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| Open AccesseQTL mapping in fetal-like pancreatic progenitor cells reveals early developmental insights into diabetes risk
Fetal development plays an important role in defining adult diabetes risk. Here, authors identified a genetic link between fetal pancreatic gene expression, obesity, and diabetes risk through eQTL mapping of iPSC-derived pancreatic progenitor cells.
- Jennifer P. Nguyen
- , Timothy D. Arthur
- & Kelly A. Frazer
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Article
| Open AccessRNA-based translation activators for targeted gene upregulation
Many diseases are driven by the insufficient expression of critical genes, but few technologies are capable of rescuing these endogenous protein levels. Here, Cao et al. present an RNA-based technology that boosts protein production from endogenous mRNAs by upregulating their translation.
- Yang Cao
- , Huachun Liu
- & Bryan C. Dickinson
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Article
| Open AccessCircular single-stranded DNA as switchable vector for gene expression in mammalian cells
Synthetic gene networks in mammalian cells are currently limited to either transcription factors or RNA regulators. Here, the authors develop a regulatory approach based on circular single-stranded DNA, which can be used as a conformationally switchable genetic vector in mammalian cells.
- Linlin Tang
- , Zhijin Tian
- & Jie Song
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Article
| Open AccessA DEAD-box helicase drives the partitioning of a pro-differentiation NAB protein into nuclear foci
The mechanism of spatiotemporal gene regulation during animal development is a fundamental question in biology. Here the authors show that the DEAD-box helicase DDX-23 controls stem cell fate by driving the formation of NAB repressive transcriptional condensates.
- Akiko Doi
- , Gianmarco D. Suarez
- & H. Robert Horvitz
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| Open AccessReprogramming of cis-regulatory networks during skeletal muscle atrophy in male mice
Skeletal muscle’s metabolic status has an impact on health and the prognosis of chronic diseases. Here the authors unveil an atlas of open chromatin regions in skeletal muscles using single-nucleus techniques on juvenile male mice, highlight regulatory dynamics between normal and denervated states, and pinpoint ELK4 as a pivotal factor in muscle atrophy.
- Hongchun Lin
- , Hui Peng
- & Zhaoyong Hu
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Article
| Open AccessRewiring of the promoter-enhancer interactome and regulatory landscape in glioblastoma orchestrates gene expression underlying neurogliomal synaptic communication
The integration of transcriptomics and epigenomics data helps to better understand the regulatory and topological changes in glioblastoma subtypes. Here, the authors map the promoter-enhancer interactome and regulatory landscape and show changes in promoter-enhancer interactions, chromatin accessibility, and redistribution of histone marks across four glioblastoma subtypes.
- Chaitali Chakraborty
- , Itzel Nissen
- & Silvia Remeseiro
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Article
| Open AccessSingle-cell allele-specific expression analysis reveals dynamic and cell-type-specific regulatory effects
Here the authors develop DAESC, a statistical method for differential allele-specific expression analysis using single-cell RNA-seq data. Application of DAESC identifies dynamic regulatory effects along endoderm differentiation and differential effects between type 2 diabetes and healthy controls.
- Guanghao Qi
- , Benjamin J. Strober
- & Alexis Battle
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Article
| Open AccessImmunosuppression causes dynamic changes in expression QTLs in psoriatic skin
Psoriasis is a chronic, systemic inflammatory condition primarily affecting skin. Here, the authors investigate the genetic basis of gene expression in skin biopsies from psoriasis patients and interactions with inflammation to better understand mechanisms of the disease.
- Qian Xiao
- , Joseph Mears
- & Soumya Raychaudhuri
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Article
| Open AccessThe endoribonuclease Arlr is required to maintain lipid homeostasis by downregulating lipolytic genes during aging
Fat is generally considered to have a negative effect on longevity but lipids can be beneficial for longevity. Here the authors show that fly Arlr endoribonuclease affects lipid metabolism by degrading the mRNAs of lipolysis genes.
- Xiaowei Sun
- , Jie Shen
- & Dan Wang
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Article
| Open AccessGlobal mapping of RNA-chromatin contacts reveals a proximity-dominated connectivity model for ncRNA-gene interactions
Many types of RNAs are associated with chromatin. Here the authors identify chromatin-bound RNAs and their binding sites in human embryonic stem cells suggesting that most chromatin-associated RNAs act proximal to their encoding loci and single RNAs are unlikely to alter gene expression.
- Charles Limouse
- , Owen K. Smith
- & Aaron F. Straight
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Article
| Open AccessA transcriptional network required for bradyzoite development in Toxoplasma gondii is dispensable for recrudescent disease
Toxoplasma gondii can develop into dormant bradyzoites that persist in tissue and can be reactivated. Here the authors identify an RNA binding protein that they call Regulator of Cystogenesis 1 (ROCY1), and show that it is required for bradyzoite development in vitro and in vivo but is not required for long term persistence of parasites that reactivate in a mouse model of recrudescence.
- Sarah L. Sokol-Borrelli
- , Sarah M. Reilly
- & Jon P. Boyle
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Article
| Open AccessEpitranscriptomic subtyping, visualization, and denoising by global motif visualization
The current available tools lack the ability to accurately classify and visually represent epitranscriptomic profiling data. Here, the authors provide a framework that offers a general solution for the visualization and interpretation of such data.
- Jianheng Liu
- , Tao Huang
- & Rui Zhang
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Article
| Open AccessTelomerase RNA-based aptamers restore defective myelopoiesis in congenital neutropenic syndromes
The RNA component telomerase (TERC) has a critical non-canonical role in the formation of the myeloid lineage. Here, the authors show aptamers that mimic the behaviour of the entire TERC molecule in myelopoiesis activation.
- Elena Martínez-Balsalobre
- , Jesús García-Castillo
- & María L. Cayuela
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Article
| Open AccessThe TNFR Wengen regulates the FGF pathway by an unconventional mechanism
Mechanistic studies of receptor action have aided our understanding of developmental processes and facilitated drug development. Here they show that the TNFR-Wengen acts by forming a complex with the FGFR-Breathless, regulating its activity during cell differentiation in the developing respiratory system of Drosophila.
- Annalisa Letizia
- , Maria Lluisa Espinàs
- & Marta Llimargas
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Article
| Open AccessLola-I is a promoter pioneer factor that establishes de novo Pol II pausing during development
Gene promoters are very often poised for expression by paused RNA polymerase II. Here, Ramalingam et al., identify a mechanism for the de novo establishment of paused Pol II at promoters and study its effects on expression.
- Vivekanandan Ramalingam
- , Xinyang Yu
- & Julia Zeitlinger
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| Open AccessA linear and circular dual-conformation noncoding RNA involved in oxidative stress tolerance in Bacillus altitudinis
The presence and/or biological functionality of circular RNAs in bacteria are unclear. Here, the authors identify a dual-conformation (linear and circular) noncoding RNA that promotes tolerance to oxidative stress in Bacillus altitutidinis, and provide evidence for the existence of other circular RNAs in diverse bacterial species.
- Ting-Ting He
- , Yun-Fan Xu
- & Hai-Yan Wang
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Article
| Open AccessGlobal impact of somatic structural variation on the cancer proteome
The relevance of non-coding somatic mutations in cancer remains elusive. Here, the combination of mass spectrometry-based proteomics and whole genome sequencing data across multiple cancer types helps to assess the effects of somatic structural variant breakpoint patterns on protein expression of nearby genes.
- Fengju Chen
- , Yiqun Zhang
- & Chad J. Creighton
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Article
| Open AccesstgCRISPRi: efficient gene knock-down using truncated gRNAs and catalytically active Cas9
CRISPRi is used for gene silencing in mammalian cells. Here the authors report a gene-suppression/activation strategy using active Cas9 complexed with truncated gRNAs (tgCRISPRi/a) without causing DNA cleavage: they use this to repress or activate expression of several target genes throughout somatic tissues in Drosophila melanogaster.
- Ankush Auradkar
- , Annabel Guichard
- & Ethan Bier
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Article
| Open AccessA nuclear receptor HR96-related gene underlies large trans-driven differences in detoxification gene expression in a generalist herbivore
Adaptation to toxins in agricultural pests is often caused by increased expression of detoxification genes. Here, the authors reveal that variation in a family of transcriptional regulators facilitates rapid evolution to diverse pesticides and host plants.
- Meiyuan Ji
- , Marilou Vandenhole
- & Thomas Van Leeuwen
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Article
| Open AccessCell-specific and shared regulatory elements control a multigene locus active in mammary and salivary glands
The authors investigate the regulatory complexity of a multigene locus with 20 candidate regulatory elements, including an ancestral super-enhancer, active in mammary and salivary tissue and local enhancers and promoter elements unique to mammary tissue.
- Hye Kyung Lee
- , Michaela Willi
- & Lothar Hennighausen
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Article
| Open AccessGain-of-function mutant p53 together with ERG proto-oncogene drive prostate cancer by beta-catenin activation and pyrimidine synthesis
TP53 alteration and TMPRSS2-ERG fusion are often found together in prostate cancer. Here, the authors show that gain-of-function mutant p53 collaborates with ERG proto-oncogene to drive prostate cancer tumourigenesis by activating beta-catenin expression and afterwards pyrimidine synthesis.
- Donglin Ding
- , Alexandra M. Blee
- & Haojie Huang
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Article
| Open AccessIntegrative analysis of transcriptome dynamics during human craniofacial development identifies candidate disease genes
Craniofacial disorders are among the most common congenital defects. Here, the authors examined the genetic causes of non-syndromic craniofacial disorders during human development through analysis of gene expression and epigenomics.
- Tara N. Yankee
- , Sungryong Oh
- & Justin Cotney
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Matters Arising
| Open AccessPotential contribution of PEP carboxykinase-dependent malate dismutation to the hypoxia response in C. elegans
- Rosina Comas-Ghierra
- , Laura Romanelli-Cedrez
- & Gustavo Salinas
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Matters Arising
| Open AccessReply to: Potential contribution of PEP carboxykinase-dependent malate dismutation to the hypoxia response in C. elegans
- Mehul Vora
- , Stephanie M. Pyonteck
- & Christopher Rongo
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Article
| Open AccessSingle-cell profiling of lncRNA expression during Ebola virus infection in rhesus macaques
Long non-coding RNAs (lncRNAs) play key roles in the immune response but their properties at the single-cell level are less well understood. Here, the authors characterize differential features of lncRNAs and protein-coding genes upon Ebola infection in macaques at single-cell resolution.
- Luisa Santus
- , Maria Sopena-Rios
- & Marta Melé
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Article
| Open AccessAn analytical framework for decoding cell type-specific genetic variation of gene regulation
Understanding genetic regulation and the underlying mechanism for genetic associations with human phenotypes is complicated by cellular heterogeneity and linkage disequilibrium. Here, the authors propose an analytical framework to decode genetic variation of gene regulation at both cell-type and single-nucleotide levels.
- Yanyu Xiao
- , Jingjing Wang
- & Guoji Guo
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Article
| Open AccessSelective binding of retrotransposons by ZFP352 facilitates the timely dissolution of totipotency network
During zygotic genome activation the embryo must re-wire the regulatory network that sustains totipotency earlier during development. Here they identify ZFP352 as an essential factor that targets retrotransposon families to facilitate dissolution of the totipotency network and enable ZGA.
- Zhengyi Li
- , Haiyan Xu
- & Hongqing Liang
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Article
| Open AccessDynamic chromatin architecture of the porcine adipose tissues with weight gain and loss
Here the authors study diet-induced weight gain/loss to identify chromatin architectures in adipose tissue (AT) associated obesity in a pig model. They found parallels and species-specific regulatory elements in humans and pigs that underpin AT specialization.
- Long Jin
- , Danyang Wang
- & Mingzhou Li
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Article
| Open AccessChromatin alternates between A and B compartments at kilobase scale for subgenic organization
Ultra-deep mapping of genome organization uncovers precise nuclear compartments and diffuse CTCF loops. This work demonstrates that compartment domains segregate the 5′ and 3′ ends of genes and that CTCF loops create proximal structures.
- Hannah L. Harris
- , Huiya Gu
- & M. Jordan Rowley
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Article
| Open AccessLight-switchable transcription factors obtained by direct screening in mammalian cells
Light-switchable variants are only available for a limited subset of proteins and pathways. Here the authors adapt strategies for protein domain insertion and mammalian-cell expression to generate and screen a library of potential optogenetic tools directly in mammalian cells.
- Liyuan Zhu
- , Harold M. McNamara
- & Jared E. Toettcher
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Article
| Open AccessThe NELF pausing checkpoint mediates the functional divergence of Cdk9
Promoter-proximal pausing by RNA Pol II is a key aspect of how gene expression is transcriptionally regulated in higher eukaryotes. Here the authors show that only NELF-mediated pausing enforces a strict early checkpoint for Cdk9 by efficiently shutting down gene transcription following loss of Cdk9.
- Michael DeBerardine
- , Gregory T. Booth
- & John T. Lis
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Article
| Open AccessBase-resolution UV footprinting by sequencing reveals distinctive damage signatures for DNA-binding proteins
Proteins binding to DNA can locally alter DNA damage formation by UV light. Here, Elliott et al. generate high-resolution quantitative UV damage profiles for genomic regions of interest, revealing distinctive damage signatures for specific proteins and elevated UV damage at melanoma mutation hotspots.
- Kerryn Elliott
- , Vinod Kumar Singh
- & Erik Larsson
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Article
| Open AccessTranscription factor binding site orientation and order are major drivers of gene regulatory activity
Gene regulatory grammar remains difficult to decipher, hindering our ability to link genotype to phenotype. Here they use massively parallel reporter assays to test over 200,000 synthetic sequences, finding that transcription factor binding site order and orientation have a major effect on gene regulatory activity.
- Ilias Georgakopoulos-Soares
- , Chengyu Deng
- & Nadav Ahituv
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Article
| Open AccessMapping genomic regulation of kidney disease and traits through high-resolution and interpretable eQTLs
Here, the authors discover over 15,000 eQTLs in human kidney samples by integrating single-nucleus open chromatin data, resulting in high resolution eQTLs, increased enrichment of GWAS heritability and colocalization, followed by downstream validation.
- Seong Kyu Han
- , Michelle T. McNulty
- & Matthew G. Sampson
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Article
| Open AccessScreening of Drosophila microRNA-degradation sequences reveals Argonaute1 mRNA’s role in regulating miR-999
miRNAs typically bind to target mRNAs to induce their degradation but when base-pairing between miRNAs and the target RNAs are extended, miRNAs themselves can be degraded. Here, by employing AGO1-CLASH in Drosophila cells, the authors show that RNA sequence in AGO1 mRNA 3′UTR induces decay of miR-999.
- Peike Sheng
- , Lu Li
- & Mingyi Xie
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Article
| Open AccessA-MYB and BRDT-dependent RNA Polymerase II pause release orchestrates transcriptional regulation in mammalian meiosis
During spermatogenic meiosis, chromatin changes due to transcription, homologous recombination, and chromosome synapsis must be coordinated. Here they show that A-MYC and BRDT regulate release of paused RNA PolII to induce a transcriptional burst during pachytene of prophase I.
- Adriana K. Alexander
- , Edward J. Rice
- & Charles G. Danko
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Article
| Open AccessA regulatory variant at 19p13.3 is associated with primary biliary cholangitis risk and ARID3A expression
Primary biliary cholangitis is a rare, chronic immune-mediated liver disease triggered by environmental exposures in genetically susceptible individuals. Here, the authors investigate the functional mechanism underlying the association of 19p13.3 variants with primary biliary cholangitis.
- You Li
- , Zhiqiang Li
- & Xiong Ma
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Article
| Open AccessThe rhythmic coupling of Egr-1 and Cidea regulates age-related metabolic dysfunction in the liver of male mice
Many transcriptomic pathways in the liver show circadian rhythms, which have been reported to be disrupted in aged mice. Here the authors report that the expression of transcription factor Egr-1 decreases and its rhythm is shifted with age in the liver of male mice, and that deletion of Egr-1 results in increased liver fat accumulation.
- Jing Wu
- , Dandan Bu
- & Chao-Jun Li
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Article
| Open AccessCombinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve split-hand/foot malformation type 3
Congenital limb defects are often associated with genomic rearrangements. Here they provide insights into the molecular mechanism underlying SHFM3-associated structural variations, offering a conceptual framework for how genomic rearrangements can alter gene expression and cause disease.
- Giulia Cova
- , Juliane Glaser
- & Stefan Mundlos
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Article
| Open AccessAn autoimmune pleiotropic SNP modulates IRF5 alternative promoter usage through ZBTB3-mediated chromatin looping
Here the authors used an evidence-based strategy to prioritize causal pleiotropic variants of autoimmune diseases, and revealed that rs4728142 modulates aberrant IRF5 alternative promoter usage by ZBTB3-mediated chromatin looping.
- Zhao Wang
- , Qian Liang
- & Mulin Jun Li
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Article
| Open AccessAdaptive partitioning of a gene locus to the nuclear envelope in Saccharomyces cerevisiae is driven by polymer-polymer phase separation
Partitioning of active genes to the nuclear periphery is commonly observed but not understood. Here, the authors show that this process occurs by phase separation of transcriptionally active chromatin providing for efficient mRNA transport and memory.
- Lidice González
- , Daniel Kolbin
- & Stephen W. Michnick
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Article
| Open AccessCvkR is a MerR-type transcriptional repressor of class 2 type V-K CRISPR-associated transposase systems
RNA-guided, CRISPR-associated transposons hold great promise for precision genome editing. Here, the authors provide genetic, biochemical and structural data how their activity is regulated in situ by CvkR, an unusual MerR family regulator.
- Marcus Ziemann
- , Viktoria Reimann
- & Wolfgang R. Hess
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Article
| Open AccessMolecular mechanisms of coronary artery disease risk at the PDGFD locus
Genes encode risk for coronary disease, identifying how they function is critical to developing new therapies. In work reported the authors have identified one culprit gene, PDGFD, and studied how it functions to promote disease risk.
- Hyun-Jung Kim
- , Paul Cheng
- & Thomas Quertermous
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Article
| Open AccessA CpG island-encoded mechanism protects genes from premature transcription termination
Here the authors discover that SET1 complexes function as transcription anti-termination factors that bind to CpG islands and protect low to moderately transcribed genes from the pervasive termination activity of the ZC3H4 complex.
- Amy L. Hughes
- , Aleksander T. Szczurek
- & Robert J. Klose
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Article
| Open AccessMulti-omics and machine learning reveal context-specific gene regulatory activities of PML::RARA in acute promyelocytic leukemia
The PML-RARA gene fusion is the characteristic driver of Acute Promyelocytic Leukaemia (APL) and is known to bind to the genome. Here, the authors characterise the impact of PML-RARA on gene regulation in APL cell lines and patient samples using transcriptomics, epigenomics, and machine learning.
- William Villiers
- , Audrey Kelly
- & Cameron S. Osborne
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Article
| Open AccessWidespread contribution of transposable elements to the rewiring of mammalian 3D genomes
Here the authors show transposable elements, formerly considered junk DNA, are a source of CTCF binding sites that contribute to species-specific 3D-genome structure, and may impact gene regulation during the course of mammalian evolution.
- Mayank N. K. Choudhary
- , Kara Quaid
- & Ting Wang
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Article
| Open AccessAlternative polyadenylation transcriptome-wide association study identifies APA-linked susceptibility genes in brain disorders
Alternative polyadenylation (APA) contributes to the post-transcriptional regulation of most human genes, yet the effects of APA are largely overlooked by conventional transcriptome-wide association studies (TWAS). Here, the authors conduct an APA-TWAS for 11 brain disorders, identifying hundreds of APA-linked disease susceptibility genes.
- Ya Cui
- , Frederick J. Arnold
- & Wei Li
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Article
| Open AccessThe function and evolution of a genetic switch controlling sexually dimorphic eye differentiation in honeybees
Sexual dimorphism results in widely diverse animal forms, but sexual determination is generally attributed to a single gene in animal models. Here they find that the glu gene regulates sexual dimorphism of honeybee eyes, demonstrating diversification of genetic programs for dimorphism.
- Oksana Netschitailo
- , Yidong Wang
- & Martin Beye
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Article
| Open AccessMechanisms and function of de novo DNA methylation in placental development reveals an essential role for DNMT3B
DNA methylation is a repressive modification that is essential for development. Here the authors reveal a critical role for DNA methylation in placental development during pregnancy. Failure to properly establish placental DNA methylation patterns compromises not only placental function, but embryo survival.
- Simon Andrews
- , Christel Krueger
- & Courtney W. Hanna