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| Open AccessVitamin C epigenetically controls osteogenesis and bone mineralization
For decades vitamin C’s primary function in bone has been attributed to its involvement in collagen synthesis. Here, the authors uncover that vitamin C’s central role in bone is to globally orchestrate osteogenesis via epigenetic mechanisms.
- Roman Thaler
- , Farzaneh Khani
- & Andre J. van Wijnen
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Article
| Open AccessMYPT1-PP1β phosphatase negatively regulates both chromatin landscape and co-activator recruitment for beige adipogenesis
How β-AR signaling coordinates epigenetic and transcriptional pathways is unknown. Here the authors show that cold-induced β-AR signaling negatively regulates MYPT1-PP1β phosphatase activity to orchestrate both pathways for beige adipogenesis.
- Hiroki Takahashi
- , Ge Yang
- & Juro Sakai
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Article
| Open AccessThe transcriptional coactivator RUVBL2 regulates Pol II clustering with diverse transcription factors
RNA polymerase II (Pol II) transcription factories play a central role in gene expression and 3D chromatin organization. Here, the authors demonstrate that RUVBL2 directly regulates Pol II clustering at active gene promoters.
- Hui Wang
- , Boyuan Li
- & Xiong Ji
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Article
| Open AccessPhosphorylation of Jhd2 by the Ras-cAMP-PKA(Tpk2) pathway regulates histone modifications and autophagy
How cells transduce nutrient availability to appropriate gene expression remains poorly understood. Here the authors show that the nutrient sensor, protein kinase A modulates histone modifications and gene transcription by phosphorylating histone demethylase.
- Qi Yu
- , Xuanyunjing Gong
- & Shanshan Li
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Article
| Open AccessDNA methylation signatures of Alzheimer’s disease neuropathology in the cortex are primarily driven by variation in non-neuronal cell-types
Here the authors identify differences in cortical DNA methylation associated with Alzheimer’s disease pathology, and profiling nuclei from specific cell-types, find that most of these differences reflect variation occurring in non-neuronal cells.
- Gemma Shireby
- , Emma L. Dempster
- & Jonathan Mill
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Article
| Open AccessVAL1 acts as an assembly platform co-ordinating co-transcriptional repression and chromatin regulation at Arabidopsis FLC
Cold-induced silencing of Arabidopsis FLC requires the binding of VAL1 to an intronic motif. Here, the authors show that ASAP and PRC1, two interacting partner complexes of VAL1, mediate co-transcriptional repression and chromatin modulation to effectively co-ordinate different steps in FLC silencing.
- Pawel Mikulski
- , Philip Wolff
- & Caroline Dean
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Article
| Open AccessDominant role of DNA methylation over H3K9me3 for IAP silencing in endoderm
Silencing of endogenous retroviruses is crucial for maintaining transcriptional and genomic integrity of cells and is maintained by histone H3K9 methylation and/or DNA methylation in various cell types. Here the authors show that loss of DNA methyltransferase DNMT1 in endoderm results in ERV derepression while H3K9me3 is unaltered.
- Zeyang Wang
- , Rui Fan
- & Gunnar Schotta
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Article
| Open AccessImprinting fidelity in mouse iPSCs depends on sex of donor cell and medium formulation
Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) is associated with epigenetic alterations. Here the authors assess DNA methylation in detail in multiple female and male mouse iPSC lines generated with different protocols and find that defects depend on the sex of donor cells and can be partially mitigated by Vitamin C.
- Maria Arez
- , Melanie Eckersley-Maslin
- & Simão Teixeira da Rocha
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Article
| Open AccessPaternal imprinting of dosage-effect defective1 contributes to seed weight xenia in maize
Xenia effects describe the genetic contribution of pollen to seed phenotypes. Here the authors show that paternal imprinting of Ded1 contributes to the xenia effect in maize by setting the pace of endosperm development.
- Dawei Dai
- , Janaki S. Mudunkothge
- & A. Mark Settles
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Article
| Open AccessRegulation associated modules reflect 3D genome modularity associated with chromatin activity
Here the authors report histone modifications show a modular pattern referred to as ‘regulation associated modules’ (RAMs) that reflect the spatial modularity of chromatin. They find enhancer-promoter interactions and extrachromosomal DNAs (ecDNAs) occur more often within the same RAMs than within the same TADs, indicating stronger insulation of the RAM boundaries.
- Lina Zheng
- & Wei Wang
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Article
| Open AccessDerivation and validation of an epigenetic frailty risk score in population-based cohorts of older adults
Frailty is associated with an increased risk for negative health outcomes in older populations, and being able to predict frailty could facilitate prevention measures. By performing an epigenome-wide screen, the authors derived a DNA methylation based measure for frailty which can predict both prevalence and longer-term incidence of frailty.
- Xiangwei Li
- , Thomas Delerue
- & Hermann Brenner
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Article
| Open AccessIsoform-specific and ubiquitination dependent recruitment of Tet1 to replicating heterochromatin modulates methylcytosine oxidation
A short isoform of the Tet1 enzyme (Tet1s) that oxidizes the DNA 5-methylcytosine (5mC) mark is overexpressed in tumors. Here the authors show Tet1s, but not full length Tet1, changes localization over the cell cycle upon ubiquitination and Uhrf1 interaction and is targeted to heterochromatin during S-phase. This leads to 5mC oxidation and loss of DNA methylation in heterochromatin.
- María Arroyo
- , Florian D. Hastert
- & M. Cristina Cardoso
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Article
| Open AccessNODULIN HOMEOBOX is required for heterochromatin homeostasis in Arabidopsis
Arabidopsis NDX was previously reported as a regulator of euchromatic gene expression. Here the authors show that NDX functions at pericentromeric regions and regulates heterochromatin homeostasis by controlling siRNA production and non-CG methylation.
- Zsolt Karányi
- , Ágnes Mosolygó-L
- & Lóránt Székvölgyi
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Article
| Open AccessReversal of the renal hyperglycemic memory in diabetic kidney disease by targeting sustained tubular p21 expression
Persistent diabetic complications despite controlled blood glucose levels, known as hyperglycemic memory, remain a poorly understood phenomenon in diabetic kidney disease. Here the authors identify senescence-associated gene p21 as a regulator of hyperglycemic memory, the suppression of which improves hyperglycemic memory and renal function.
- Moh’d Mohanad Al-Dabet
- , Khurrum Shahzad
- & Berend Isermann
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Article
| Open AccessEpigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology
Parkinson’s disease and dementia with Lewy bodies are closely related neurodegenerative disorders, although the epigenetic similarities are not well known. Here, the authors study Lewy pathology and DNA methylation in postmortem human frontal cortex, identifying differentially methylated genomic loci.
- Lasse Pihlstrøm
- , Gemma Shireby
- & Mathias Toft
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Article
| Open AccessCross-tissue analysis of blood and brain epigenome-wide association studies in Alzheimer’s disease
DNA methylation differences in Alzheimer’s disease have been previously reported, although the interpretation of the differences is unclear. Here, the authors performed epigenome-wide meta-analyses of DNA methylation in blood and brain, and developed a methylation-based risk prediction model for AD.
- Tiago C. Silva
- , Juan I. Young
- & Lily Wang
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Article
| Open AccessTET enzymes regulate skeletal development through increasing chromatin accessibility of RUNX2 target genes
Here the authors investigate the role of the TET family of DNA demethylases in mammalian skeletal development. They find that loss of TETs leads to hypermethylation that results in decreased chromatin accessibility of RUNX2 target genes, repressing osteoblast differentiation and leading to skeletal defects in mouse such as short limbs.
- Lijun Wang
- , Xiuling You
- & Weiguo Zou
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Article
| Open AccessPRC1-mediated epigenetic programming is required to generate the ovarian reserve
In humans, the ovarian reserve is maintained over decades by meiotic arrest of oocytes. Here the authors show that Polycomb Repressive Complex 1 (PRC1)-mediated epigenetic programming is essential for formation of ovarian reserve and thus female reproductive lifespan.
- Mengwen Hu
- , Yu-Han Yeh
- & Satoshi H. Namekawa
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Article
| Open AccessThe SWI/SNF chromatin remodeling factor DPF3 regulates metastasis of ccRCC by modulating TGF-β signaling
The functional role of DPF3, a component of the SWI/SNF chromatin remodelling complex associated with clear cell renal cell carcinoma (ccRCC), remains unknown. Here, the authors characterise the mechanism by which DPF3 promotes metastasis via the activation of the TGF-β signalling pathway in ccRCC.
- Huanhuan Cui
- , Hongyang Yi
- & Wei Chen
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Article
| Open AccessIntegrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health
Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, blood protein markers of brain health are integrated with omics data to reveal DNA methylation differences that associate with these protein markers.
- Danni A. Gadd
- , Robert F. Hillary
- & Riccardo E. Marioni
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Article
| Open AccessHistone H3K36me2 and H3K36me3 form a chromatin platform essential for DNMT3A-dependent DNA methylation in mouse oocytes
DNMT3A is known to methylate DNA at histone H3 lysine 36 (H3K36me3)-marked transcriptionally active regions in mouse oocytes. Here the authors show that DNMT3A is also guided by H3K36me2 to methylate broad domains in genic and intergenic loci, as well as on the X chromosome. These two histone marks together comprise the minimal chromatin signature for global DNA methylation in mouse oocytes.
- Seiichi Yano
- , Takashi Ishiuchi
- & Hiroyuki Sasaki
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Article
| Open AccessA common deletion at BAK1 reduces enhancer activity and confers risk of intracranial germ cell tumors
Intracranial germ cell tumors (IGCTs) are rare brain tumors mainly diagnosed in children and young adults. Here, the authors conduct a genome-wide association study for IGCTs, identify a risk locus at BAK1, and characterize its functional consequences.
- Kyuto Sonehara
- , Yui Kimura
- & Keita Terashima
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Article
| Open AccessXist exerts gene-specific silencing during XCI maintenance and impacts lineage-specific cell differentiation and proliferation during hematopoiesis
Here the authors investigate the functional relevance of X-chromosome inactivation (XCI) regulator Xist in hematopoiesis. They find that Xist loss leads to changes in the ratio of hematopoietic progenitor cells and results in chromatin accessibility and transcriptional upregulation on the inactive X chromosome, including XCI escape genes known to be associated with cell cycle and immune response.
- Tianqi Yang
- , Jianhong Ou
- & Eda Yildirim
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Article
| Open AccessBalanced gene dosage control rather than parental origin underpins genomic imprinting
Here the authors investigate whether for imprinted genes the parent-of-origin of the expressed allele or rather appropriate gene dosage is more important for normal development. Using the differentially methylated region of Dlk1-Dio3 gene involved in imprinting, they show that correct parent-of-origin imprinting pattern is secondary to balanced gene dosage.
- Ariella Weinberg-Shukron
- , Raz Ben-Yair
- & Yonatan Stelzer
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Article
| Open AccessExtensive co-binding and rapid redistribution of NANOG and GATA6 during emergence of divergent lineages
The authors show that the transcription factors NANOG and GATA6 co-bind the same enhancers in common progenitors before divergent epiblast and primitive endoderm lineages emerge. This may help maintain plasticity at early stages and facilitate bifurcation into distinct lineages
- Joyce J. Thompson
- , Daniel J. Lee
- & Pedro P. Rocha
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Article
| Open AccessStructure of DNMT3B homo-oligomer reveals vulnerability to impairment by ICF mutations
In mammals, de novo DNA methyltransferase DNMT3B is essential for establishing DNA methylation patterns during embryonic development. Here the authors provide a structure-function characterization of homo-oligomeric DNMT3B, revealing the molecular basis for its vulnerability to ICF mutations.
- Linfeng Gao
- , Yiran Guo
- & Jikui Song
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Article
| Open AccessInactivation of Sirt6 ameliorates muscular dystrophy in mdx mice by releasing suppression of utrophin expression
Utrophin is a dystrophin-related protein stabilizing the sarcolemma in absence of dystrophin. Here the authors report that inactivation of the protein deacetylase SIRT6, involved in the deacetylation of the epigenetic mark H3K56ac in muscle cells, increases expression of utrophin and ameliorates dystrophic muscle pathology in mice.
- Angelina M. Georgieva
- , Xinyue Guo
- & Thomas Braun
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Article
| Open AccessTET1 dioxygenase is required for FOXA2-associated chromatin remodeling in pancreatic beta-cell differentiation
Here the authors show that TET1 is required for the generation of functional insulin-producing cells, FOXA2 physically interacts with TET1 and contributes to specific recruitment of TET1 to mediate chromatin opening at the regulatory elements of pancreatic lineage determinants.
- Jianfang Li
- , Xinwei Wu
- & Ruiyu Xie
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Article
| Open AccessMechanistic basis for maintenance of CHG DNA methylation in plants
In plants, DNA methylation in the CHG context is maintained by the CMT3 chromomethylases. Here the authors provide a structure-function characterization of a maize CMT3 ortholog to show how recognition of histone modifications stimulate DNA methylation.
- Jian Fang
- , Jianjun Jiang
- & Jikui Song
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Article
| Open AccessHOX epimutations driven by maternal SMCHD1/LRIF1 haploinsufficiency trigger homeotic transformations in genetically wildtype offspring
Hox genes are known to control anteroposterior patterning, including the vertebrate spine. Here Xue et al. show that maternal Smchd1 regulates Hox expression in an epigenetic manner, and that wild type offspring from heterozygous mothers show skeletal homeotic transformations as a result of this dysregulation.
- Shifeng Xue
- , Thanh Thao Nguyen Ly
- & Bruno Reversade
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Article
| Open AccessSMYD5 catalyzes histone H3 lysine 36 trimethylation at promoters
SETD2 methylates histone H3K36me3 in gene bodies in mammalian cells. Here the authors show H3K36me3 is also enriched at the promoter regions, and that this methylation is carried out by SMYD5, which is recruited by RNA polymerase II. They furthermore show SMYD5 is elevated in liver cancer and is correlated with changes in gene expression.
- Yanjun Zhang
- , Yuan Fang
- & Dong Fang
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Article
| Open AccessDynamic mRNA degradome analyses indicate a role of histone H3K4 trimethylation in association with meiosis-coupled mRNA decay in oocyte aging
Developmental potential of oocytes decreases in women of advanced age. Here the authors observe impaired meiosis-coupled mRNA decay and reduced CXXC1-maintained histone H3K4 trimethylation in old oocytes of mouse and humans.
- Yun-Wen Wu
- , Sen Li
- & Qian-Qian Sha
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Article
| Open AccessThe microRNA cluster C19MC confers differentiation potential into trophoblast lineages upon human pluripotent stem cells
Little is known about the epigenetic mechanisms of the first cell fate commitment in humans. Here, the authors show that activation of the miRNA cluster C19MC confers differentiation potential into trophoblast lineages on human embryonic stem cells.
- Norio Kobayashi
- , Hiroaki Okae
- & Takahiro Arima
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Article
| Open AccessPRRX1 is a master transcription factor of stromal fibroblasts for myofibroblastic lineage progression
Cancer associated fibroblasts are an important and highly heterogeneous component of the tumor microenvironment. Here the authors identify PRRX1 as a master transcription factor determining a fibroblast lineage with myofibroblastic phenotype, associated with unfavourable prognosis in several cancer types.
- Keun-Woo Lee
- , So-Young Yeo
- & Seok-Hyung Kim
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Article
| Open AccessEnhancers regulate 3′ end processing activity to control expression of alternative 3′UTR isoforms
Transcriptional enhancers are known to regulate transcript production. Here, the authors show that transcription factors that bind to enhancers also regulate polyadenylation site cleavage activity, thus changing expression of alternative 3’ UTRs.
- Buki Kwon
- , Mervin M. Fansler
- & Christine Mayr
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Article
| Open AccessReconstruct high-resolution 3D genome structures for diverse cell-types using FLAMINGO
High-resolution reconstruction of spatial chromosome organisation is in demand. Here the authors report FLAMINGO, for reconstructing high-resolution 3D Genome Organisation from HiC data which they use to generate both 5 kb and 1 kb-resolution 3D chromosomal structures for the human genome.
- Hao Wang
- , Jiaxin Yang
- & Jianrong Wang
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Article
| Open AccessActivation of Xist by an evolutionarily conserved function of KDM5C demethylase
Here the authors show eutherian mammals co-opted the histone demethylase KDM5C during sex-chromosome evolution to induce X-chromosome inactivation by upregulating Xist expression selectively in females.
- Milan Kumar Samanta
- , Srimonta Gayen
- & Sundeep Kalantry
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Article
| Open AccessStable inheritance of H3.3-containing nucleosomes during mitotic cell divisions
How nucleosome assembly of parental histones is regulated following DNA replication is still an open question. Here the authors show that unlike deposition of new histones H3.1 and H3.3 that utilizes different histone chaperones, parental H3.1 and H3.3 are both stably inherited during mitotic cell division in mouse embryonic stem cells, and this involves histone chaperones Mcm2, Pole3 and Pole4.
- Xiaowei Xu
- , Shoufu Duan
- & Zhiguo Zhang
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Article
| Open AccessEpigenetic changes induced by in utero dietary challenge result in phenotypic variability in successive generations of mice
Here the authors show that a high-fat diet in pregnant mice can release silencing of the imprinted Dlk1 locus in multiple generations of offspring. They found that this occurs via changes in microRNA expression at the locus of interest, as well as transcriptional changes across the genome, in the developing oocytes.
- Mathew Van de Pette
- , Andrew Dimond
- & Amanda G. Fisher
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Article
| Open AccessDNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases
Chronic inflammation, marked by C-reactive protein, has been associated with changes in methylation, but the causal relationship is unclear. Here, the authors perform a Epigenome-wide association meta-analysis for C-reactive protein levels and find that these methylation changes are likely the consequence of inflammation and could contribute to disease.
- Matthias Wielscher
- , Pooja R. Mandaviya
- & Marjo-Riitta Järvelin
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Article
| Open AccessRegulation of chromatin accessibility by the histone chaperone CAF-1 sustains lineage fidelity
Cell fate commitment involves transcription factor activity and changes in chromatin architecture. Here the authors show that CAF-1 maintains lineage fidelity by controlling chromatin accessibility at specific sites; suppressing CAF-1 triggers differentiation of myeloid stem and progenitor cells into a mixed lineage state.
- Reuben Franklin
- , Yiming Guo
- & Sihem Cheloufi
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Article
| Open AccessEWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma
The relationship between cellular histogenesis and molecular phenotypes for the EWSR1- ATF1 fusion in clear cell sarcoma (CCS) requires further characterization. Here, the authors investigate the EWSR1-ATF1 gene regulation networks in CCS cell lines, primary tumors, and mesenchymal stem cells.
- Emely Möller
- , Viviane Praz
- & Nicolò Riggi
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Article
| Open AccessASCL1 activates neuronal stem cell-like lineage programming through remodeling of the chromatin landscape in prostate cancer
Following androgen receptor pathway inhibition prostate cancers can differentiate towards the neuroendocrine lineage. Here, the authors identify epigenetic alterations regulated by ASCL1 and suggest targeting ASCL1 to reverse the neuroendocrine phenotype.
- Shaghayegh Nouruzi
- , Dwaipayan Ganguli
- & Amina Zoubeidi
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Article
| Open AccessChromatin profiling in human neurons reveals aberrant roles for histone acetylation and BET family proteins in schizophrenia
Schizophrenia (SZ) is a severe psychiatric disorder; unfortunately, only ~1/3 of patients respond favorably to treatment. Here, the authors reveal hyperacetylation of histone H2A.Z in SZ neurons and postmortem SZ human brain tissues. They further show BRD4 is a reader of hyperacetylated H2A.Z and treatment with bromodomain inhibitor JQ1 largely rescues abnormal gene expression associated with SZ.
- Lorna A. Farrelly
- , Shuangping Zheng
- & Ian Maze
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Article
| Open AccessAccelerated biological aging in COVID-19 patients
Age is a risk factor for SARS-CoV-2 infection and severe disease. Here the authors perform DNA methylation analyses in whole blood from COVID-19 patients using established epigenetic clocks and telomere length estimators, and describing correlations between epigenetic aging and the risk of SARS-CoV-2 infection and severe disease.
- Xue Cao
- , Wenjuan Li
- & Huichuan Yu
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Article
| Open AccessHigh-quality genome and methylomes illustrate features underlying evolutionary success of oaks
The genus Quercus (oaks) has diversified into over 450 species which often play dominant roles in the ecosystems in which they occur. Here the authors present a genome and methylome for a California endemic oak, Quercus lobata, and describe features relevant to its evolutionary success.
- Victoria L. Sork
- , Shawn J. Cokus
- & Steven L. Salzberg
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Article
| Open AccessDNA methylation in newborns conceived by assisted reproductive technology
Timing of assisted reproduction technology (ART) procedures coincides with extensive epigenetic remodeling early after conception. Here the authors identify 176 DNA methylation differences in cord blood of newborns conceived with ART. including genes related to growth, neurodevelopment, and cancer.
- Siri E. Håberg
- , Christian M. Page
- & Robert Lyle
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Article
| Open AccessLupus enhancer risk variant causes dysregulation of IRF8 through cooperative lncRNA and DNA methylation machinery
The functional effects of genetic loci associated with autoimmune disease are not well understood. By dissecting an autoimmune disease genetic locus, the authors define an immune cell-type-specific enhancer and the molecular mechanisms underlying the dysregulation of IRF8 expression by lupus risk variants.
- Tian Zhou
- , Xinyi Zhu
- & Nan Shen
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Article
| Open AccessElastic dosage compensation by X-chromosome upregulation
The concerted dynamics of X-chromosome upregulation and X-chromosome inactivation, which collectively balance X-chromosome expression, are not well understood. Using allelic single-cell genomics, the authors characterize the dynamics of X-chromosome upregulation and inactivation along mouse embryonic and stem cell development, calling to question keys aspects of the established model of mammalian dosage compensation.
- Antonio Lentini
- , Huaitao Cheng
- & Björn Reinius