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| Open AccessA negative feedback loop between TET2 and leptin in adipocyte regulates body weight
The epigenetic regulation in adipocytes during obesity remains poorly understood. Here, the authors demonstrate a negative feedback loop between TET2, a DNA demethylation enzyme, and leptin, an adipokine, in adipocytes, unveiling a compensatory mechanism by which the body counteracts the metabolic dysfunction induced by obesity.
- Qin Zeng
- , Jianfeng Song
- & Tuo Deng
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Article
| Open Accessp53 rapidly restructures 3D chromatin organization to trigger a transcriptional response
Here the authors uncover p53’s role as the master regulator of spatio-temporal genome organization. p53 controls the expression of 340 distal genes through newly formed and pre-existing loops between p53-bound enhancers and promoters.
- François Serra
- , Andrea Nieto-Aliseda
- & Biola M. Javierre
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Article
| Open AccessGenetic associations of protein-coding variants in venous thromboembolism
Here, the authors perform a large exome-wide study for venous thromboembolism and identify 18 potential risk genes, including 4 new genes, revealing a significant role of rare coding variants, and offering insights into genetic risk factors.
- Xiao-Yu He
- , Bang-Sheng Wu
- & Jin-Tai Yu
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Article
| Open AccessFinaleMe: Predicting DNA methylation by the fragmentation patterns of plasma cell-free DNA
DNA methylation from cell-free DNA (cfDNA) can be profiled using whole genome bisulfite sequencing (WGBS). Here, the authors develop a computational method, FinaleMe, that predicts DNA methylation and tissues of-origin in cfDNA and validate its performance using paired deep and shallow-coverage whole-genome sequencing (WGS) and WGBS data.
- Yaping Liu
- , Sarah C. Reed
- & Manolis Kellis
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Article
| Open AccessA conserved NR5A1-responsive enhancer regulates SRY in testis-determination
Disease-causing variants define a conserved and unique NR5A1 responsive enhancer for SRY expression to initiate testis-determination in humans. Modelling regulatory variants causing sex-reversal provides a tool to understand global enhancer activity.
- Denis Houzelstein
- , Caroline Eozenou
- & Ken McElreavey
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Article
| Open AccessHigh temperature delays and low temperature accelerates evolution of a new protein phenotype
The effect of temperature fluctuations on the evolution of new phenotypes is largely unknown. Using experimental evolution of fluorescent protein in E. coli, this study shows that a cooling environment can accelerate, and a warming environment decelerate, the evolution of a new protein phenotype.
- Jia Zheng
- , Ning Guo
- & Andreas Wagner
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Article
| Open AccessGenetic control of DNA methylation is largely shared across European and East Asian populations
Most functional genomic resources have been based on individuals with European ancestry. Here, the authors perform DNA methylation quantitative trait locus (mQTL) analyses in 3,701 European and 2,099 East Asian individuals to identify thousands of genetic variants, a large degree of which are shared between the two populations.
- Alesha A. Hatton
- , Fei-Fei Cheng
- & Allan F. McRae
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Article
| Open AccessReal-time monitoring of replication errors’ fate reveals the origin and dynamics of spontaneous mutations
An interdisciplinary approach following replication errors in Escherichia coli unveils that many spontaneous mutations originate from inefficient repair, and that repair capacity is variable between single cells within a bacterial population.
- Chiara Enrico Bena
- , Jean Ollion
- & Marina Elez
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Article
| Open AccessAn analysis of the accuracy of retrospective birth location recall using sibling data
Many surveys ask participants to retrospectively record their location of birth. Here, the authors find misreporting in retrospective birth location data in UK Biobank using data from siblings, which can lead to bias in estimates of the impact of location-based exposures.
- Stephanie von Hinke
- & Nicolai Vitt
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Article
| Open AccessMacroevolutionary dynamics of gene family gain and loss along multicellular eukaryotic lineages
Correspondence between genome and organismal complexity over macroevolutionary time is poorly understood. Here the authors show that multicellular eukaryotes increasingly simplify their genomes and suggest that the concept of functional outsourcing, via ecological interactions, could explain this paradoxical complexity decoupling.
- Mirjana Domazet-Lošo
- , Tin Široki
- & Tomislav Domazet-Lošo
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Article
| Open AccessGenetic similarity between relatives provides evidence on the presence and history of assortative mating
Non-random mating can complicate genetic studies, but implications hinge on its history in prior generations. Here, the authors use genetic similarity between relatives to investigate which traits show evidence of recent changes in mating behavior.
- Hans Fredrik Sunde
- , Nikolai Haahjem Eftedal
- & Fartein Ask Torvik
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Article
| Open AccessAbundant pleiotropy across neuroimaging modalities identified through a multivariate genome-wide association study
The authors uncover extensive genetic overlap across brain structure, functional connectivity, and brain tissue composition using multivariate methods. Insights gained enhance understanding of brain biology and prediction of psychiatric conditions.
- E. P. Tissink
- , A. A. Shadrin
- & O. A. Andreassen
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Article
| Open AccessUsing rare genetic mutations to revisit structural brain asymmetry
Asymmetry is a key organising principle of the brain. Here the authors leveraged rare genetic mutations to revisit structural brain asymmetry showing the planum temporale is susceptible to deletions & duplications of specific gene sets.
- Jakub Kopal
- , Kuldeep Kumar
- & Danilo Bzdok
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Article
| Open AccessDevelopmental progression of DNA double-strand break repair deciphered by a single-allele resolution mutation classifier
DNA double-strand breaks (DSBs) are repaired by a hierarchically regulated network of pathways. Here, authors develop ICP for deciphering somatic DSB repair patterns in multicellular organisms and discover developmental regulation in flies and mosquitoes, enabling tracking of mutant alleles and interhomolog copying of gene cassettes.
- Zhiqian Li
- , Lang You
- & Ethan Bier
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Article
| Open AccessThe aldehyde dehydrogenase 2 rs671 variant enhances amyloid β pathology
Here, Wang et al. report that the ALDH2 rs671 variant exacerbates amyloid-β pathology in the human brain. Mechanistically, the variant leads to 4-HNE accumulation, adducting Lys53 of C99 and promoting the production of Aβ40.
- Xia Wang
- , Jiayu Wang
- & Wei Ge
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Article
| Open AccessMutational scanning pinpoints distinct binding sites of key ATGL regulators in lipolysis
ATGL is a key enzyme in intracellular lipolysis. Here, the authors use deep mutational scanning to define the determinants of protein interaction between ATGL and its regulatory partners, gaining insights into lipolysis mechanisms in cells.
- Johanna M. Kohlmayr
- , Gernot F. Grabner
- & Ulrich Stelzl
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Article
| Open AccessGAS41 modulates ferroptosis by anchoring NRF2 on chromatin
GAS41 is recognized as a histone reader and oncogene, but the mechanism by which GAS41 contributes to tumorigenesis is not well understood. Here, the authors discover that GAS41 is a ferroptosis repressor that anchors NRF2 to chromatin, promoting tumor growth.
- Zhe Wang
- , Xin Yang
- & Wei Gu
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Article
| Open AccessSwitching action modes of miR408-5p mediates auxin signaling in rice
miR408-5p typically regulates target IAA30 via translation repression, but switches to cleaving IAA30 mRNA under high auxin conditions. miR393, miR156, miR408-5p and their targets could hierarchically act in auxin pathway and regulate leaf inclination.
- Fuxi Rong
- , Yusong Lv
- & Liang Wu
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Article
| Open AccessAberrant non-canonical NF-κB signalling reprograms the epigenome landscape to drive oncogenic transcriptomes in multiple myeloma
The downstream molecular mechanisms following the activation of the NF-κB pathway in multiple myeloma (MM) remain to be characterised. Here, it is shown that aberrant non-canonical NF-κB signalling causes epigenomic reprogramming leading to transcriptional changes that favour MM progression.
- Daniel A. Ang
- , Jean-Michel Carter
- & Yinghui Li
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Article
| Open AccessA double-stranded RNA binding protein enhances drought resistance via protein phase separation in rice
Drought is one of the major abiotic stresses affecting rice growth and development. Here, the authors identify a dsRNA-binding protein positively regulates rice drought resistance through promoting stability of OsNCED4 mRNAs, transcript of a key gene for the biosynthesis of abscisic acid, via protein phase separation.
- Huaijun Wang
- , Tiantian Ye
- & Lizhong Xiong
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Article
| Open AccessDynamics of accessible chromatin regions and subgenome dominance in octoploid strawberry
Subgenome dominance is widely observed in allopolyploid species, but the molecular mechanisms remain unclear. Here, the authors generate genome-wide map of accessible chromatin regions (ACRs) in allo-octoploid cultivated strawberry and reveal that dynamics of the ACRs play an important role in its subgenome dominance.
- Chao Fang
- , Ning Jiang
- & Jiming Jiang
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Article
| Open AccessMapping human tissues with highly multiplexed RNA in situ hybridization
Application of multiplexed RNA in situ mapping techniques to human tissues remains challenging. Here, the authors report DART-FISH, a padlock probe-based technology capable of profiling large numbers of genes in centimetre-sized human tissue sections.
- Kian Kalhor
- , Chien-Ju Chen
- & Kun Zhang
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Article
| Open AccessStrong positive selection biases identity-by-descent-based inferences of recent demography and population structure in Plasmodium falciparum
Identity-by-descent (IBD) is used to infer malaria parasite population demography, but positive selection imposed by drug pressure can bias IBD estimates. This study shows that strong selection distorts IBD distributions impacting downstream inferences and presents an approach to correct these biases.
- Bing Guo
- , Victor Borda
- & Shannon Takala-Harrison
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Article
| Open AccessExtended stop codon context predicts nonsense codon readthrough efficiency in human cells
Stop codon readthrough, the ribosomal bypass of mRNA nonsense codons, has therapeutic potential for diseases caused by nonsense mutations. Here, the authors used machine learning to define readthrough-conducive mRNA sequences and predict specific CFTR alleles likely amenable to readthrough therapy.
- Kotchaphorn Mangkalaphiban
- , Lianwu Fu
- & Allan Jacobson
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Article
| Open AccessGenetic gains underpinning a little-known strawberry Green Revolution
Cultivated strawberry is a hybrid species with a 250-year domestication history. Here, the authors use genomic prediction and a historically important breeding population to show that the introduction of photoperiod-insensitive hybrids and genetic gains from breeding have been catalysts for a strawberry Green Revolution.
- Mitchell J. Feldmann
- , Dominique D. A. Pincot
- & Steven J. Knapp
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Article
| Open AccessGenetic imputation of kidney transcriptome, proteome and multi-omics illuminates new blood pressure and hypertension targets
Genetic mechanisms of blood pressure regulation remain poorly defined. Here, the authors perform a kidney multi-omics study to identify 399 kidney effector genes, 11 miRNAs and 97 proteins for blood pressure and hypertension.
- Xiaoguang Xu
- , Chachrit Khunsriraksakul
- & Maciej Tomaszewski
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Article
| Open AccessWheat powdery mildew resistance gene Pm13 encodes a mixed lineage kinase domain-like protein
Wheat powdery mildew is one of the most destructive diseases threatening global wheat production. Here, the authors report the cloning of powdery mildew resistance gene Pm13 from the wild wheat species Aegilops longissima encoding a mixed lineage kinase domain-like (MLKL) protein.
- Huanhuan Li
- , Wenqiang Men
- & Wenxuan Liu
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Article
| Open AccessSCGB1D2 inhibits growth of Borrelia burgdorferi and affects susceptibility to Lyme disease
The genetic basis of susceptibility to Lyme disease is largely unknown. Here, the authors discover a risk locus in the gene encoding the protein Secretoglobin family 1D member 2, which is expressed in skin and affects infection by the bacteria that causes Lyme disease in vitro and in vivo.
- Satu Strausz
- , Erik Abner
- & Hanna M. Ollila
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Article
| Open AccessDynamics of extrachromosomal circular DNA in rice
Comparing to other biological systems, our understanding of plant extrachromosomal circular DNA (eccDNA) is limited. Here, the authors profile eccDNA from six rice tissues and investigate eccDNA characteristics, formation mechanisms, distribution, and functional implications.
- Jundong Zhuang
- , Yaoxin Zhang
- & Tingting Lu
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Article
| Open AccessIntegrative genomic analyses identify candidate causal genes for calcific aortic valve stenosis involving tissue-specific regulation
Here the authors report 20 novel genomic risk loci for calcific aortic valve stenosis, the most common heart valve disorder. Using RNA sequencing in 500 human aortic valves, they prioritize candidate causal genes including TWIST1, a gene involved in endothelial-mesenchymal transition.
- Sébastien Thériault
- , Zhonglin Li
- & Yohan Bossé
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Article
| Open AccessDistinguishing preferences of human APOBEC3A and APOBEC3B for cytosines in hairpin loops, and reflection of these preferences in APOBEC-signature cancer genome mutations
Human APOBEC3A (A3A) and APOBEC3B (A3B) proteins convert cytosines in hairpin loops to uracils and cause mutations with differing preferences for loop sizes and sequences. Examination of human tumor mutations reflects largely the preferences of A3A, not A3B.
- Yasha Butt
- , Ramin Sakhtemani
- & Ashok S. Bhagwat
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Article
| Open AccessIntegrative cross-omics and cross-context analysis elucidates molecular links underlying genetic effects on complex traits
Genetic effects on functionally related ‘omic’ traits often co-occur in relevant cellular contexts, such as tissues. Here, the authors introduce X-ING, an integrative analysis method for cross-omics, cross-context associations based on summary-level data. Application to quantitative trait locus analysis yields insights into complex disease/trait mechanisms.
- Yihao Lu
- , Meritxell Oliva
- & Lin S. Chen
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Article
| Open AccessThe chromatin factors SET-26 and HCF-1 oppose the histone deacetylase HDA-1 in longevity and gene regulation in C. elegans
SET-26, HCF-1, HDA-1 are factors that help package DNA and regulate gene expression. Here, the authors find that SET-26 recruits HCF-1 to specific locations along the genome, where they antagonize the activity of HDA-1. Together, they maintain balanced gene expression and longevity in C. elegans.
- Felicity J. Emerson
- , Caitlin Chiu
- & Siu Sylvia Lee
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Article
| Open AccessA transposon insertion in the promoter of OsUBC12 enhances cold tolerance during japonica rice germination
Japonica rice generally has greater capacity for low temperatures germination (LTG) than indica rice. Here, the authors report an E2 ubiquitin-conjugating enzyme-encoding gene OsUBC12 can increase LTG in japonica rice by negatively regulate ABA signaling via promoting the proteasomal degradation of OsSnRK1.1.
- Chuanzhong Zhang
- , Hongru Wang
- & Jun Fang
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Article
| Open AccessNatural variation in OsMYB8 confers diurnal floret opening time divergence between indica and japonica subspecies
Florets of indica rice open earlier than japonica rice, hindering utilization of the cross subspecies heterosis. Here, the authors show that an OsMYB8-OsJAR1 module regulates diurnal floret opening time divergences between the two subspecies.
- Yajun Gou
- , Yueqin Heng
- & Rongxin Shen
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Article
| Open AccessBiallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications
Most individuals with primary familial brain calcification (PFBC) remain genetically unsolved. Here the authors show that NAA60 biallelic variants cause PFBC, likely via reduced N-terminal acetylation and SLC20A2 levels with impaired phosphate uptake.
- Viorica Chelban
- , Henriette Aksnes
- & Henry Houlden
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Article
| Open AccessIdentifying regulators of aberrant stem cell and differentiation activity in colorectal cancer using a dual endogenous reporter system
Aberrant stem cell-like activity and impaired differentiation are central to the development of colorectal cancer. Here, authors develop a dual endogenous reporter system to identify functional regulators of aberrant stem cell and differentiation programs, showing that SMARCB1 restricts differentiation, and nominating other regulators with therapeutic potential.
- Sandor Spisak
- , David Chen
- & Nilay S. Sethi
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Article
| Open AccessYTHDF2 governs muscle size through a targeted modulation of proteostasis
This study highlights the role of YTHDF2, a protein that recognizes m6A-modified RNA, in determining muscle size. The authors show a post-transcriptional mechanism regulating muscle catabolism and growth, prompting interest to address muscle wasting.
- Christopher J. Gilbert
- , Charles P. Rabolli
- & Federica Accornero
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Article
| Open AccessGWAS reveals determinants of mobilization rate and dynamics of an active endogenous retrovirus of cattle
Endogenous retroviruses constitute 5–10% of mammalian genome space. This study characterize the bovine ERVK[2-1- LTR] clade showing that its activity varies between individuals as a function of the number of inherited autonomous elements, yet that most de novo insertions are non-autonomous elements lacking functional genes.
- Lijing Tang
- , Benjamin Swedlund
- & Carole Charlier
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Article
| Open AccessDependency on host vitamin B12 has shaped Mycobacterium tuberculosis Complex evolution
Campos-Pardos et al show that the virulence of Mycobacterium tuberculosis is dependent on sufficient uptake of exogenous vitamin B12 from host serum and this phenotype is not conserved in environmental, opportunistic and ancestral lineages.
- Elena Campos-Pardos
- , Santiago Uranga
- & Jesús Gonzalo-Asensio
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Article
| Open AccessInterrogations of single-cell RNA splicing landscapes with SCASL define new cell identities with physiological relevance
RNA splicing serves as a critical layer of gene expression regulation. Here, authors introduce SCASL for investigating the heterogeneity of RNA splicing landscapes at single-cell resolution, offering a novel scheme for classifying cell identities with physiological relevance.
- Xianke Xiang
- , Yao He
- & Xuerui Yang
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Article
| Open AccessThe defensome of complex bacterial communities
Bacteria have evolved numerous innate and adaptive defence mechanisms. Here, Beavogui et al characterise the impact of biogeography, genetic mobility, and clustering in defense islands, on the defence systems of soil, marine, and human gut bacterial populations genomes.
- Angelina Beavogui
- , Auriane Lacroix
- & Pedro H. Oliveira
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Article
| Open AccessN-Acetyltransferase 10 represses Uqcr11 and Uqcrb independently of ac4C modification to promote heart regeneration
Here, Ma et al. investigate the translational profile of cardiac regeneration, pointing to Nat10 as a key regulator of cardiomyocyte proliferative potential, and describing how it regulates cardiac gene expression.
- Wenya Ma
- , Yanan Tian
- & Benzhi Cai
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Article
| Open AccessNatural variation in BnaA9.NF-YA7 contributes to drought tolerance in Brassica napus L
Rapeseed production is often threatened by drought stress. Here, the authors report transcription factor BnaA9.NFYA7 negatively regulates rapeseed drought tolerance through ABA signal transduction pathway via feedback inhibition of the expression of BnaABF3/4s-related genes.
- Jia Wang
- , Lin Mao
- & Liezhao Liu
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Article
| Open AccessPla2g12b drives expansion of triglyceride-rich lipoproteins
Thierer and colleagues identify PLA2G12B as a key gene driving triglyceride incorporation into lipoproteins and show that disruption of this activity provides protection from atherosclerosis.
- James H. Thierer
- , Ombretta Foresti
- & Steven A. Farber
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Article
| Open AccessEnhancing prime editor activity by directed protein evolution in yeast
Compared to traditional Cas9 nucleases prime editors (PEs) are less active. Here the authors use OrthoRep, a yeast-based platform for directed protein evolution to enhance the editing efficiency of PEs: they identify mutations that have a positive effect on kinetics and use this knowledge to generate an efficient in vivo PE.
- Yanik Weber
- , Desirée Böck
- & Gerald Schwank
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Article
| Open AccessProTInSeq: transposon insertion tracking by ultra-deep DNA sequencing to identify translated large and small ORFs
Identifying small proteins is challenging. ProTInSeq uses modified transposons to express markers inserted in-frame to protein-coding genes. This method identifies 153 unannotated small proteins in M. pneumoniae and additional proteomic information.
- Samuel Miravet-Verde
- , Rocco Mazzolini
- & Luis Serrano
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Article
| Open AccessNatural variation of STKc_GSK3 kinase TaSG-D1 contributes to heat stress tolerance in Indian dwarf wheat
Indian dwarf wheat (Triticum sphaerococcum) is thermotolerant, but the underlying mechanism is unclear. Here, the authors report the cloning of the heat tolerance gene encoding a STKc_GSK3 kinase and its variation affects phosphorylation level of downstream TaPIF4 in determining thermotolerance.
- Jie Cao
- , Zhen Qin
- & Mingming Xin
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Article
| Open AccessA SWI/SNF-dependent transcriptional regulation mediated by POU2AF2/C11orf53 at enhancer
POU2AF2 is a co-activator of POU2F3 in normal and neoplastic tuft cells, such as small cell lung cancer. Here, the authors report that POU2AF2 dictates opposing transcriptional regulation at distal enhance elements.
- Aileen Szczepanski
- , Natsumi Tsuboyama
- & Lu Wang
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