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| Open AccessMouse strain-specific polymorphic provirus functions as cis-regulatory element leading to epigenomic and transcriptomic variations
How polymorphic elements can drive intra-species variation has not been clearly examined. Here the authors show that the polymorphic GLN endogenous retrovirus (ERV) functions as a cis-regulatory element for neighboring genes, leading to differences in how two mouse strains respond to stress.
- Xuemeng Zhou
- , Tsz Wing Sam
- & Danny Leung
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Article
| Open AccessGenome-wide profiling in colorectal cancer identifies PHF19 and TBC1D16 as oncogenic super enhancers
Active enhancers are still understudied in colorectal cancers (CRC). Here the authors analyse active enhancers in CRC patients using genomics, transcriptomics, and epigenomics, identifying and validating variant super-enhancer loci as well as KLF3 as a relevant transcription factor.
- Qing-Lan Li
- , Xiang Lin
- & Min Wu
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Article
| Open AccessHNF4A defines tissue-specific circadian rhythms by beaconing BMAL1::CLOCK chromatin binding and shaping the rhythmic chromatin landscape
Genome-wide occupancy of the master circadian clock transcription factor BMAL1::CLOCK varies across tissues and is reprogrammed in cancers, but how specificity is governed is not known. Here the authors show BMAL1::CLOCK in liver tissue is guided by chromatin accessibility remodeled by HNF4A, shedding new lights onto mechanisms of dysregulated circadian rhythms in hepatocarcinoma.
- Meng Qu
- , Han Qu
- & Steve A. Kay
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Article
| Open AccessTET2 mutations are associated with hypermethylation at key regulatory enhancers in normal and malignant hematopoiesis
TET2 mutations are frequent in myeloid malignancies and in elderly individuals with or without cytopenia. Here, the authors analyse the association between TET2 mutations and methylation changes in healthy elderly twins and patients with cytopenia and compare them to those from leukemia.
- Morten Tulstrup
- , Mette Soerensen
- & Kirsten Grønbæk
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Article
| Open AccessMapping epigenetic divergence in the massive radiation of Lake Malawi cichlid fishes
The Lake Malawi cichlid fishes are an example of extreme vertebrate radiation; however, there is very little sequence divergence among the species. Here the authors present a comparative genome-wide methylome study to suggest DNA methylation played a major role in the extensive phenotypic diversity amongst these fishes.
- Grégoire Vernaz
- , Milan Malinsky
- & Eric A. Miska
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Article
| Open AccessEpigenetic modifications affect the rate of spontaneous mutations in a pathogenic fungus
While a correlation between epigenetic modifications and mutation rates has been observed, experimental evidence of causality is limited. Here the authors measure the mutation rate in fungal mutants lacking histone modifications and confirm experimentally a causal effect of epigenetic modifications on mutation rates.
- Michael Habig
- , Cecile Lorrain
- & Eva H. Stukenbrock
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Article
| Open AccessPig genome functional annotation enhances the biological interpretation of complex traits and human disease
Annotating functional elements of the genome helps the interpretation of genetic variation. Here, the authors compile functional genomics data for the pig genome over 14 tissues with 15 different chromatin states, integrate the data with WGS and GWAS data, and compare conservation of regulatory elements across mouse and human tissues.
- Zhangyuan Pan
- , Yuelin Yao
- & Huaijun Zhou
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| Open AccessEnhancer-associated H3K4 methylation safeguards in vitro germline competence
While inductive signals controlling germline specification are well characterized, the intrinsic factors that allow epiblast cells to respond to such signals remain largely unknown. Here the authors use in vitro differentiated primordial germ cells to show that partial retention of histone H3K4 monomethylation within relevant enhancers is important for germline competence and specification.
- Tore Bleckwehl
- , Giuliano Crispatzu
- & Álvaro Rada-Iglesias
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Article
| Open AccessChromatin accessibility associates with protein-RNA correlation in human cancer
Studies show the cancer transcriptome correlates poorly with the cancer proteome, questioning the role of chromatin regulation. Here the authors demonstrate proximal-gene-body chromatin elements and transcription predict abundances of differentially expressed proteins in thyroid and breast cancers.
- Akshay Sanghi
- , Joshua J. Gruber
- & Michael P. Snyder
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Article
| Open AccessIdentical twins carry a persistent epigenetic signature of early genome programming
The mechanisms underlying how monozygotic (or identical) twins arise are yet to be determined. Here, the authors investigate this in an epigenome-wide association study, showing that monozygotic twinning has a characteristic DNA methylation signature in adult somatic tissues.
- Jenny van Dongen
- , Scott D. Gordon
- & Dorret I. Boomsma
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Article
| Open AccessDNA methylation landscapes of 1538 breast cancers reveal a replication-linked clock, epigenomic instability and cis-regulation
Understanding the molecular mechanisms underlying DNA methylation in cancer and its clinical relevance remains crucial. Here, the authors study RRBS-based profiles of 1538 breast tumours and 244 normal breast tissues from the METABRIC cohort and report epigenomic instability and cis-regulatory effects.
- Rajbir Nath Batra
- , Aviezer Lifshitz
- & Carlos Caldas
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Article
| Open AccessA functional genomics pipeline identifies pleiotropy and cross-tissue effects within obesity-associated GWAS loci
Many genetic loci have been linked to obesity, but knowledge of their functional mechanisms is limited. Here, the authors perform reporter assays and temporal functional genomics data generation to characterize obesity genetic loci and find that loci often harbor multiple functional variants.
- Amelia C. Joslin
- , Débora R. Sobreira
- & Marcelo A. Nóbrega
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Article
| Open AccessThe concurrence of DNA methylation and demethylation is associated with transcription regulation
The global pattern of the mammalian methylome is formed by changes in methylation and demethylation. Here the authors describe a metric methylation concurrence that measures the ratio of unmethylated CpGs inside the partially methylated reads and show that methylation concurrence is associated with epigenetically regulated tumour suppressor genes.
- Jiejun Shi
- , Jianfeng Xu
- & Wei Li
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Article
| Open AccessGenome-wide sequencing-based identification of methylation quantitative trait loci and their role in schizophrenia risk
The authors provide a comprehensive, single base resolution view of association between genetic variation and DNA methylation in human brain. They also show that heritability attributed to schizophrenia GWAS-associated variants reflects the epigenetic plasticity of the brain.
- Kira A. Perzel Mandell
- , Nicholas J. Eagles
- & Andrew E. Jaffe
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Article
| Open AccessCTCF and transcription influence chromatin structure re-configuration after mitosis
Higher-order chromatin structure is temporarily disrupted during mitosis. Here the authors show that loss of the architectural factor CTCF results in failure to form structural loops and leads to inappropriate cis-regulatory contacts and alterations of compartmental interactions after mitosis. Furthermore, they show global 3D architecture is set up without transcription, but that transcription contributes to proper gene domain formation.
- Haoyue Zhang
- , Jessica Lam
- & Gerd A. Blobel
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Article
| Open AccessComprehensive mapping of SARS-CoV-2 interactions in vivo reveals functional virus-host interactions
Here, Yang et al. apply different RNA sequencing approaches to characterize the secondary structure of SARS-CoV-2 viral RNAs, report on long-range interactions along the viral genome, and uncover the virus-host RNA interactome in cells.
- Siwy Ling Yang
- , Louis DeFalco
- & Yue Wan
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Article
| Open AccessPlacental DNA methylation signatures of maternal smoking during pregnancy and potential impacts on fetal growth
Maternal smoking during pregnancy contributes to poor birth outcomes. Here the authors perform a meta-analysis of the associations between maternal smoking during pregnancy and placental DNA methylation and identify links between these and poor birth outcomes, which may better inform the mechanisms through which smoking impacts placental function and fetal growth.
- Todd M. Everson
- , Marta Vives-Usano
- & Mariona Bustamante
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Article
| Open AccessOncogenic enhancers drive esophageal squamous cell carcinogenesis and metastasis
The role of regulatory cis-elements in carcinogenesis and metastasis in esophageal squamous cell carcinoma remains crucial. Here the authors investigate H3K27ac-marked active enhancer profiles and transcriptomes in different types of esophageal tissues and identify oncogenic events and potential therapeutic targets.
- Bo Ye
- , Dandan Fan
- & Yunbo Qiao
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Article
| Open AccessTissue-specific 5-hydroxymethylcytosine landscape of the human genome
Charting the landscape of 5hmC in human tissues is fundamental to understanding its regulatory functions. Here, we systematically profiled the whole-genome 5hmC landscape at single-base resolution for 19 types of human tissues and found 5hmC shows tissue-specific patterns.
- Bo He
- , Chao Zhang
- & Chengqi Yi
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Article
| Open AccessA multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids
Abnormal blood lipid levels are important risk factors for cardiovascular and other various diseases. Here the authors conduct a large-scale multi-ethnic epigenome-wide association study combined with epigenetic (cis-QTL and eQTM) data, and identify CpG-lipid traits associations that are specific to or common across racial/ethnic groups.
- Min-A Jhun
- , Michael Mendelson
- & Themistocles L. Assimes
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Article
| Open AccessNeuronal and glial 3D chromatin architecture informs the cellular etiology of brain disorders
The cellular heterogeneity in brain obscures the identification of robust cellular regulatory networks. Here the authors integrate genome-wide chromosome conformation data from sorted neurons and glia, with transcriptomic and enhancer profiles, to characterize cell-type-specific gene regulatory landscapes in the human brain, and provide insights into cell-type-specific gene regulatory networks in brain disorders.
- Benxia Hu
- , Hyejung Won
- & Daniel H. Geschwind
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Article
| Open AccessAnalysis of gene network bifurcation during optic cup morphogenesis in zebrafish
The gene regulatory network controlling the bifurcation of common progenitors into the neural retina and retinal-pigmented epithelium programs remains poorly understood. Here the authors study transcriptome dynamics and chromatin accessibility during this process in zebrafish, revealing network redundancy, as well as context-dependent and sequential transcription factor activity.
- Lorena Buono
- , Jorge Corbacho
- & Juan-Ramón Martínez-Morales
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Article
| Open AccessEnvironmental enrichment preserves a young DNA methylation landscape in the aged mouse hippocampus
Decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Here the authors provide evidence that environmental enrichment delays age-related DNA methylation alterations in the mouse hippocampus.
- Sara Zocher
- , Rupert W. Overall
- & Gerd Kempermann
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Article
| Open AccessThe combined action of CTCF and its testis-specific paralog BORIS is essential for spermatogenesis
Although CTCF is a well-established 3D chromatin organizer in multicellular eukaryotes, relatively little is known about its male germ cell-specific paralogue, BORIS. Here the authors investigate how CTCF and BORIS interact and compensate in the male germline of mice to ensure appropriate activation of spermatogenesis-specific genes.
- Samuel Rivero-Hinojosa
- , Elena M. Pugacheva
- & Victor V. Lobanenkov
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Article
| Open AccessArginine methylation of METTL14 promotes RNA N6-methyladenosine modification and endoderm differentiation of mouse embryonic stem cells
The methyltransferase complex of METTL3-METTL14-WTAP is responsible for m6A modification on RNA. Here the authors report that METTL14 arginine 255 (R255) is methylated by PRMT1 and this modification increases interaction of METTL3/METTL14 interaction with WTAP and substrate RNA, promoting m6A methylation activity of the complex.
- Xiaona Liu
- , Hailong Wang
- & Shan Xiao
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Article
| Open AccessE2F6 initiates stable epigenetic silencing of germline genes during embryonic development
DNA methylation targets CpG island promoters of germline genes to repress their expression in mouse somatic cells. Here the authors show that a transcription factor E2F6 is required to target CpG island DNA methylation and epigenetic silencing to germline genes during early mouse development.
- Thomas Dahlet
- , Matthias Truss
- & Michael Weber
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Article
| Open AccessA meta-analysis of epigenome-wide association studies in Alzheimer’s disease highlights novel differentially methylated loci across cortex
Although epigenome-wide association studies of Alzheimer’s disease have highlighted neuropathology-associated DNA methylation differences, previous studies have been limited in sample size and brain region used. Here, the authors combine data from six DNA methylomic studies of Alzheimer’s disease (N = 1453 unique individuals) to identify differentially methylated loci across cortex.
- Rebecca G. Smith
- , Ehsan Pishva
- & Katie Lunnon
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Article
| Open AccessChromosome compartments on the inactive X guide TAD formation independently of transcription during X-reactivation
Both A/B compartments and TADs are thought to be absent from the inactive X chromosome, but to be re-established with transcriptional reactivation and chromatin opening during X-reactivation. Here, the authors characterise gene reactivation, chromatin opening and chromosome topology during X-reactivation, observe A/B-like compartments on the inactive X that guide TAD formation independently of transcription during X-reactivation.
- Moritz Bauer
- , Enrique Vidal
- & Bernhard Payer
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Article
| Open AccessSystematic benchmarking of tools for CpG methylation detection from nanopore sequencing
Several existing algorithms predict the methylation of DNA using Nanopore sequencing signals, but it is unclear how they compare in performance. Here, the authors benchmark the performance of several such tools, and propose METEORE, a consensus tool that improves prediction accuracy.
- Zaka Wing-Sze Yuen
- , Akanksha Srivastava
- & Eduardo Eyras
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Article
| Open AccessLeveraging supervised learning for functionally informed fine-mapping of cis-eQTLs identifies an additional 20,913 putative causal eQTLs
Finding causal variants and genes from GWAS loci results remains a challenge. Here, the authors train a model to predict if a variant affects nearby gene expression, and apply the method to identify new possible causal eQTLs and mechanisms of GWAS loci.
- Qingbo S. Wang
- , David R. Kelley
- & Hilary K. Finucane
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Article
| Open AccessMultimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden
Liquid biopsies enable minimally invasive applications for diagnosis and treatment monitoring. Here the authors analyse fragmentation patterns of circulating tumour DNA on multiple levels and develop a bioinformatic tool, LIQUORICE, to accurately detect and classify paediatric cancers with low mutational burden.
- Peter Peneder
- , Adrian M. Stütz
- & Eleni M. Tomazou
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Article
| Open AccessEpigenomic profiling of primate lymphoblastoid cell lines reveals the evolutionary patterns of epigenetic activities in gene regulatory architectures
Comparative epigenomics has revealed principles underlying the evolution of gene expression regulation, and the integration of epigenomic data is important for a deeper understanding of this evolution. Here the authors report the evolutionary dynamics of the epigenomic regulatory landscape in primates and their impact in recent human evolution.
- Raquel García-Pérez
- , Paula Esteller-Cucala
- & Tomàs Marquès-Bonet
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Article
| Open AccessOverarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology
Members of the CHD chromatin remodeler family are implicated in human pathologies, however CHD6 remained poorly studied. Here, the authors show that CHD6 binds to and regulates autophagy and stress response genes across cell types. They identify a clinical mutation that affects its ability to recruit cofactors, leading to impaired autophagy induction and DNA repair.
- Yulia Kargapolova
- , Rizwan Rehimi
- & Argyris Papantonis
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Article
| Open AccessHigh-throughput single-cell chromatin accessibility CRISPR screens enable unbiased identification of regulatory networks in cancer
Transcription factor binding dynamics can drive epigenetic states, enabling a diversity of phenotypes. Here the authors present Spear-ATAC to quantify and map perturbations to chromatin accessibility in single cells at high throughput.
- Sarah E. Pierce
- , Jeffrey M. Granja
- & William J. Greenleaf
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Article
| Open AccessEpigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption
While coffee and tea consumption has been associated with risk of diseases, their mechanisms of action remain elusive. Here the authors present a large EWAS on coffee and tea consumption in cohorts of European and African-American ancestries, finding that coffee consumption is associated with differential DNA methylation levels at multiple CpGs.
- Irma Karabegović
- , Eliana Portilla-Fernandez
- & Mohsen Ghanbari
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Article
| Open AccessThe genomic loci of specific human tRNA genes exhibit ageing-related DNA hypermethylation
The epigenome has been shown to change with age, potentially impacting on ageing-related disease. Here the authors investigate the DNA methylation state of the genomic loci of human tRNA and observe enrichment for age-related DNA hypermethylation at tRNA loci.
- Richard J. Acton
- , Wei Yuan
- & Christopher G. Bell
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Article
| Open AccessThe histone variant H2A.W and linker histone H1 co-regulate heterochromatin accessibility and DNA methylation
T-DNA mutants have been widely used for Arabidopsis gene function characterization. Here, by characterizing a null mutant created by CRISPR, the authors show that previous reported function of H2A.W is confounded by a T-DNA insertion induced chromosomal rearrangement and reveal its role in regulating heterochromatin accessibility.
- Pierre Bourguet
- , Colette L. Picard
- & Olivier Mathieu
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Article
| Open AccessComprehensive cell type decomposition of circulating cell-free DNA with CelFiE
Tissue damage and turnover lead to the release of DNA in the blood and can be used to monitor changes in tissue state. Here, the authors developed a tool to accurately estimate the proportion of cell types contributing to cell-free DNA in the blood, with an application to pregnant women and ALS patients.
- Christa Caggiano
- , Barbara Celona
- & Noah Zaitlen
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Article
| Open AccessMultiple roles of H2A.Z in regulating promoter chromatin architecture in human cells
Histone variant H2A.Z has been suggested to contribute to the regulation of promoter accessibility. Here, the authors present high-depth maps of the position and accessibility of H2A.Z-containing nucleosomes for human Pol II promoters and provide evidence that H2A.Z has multiple and distinct roles in regulating gene expression dependent upon its location in a promoter.
- Lauren Cole
- , Sebastian Kurscheid
- & David J. Tremethick
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Article
| Open AccessLearning a genome-wide score of human–mouse conservation at the functional genomics level
Understanding conserved functional genomic properties between human and mouse provides important context for mouse model studies. Here, the authors present a genome-wide conservation score integrating epigenomic, transcription factor binding, and transcriptomic data from mouse and human genomes.
- Soo Bin Kwon
- & Jason Ernst
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Article
| Open AccessA pan-cancer analysis of CpG Island gene regulation reveals extensive plasticity within Polycomb target genes
A subset of CpG Island promoter genes are regulated by Polycomb-Repressive Complex 2 (PRC2+-CGI), which become DNA hypermethylated and silenced in cancer. Here, the authors investigate the transcriptomic and epigenomic characteristics of PRC2-occupied CGI and free CGI across pan-cancer types.
- Yueyuan Zheng
- , Guowei Huang
- & Benjamin P. Berman
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Article
| Open AccessEpigenomic landscape of human colorectal cancer unveils an aberrant core of pan-cancer enhancers orchestrated by YAP/TAZ
The role of epigenetic deregulation in colorectal cancer (CRC) is not fully understood yet. Here the authors use patient-derived organoids, epigenomics and single-cell RNA-seq to reveal that YAP/TAZ are key regulators that bind to active enhancers in CRC and promote tumour survival.
- Giulia Della Chiara
- , Federica Gervasoni
- & Massimiliano Pagani
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Article
| Open AccessSingle cell regulatory landscape of the mouse kidney highlights cellular differentiation programs and disease targets
Epigenetic and transcriptional dynamics are critical for both tissue homeostasis and injury response in the kidney. Leveraging a single cell multiomics atlas of the developing mouse kidney, the authors reveal key events in chromatin regulation and gene expression dynamics during postnatal development.
- Zhen Miao
- , Michael S. Balzer
- & Katalin Susztak
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Article
| Open AccessA compendium and comparative epigenomics analysis of cis-regulatory elements in the pig genome
To date, little is known about the regulatory landscape of the pig genome. Here, the authors characterize cis-regulatory elements in the pig genome using RNA-seq, ChIP-Seq and ATAC-seq, finding a higher degree of usage conservation between pig and human than mouse and human.
- Yunxia Zhao
- , Ye Hou
- & Shuhong Zhao
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Article
| Open AccessWidespread reorganisation of pluripotent factor binding and gene regulatory interactions between human pluripotent states
The role of transcriptional enhancers and 3D chromatin organisation in coordinating the transition from naive to primed pluripotency remains poorly understood. Here the authors generate a high-resolution atlas of gene regulatory interactions, chromatin profiles and transcription factor occupancy in naive and primed human pluripotent stem cells to provide insights into these developmental processes.
- Peter Chovanec
- , Amanda J. Collier
- & Peter J. Rugg-Gunn
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Article
| Open AccessEvolution of DNA methylation in the human brain
DNA methylation plays an important role in brain development and function. Here, the authors compare whole-genome methylation in neurons and oligodendrocytes in humans, chimpanzees and macaques to reconstruct evolution of DNA methylation at cell-type level, including in regions associated with schizophrenia heritability.
- Hyeonsoo Jeong
- , Isabel Mendizabal
- & Soojin V. Yi
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Article
| Open AccessReprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer
The molecular processes that lead to neuroendocrine prostate cancer after treating prostate adenocarcinoma (PRAD) are not well understood. Here the authors show that regulation by FOXA1 and changes in the epigenomic profile drive the transition from PRAD to a neuroendocrine phenotype.
- Sylvan C. Baca
- , David Y. Takeda
- & Matthew L. Freedman
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Article
| Open AccessFunctional annotations of three domestic animal genomes provide vital resources for comparative and agricultural research
In order to interpret non-coding variants, information about regulatory elements in the genome is essential. Here, the authors annotate regulatory elements in chicken, pig and cattle, and characterize conservation of these elements between species.
- Colin Kern
- , Ying Wang
- & Huaijun Zhou
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Article
| Open AccessDNA methylation predicts age and provides insight into exceptional longevity of bats
DNA methylation profiles from 26 bat species accurately predicts chronological age, while longevity-related methylation patterns across the genome suggest that bat longevity results from augmented immune response and cancer suppression.
- Gerald S. Wilkinson
- , Danielle M. Adams
- & Steve Horvath