AccessUnveiling the A-to-I mRNA editing machinery and its regulation and evolution in fungi
A-to-I editing in animals is catalyzed by enzymes of the Adenosine Deaminase Acting on RNA family, orthologues of which do not exist in fungi. Here, Feng et al. characterise the enzymes involved in A-to-I mRNA editing in Fusarium graminearum.
- Chanjing Feng
- , Kaiyun Xin
- & Huiquan Liu
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Article
| Open AccessThree concurrent mechanisms generate gene copy number variation and transient antibiotic heteroresistance
Bacterial heteroresistance is a medically relevant phenotype where small antibiotic-resistant subpopulations coexist within predominantly susceptible bacterial populations. Here, Nicoloff et al. describe how three different mechanisms that increase the copy number of resistance genes can lead to unstable and transient heteroresistance.
- Hervé Nicoloff
- , Karin Hjort
- & Helen Wang
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Article
| Open AccessA common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma
Type 2 inflammation drives the formation of pathologic mucus in patients with asthma. Here, authors reveal a role for intelectin-1 in IL-13-induced mucus properties, and that an ITLN1 eQTL is associated with protection from the formation of mucus plugs in T2-high asthma.
- Jamie L. Everman
- , Satria P. Sajuthi
- & Max A. Seibold
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Article
| Open AccessPervasive structural heterogeneity rewires glioblastoma chromosomes to sustain patient-specific transcriptional programs
By applying Hi-C to cells derived from the tumors of 24 GBM patients, the authors show pervasive structural variation in GBM chromosomal organization. How such patient-to-patient variation explains the characteristic gene expression patterns in each tumor is investigated.
- Ting Xie
- , Adi Danieli-Mackay
- & Argyris Papantonis
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Article
| Open AccessIntramolecular autoinhibition regulates the selectivity of PRPF40A tandem WW domains for proline-rich motifs
The specific recognition of a proline-rich motif in the intrinsically disordered region of SF1 by the PRPF40A tandem WW domains is modulated by an intramolecular autoinhibition, suggesting a general mechanism to enhance WW binding selectivity.
- Santiago Martínez-Lumbreras
- , Lena K. Träger
- & Michael Sattler
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Article
| Open AccessHarnessing noncanonical crRNA for highly efficient genome editing
The inclusion of base Z has the potential to heighten the binding affinity between complementary nucleic acids. Here, the authors integrated base Z into CRISRP-Cas12a crRNA to augment the interaction between the crRNA and the target DNA, resulting in a significant enhancement of editing efficiency.
- Guanhua Xun
- , Zhixin Zhu
- & Huimin Zhao
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Article
| Open AccessDeterminants of mosaic chromosomal alteration fitness
Here, the authors use passenger mutations to quantify expansion rate in ~6,000 people with mosaic chromosomal alterations in the NHLBI TOPMed cohort, finding associations between growth rate and blood counts along with germline genetic modulators of growth rate.
- Yash Pershad
- , Taralynn Mack
- & Alexander G. Bick
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Article
| Open AccessComplete male-to-female sex reversal in XY mice lacking the miR-17~92 cluster
The cluster miR-17~92 modulates the expression of genes networks and signalling pathways to ensure proper Sry expression timing and subsequent testis differentiation, an unexpected role for miRNAs in the early steps of mammalian sex determination.
- Alicia Hurtado
- , Irene Mota-Gómez
- & Francisco J. Barrionuevo
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Article
| Open AccessSpatially revealed roles for lncRNAs in Drosophila spermatogenesis, Y chromosome function and evolution
In Drosophila, long noncoding RNAs (lncRNAs) are expressed most highly in male germline cells. Here the authors report the subcellular distributions of approximately 600 Drosophila lncRNAs in male reproductive tissues, indicating potential involvement in spermatogenesis, fertility and evolution.
- Zhantao Shao
- , Jack Hu
- & Henry M. Krause
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Article
| Open AccessDisentangling genetic effects on transcriptional and post-transcriptional gene regulation through integrating exon and intron expression QTLs
Expression quantitative trait loci (eQTL) studies typically only consider exon expression levels and discard intronic RNA sequencing reads. Here, the authors show that analyzing eQTLs together with QTLs for intron levels and exon-intron ratios expands the number and functional understanding of genetic effects on gene regulatory processes.
- Anneke Brümmer
- & Sven Bergmann
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Article
| Open AccessGenetic influence on within-person longitudinal change in anthropometric traits in the UK Biobank
The availability of longitudinal data in large biobanks is increasing. Here, using data from the UK Biobank, the authors develop and apply analytical approaches to quantify genetic contributions to change over time for traits like height and weight.
- Kathryn E. Kemper
- , Julia Sidorenko
- & Peter M. Visscher
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Article
| Open AccessIn vivo genome editing via CRISPR/Cas9-mediated homology-independent targeted integration for Bietti crystalline corneoretinal dystrophy treatment
Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive chorioretinal degenerative disease without approved therapeutic drug. Here, the authors show a promising CRISPR/Cas9 mediated homology-independent targeted integration therapy in patient derived cells and humanized mice carrying BCD mutations.
- Xiang Meng
- , Ruixuan Jia
- & Liping Yang
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Article
| Open AccessGenetic association of inflammatory marker GlycA with lung function and respiratory diseases
Here, the authors observed significant genetic correlation of GlycA with lung function, asthma and COPD and identified ten shared loci revealing potential shared biological mechanisms involving ubiquitination and Wnt/β-catenin signaling.
- Yanjun Guo
- , Quanhong Liu
- & Weihong Chen
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Article
| Open AccessA human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations
Copy number alterations in stem cells impair neural crest differentiation and set the stage for neuroblastoma-like traits and tumours. This study hints at early tumourigenesis mechanisms and finds developmental gene signatures linked to prognosis.
- Ingrid M. Saldana-Guerrero
- , Luis F. Montano-Gutierrez
- & Florian Halbritter
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Article
| Open AccessDisease related changes in ATAC-seq of iPSC-derived motor neuron lines from ALS patients and controls
Amyotrophic Lateral Sclerosis (ALS) is highly heritable but the mechanisms of sporadic ALS are not fully understood. In this study, the authors identify drivers of variation and disease-relevant changes in the epigenomic profile of iPSC-derived motor neuron lines generated from ALS patients and healthy controls as part of the Answer ALS program.
- Stanislav Tsitkov
- , Kelsey Valentine
- & Ernest Fraenkel
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Article
| Open AccessUsing genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes
Here, the authors integrate genomic and transcriptomic data obtained from African-ancestry female participants and identify six genes associated with breast cancer risk which provides biological insights into this common cancer in an underrepresented population.
- Jie Ping
- , Guochong Jia
- & Wei Zheng
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Article
| Open AccessInvestigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment
The effect of noncoding genetic variation on acute lymphoblastic leukemia treatment response is not fully understood. Here, the authors functionally evaluated variants associated with pharmacological traits and validate the role of rs1247117 in gene regulation impacting therapeutic response.
- Kashi Raj Bhattarai
- , Robert J. Mobley
- & Daniel Savic
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Article
| Open AccessThe impact of exercise on gene regulation in association with complex trait genetics
It is known that exercise influences many human traits, but not which tissues and genes are most important. This study connects transcriptome data collected across 15 tissues during exercise training in rats as part of the Molecular Transducers of Physical Activity Consortium with human data to identify traits with similar tissue specific gene expression signatures to exercise.
- Nikolai G. Vetr
- , Nicole R. Gay
- & Stephen B. Montgomery
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Article
| Open AccessLarge-language models facilitate discovery of the molecular signatures regulating sleep and activity
The knowledge in the large language model (LLM), generative pre-trained transformer (GPT) 3.5, is elicited to facilitate the discovery of MRE11 in regulating sleep in the presence of conspecifics by a multi-object video tracking system.
- Di Peng
- , Liubin Zheng
- & Luoying Zhang
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Article
| Open AccessGlis2 is an early effector of polycystin signaling and a target for therapy in polycystic kidney disease
Cyst growth in autosomal dominant polycystic kidney disease (ADPKD) is driven by unknown molecular signals that require the presence of intact primary cilia in the absence of the PKD gene products. Here, the authors show that the transcription factor Glis2 is a key effector of this cilia dependent cyst growth pathway and a potential target for therapy in ADPKD
- Chao Zhang
- , Michael Rehman
- & Stefan Somlo
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Article
| Open AccessThe gene “degrees of kevin bacon” (dokb) regulates a social network behaviour in Drosophila melanogaster
The structure of a social network is thought to be heritable in many animals, including humans. Here, Rooke and colleagues identify a gene, which they name “degrees of kevin bacon (dokb)”, that is expressed in the central nervous system of Drosophila melanogaster and regulates the structure of social networks.
- Rebecca Rooke
- , Joshua J. Krupp
- & Joel D. Levine
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Article
| Open AccessUnraveling the mechanisms of PAMless DNA interrogation by SpRY-Cas9
CRISPR-Cas9 is a powerful tool, but the strict requirement for an “NGG” protospacer-adjacent motif (PAM) sequence limits the number of editable genes. Here the authors combine enzyme kinetics, cryo-EM, and single-molecule imaging to determine how SpRY interrogates DNA and recognises target sites for cleavage.
- Grace N. Hibshman
- , Jack P. K. Bravo
- & David W. Taylor
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Article
| Open AccessA case of T-cell acute lymphoblastic leukemia in retroviral gene therapy for ADA-SCID
Leukaemia development has been reported as an associated risk of haematopoietic stem cell gene therapy (HSPC-GT) using retroviral vectors in different diseases. Here, the authors show a case of T-cell acute lymphoid leukaemia in a patient with Adenosine Deaminase-deficient Severe Combined Immunodeficiency (ADA-SCID) treated with retroviral gene therapy.
- Daniela Cesana
- , Maria Pia Cicalese
- & Alessandro Aiuti
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Article
| Open AccessDopamine signaling enriched striatal gene set predicts striatal dopamine synthesis and physiological activity in vivo
Here, the authors report that schizophrenia risk variants mapping to a striatal dopamine-related gene set are associated with increased striatal dopamine synthesis capacity and increased striatal activity during reward anticipation in humans.
- Leonardo Sportelli
- , Daniel P. Eisenberg
- & Giulio Pergola
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Article
| Open AccessPositive selection in the genomes of two Papua New Guinean populations at distinct altitude levels
This study explores selection signals of Papua New Guinean highlanders and lowlanders using 128 new whole genome sequences. It highlights two genetic variants associated with blood traits that also influence the heart rate of these populations.
- Mathilde André
- , Nicolas Brucato
- & François-Xavier Ricaut
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Article
| Open AccessHIV transmission dynamics and population-wide drug resistance in rural South Africa
There is limited data on drug resistance in South African communities strongly affected by HIV. In this study, the authors observed low levels of resistance to newer drugs but widespread resistance to older HIV medications in a South African community. Resistance to rilpivirine was detected even in untreated individuals.
- Steven A. Kemp
- , Kimia Kamelian
- & Ravindra K. Gupta
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Article
| Open AccessMitochondrial complex I deficiency stratifies idiopathic Parkinson’s disease
Idiopathic Parkinson’s disease can be stratified according to the severity of neuronal respiratory complex I deficiency. The emerging disease subtypes show distinct molecular and clinical profiles.
- Irene H. Flønes
- , Lilah Toker
- & Charalampos Tzoulis
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Article
| Open AccessLinear interaction between replication and transcription shapes DNA break dynamics at recurrent DNA break Clusters
In neural progenitor cells, recurrent DNA break clusters (RDCs) occur to genes crucial for brain function. Here the authors find that most RDCs emerge at long-traveling unidirectional replication forks, and often unrelated to R-loops.
- Lorenzo Corazzi
- , Vivien S. Ionasz
- & Pei-Chi Wei
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Article
| Open AccessDiphthamide deficiency promotes association of eEF2 with p53 to induce p21 expression and neural crest defects
Rare disease DEDSSH1-associated DPH1 mutations impair eEF2 diphthamide modification that leads to eEF2 as a transcriptional coactivator for p53 to enhance expression of the cell proliferation inhibitor p21, resulting in birth defects.
- Yu Shi
- , Daochao Huang
- & Weihong Song
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Article
| Open AccessDeep learning the cis-regulatory code for gene expression in selected model plants
This study explores the variation in gene regulation across plant species and genotypes using interpretable deep learning on DNA sequence and RNA-seq data, demonstrating the models’ utility in functional genomics and phenotypic trait prediction.
- Fritz Forbang Peleke
- , Simon Maria Zumkeller
- & Jędrzej Szymański
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Article
| Open AccessPatrilineal segmentary systems provide a peaceful explanation for the post-Neolithic Y-chromosome bottleneck
Prior work has identified a male-only effective population size bottleneck 3-5000 years ago. While violent competition has been proposed as a cause, the authors here show that a segmentary patrilineal system with lineal fission provides a peaceful alternative explanation.
- Léa Guyon
- , Jérémy Guez
- & Raphaëlle Chaix
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Article
| Open AccessEmergence of enhancers at late DNA replicating regions
Here the authors report that enhancers appear more often in late-replicating DNA regions and are enriched for mutations affecting TF binding. This relationship with DNA replication time is seen in species evolution and cancer, suggesting a fundamental principle of genome evolution.
- Paola Cornejo-Páramo
- , Veronika Petrova
- & Emily S. Wong
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Article
| Open AccessEZH2 mutations in follicular lymphoma distort H3K27me3 profiles and alter transcriptional responses to PRC2 inhibition
Cells carrying EZH2 mutations found in lymphoma show a specific transcriptional response to PRC2 inhibition. A longitudinal study reveals unexpected genetic heterogeneity in follicular lymphomas, with implications for therapeutic strategies.
- Pierre Romero
- , Laia Richart
- & Raphaël Margueron
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Article
| Open AccessLarge-scale cross-ancestry genome-wide meta-analysis of serum urate
This large-scale cross-ancestry genome-wide association study reveals the genetic architecture of serum urate across ancestries and identifies urate-associated diseases and potential targets of urate-lowering drugs.
- Chamlee Cho
- , Beomsu Kim
- & Hong-Hee Won
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Article
| Open AccessA genomic basis of vocal rhythm in birds
Little is known about the genetic basis of the rhythmic component of bird song, an important trait in sexual selection and species recognition. By studying a system with innate vocalizations, the Pogoniulus tinkerbirds, this study finds candidate genes that underlie differences in speed in vocal rhythm in this system.
- Matteo Sebastianelli
- , Sifiso M. Lukhele
- & Alexander N. G. Kirschel
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Article
| Open AccessClinical associations with a polygenic predisposition to benign lower white blood cell counts
Here, the authors find that a benign polygenic predisposition to lower white blood cell counts is associated with multiple clinical endpoints, suggesting that predisposed individuals are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.
- Jonathan D. Mosley
- , John P. Shelley
- & Vivian K. Kawai
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Article
| Open AccessAn approach to identify gene-environment interactions and reveal new biological insight in complex traits
Here, the authors report 5 loci interacting with smoking/alcohol for serum lipids using a new method akin to Mendelian randomization. They unveil significant heritability through gene-environment interaction and mediation, enhancing understanding of complex trait genetics.
- Xiaofeng Zhu
- , Yihe Yang
- & Hugues Aschard
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Article
| Open AccessTAD boundary deletion causes PITX2-related cardiac electrical and structural defects
This study identifies an altered chromatin conformation associated to a cardiac disorder observed in 7 independent families. A deletion of 2 diverging CTCF binding sites on 4q25 induces TAD fusion and leads to PITX2 expression dysregulation.
- Manon Baudic
- , Hiroshige Murata
- & Julien Barc
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