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Featured researches published by Ryan Lister.


Nature | 2009

Human DNA methylomes at base resolution show widespread epigenomic differences

Ryan Lister; Mattia Pelizzola; Robert H. Dowen; R. David Hawkins; Gary C. Hon; Julian Tonti-Filippini; Joseph R. Nery; Leonard K. Lee; Zhen Ye; Que Minh Ngo; Lee Edsall; Jessica Antosiewicz-Bourget; Ron Stewart; Victor Ruotti; A. Harvey Millar; James A. Thomson; Bing Ren; Joseph R. Ecker

DNA cytosine methylation is a central epigenetic modification that has essential roles in cellular processes including genome regulation, development and disease. Here we present the first genome-wide, single-base-resolution maps of methylated cytosines in a mammalian genome, from both human embryonic stem cells and fetal fibroblasts, along with comparative analysis of messenger RNA and small RNA components of the transcriptome, several histone modifications, and sites of DNA–protein interaction for several key regulatory factors. Widespread differences were identified in the composition and patterning of cytosine methylation between the two genomes. Nearly one-quarter of all methylation identified in embryonic stem cells was in a non-CG context, suggesting that embryonic stem cells may use different methylation mechanisms to affect gene regulation. Methylation in non-CG contexts showed enrichment in gene bodies and depletion in protein binding sites and enhancers. Non-CG methylation disappeared upon induced differentiation of the embryonic stem cells, and was restored in induced pluripotent stem cells. We identified hundreds of differentially methylated regions proximal to genes involved in pluripotency and differentiation, and widespread reduced methylation levels in fibroblasts associated with lower transcriptional activity. These reference epigenomes provide a foundation for future studies exploring this key epigenetic modification in human disease and development.


Cell | 2008

Highly Integrated Single-Base Resolution Maps of the Epigenome in Arabidopsis

Ryan Lister; Ronan O'Malley; Julian Tonti-Filippini; Brian D. Gregory; Charles C. Berry; A. Harvey Millar; Joseph R. Ecker

Deciphering the multiple layers of epigenetic regulation that control transcription is critical to understanding how plants develop and respond to their environment. Using sequencing-by-synthesis technology we directly sequenced the cytosine methylome (methylC-seq), transcriptome (mRNA-seq), and small RNA transcriptome (smRNA-seq) to generate highly integrated epigenome maps for wild-type Arabidopsis thaliana and mutants defective in DNA methyltransferase or demethylase activity. At single-base resolution we discovered extensive, previously undetected DNA methylation, identified the context and level of methylation at each site, and observed local sequence effects upon methylation state. Deep sequencing of smRNAs revealed a direct relationship between the location of smRNAs and DNA methylation, perturbation of smRNA biogenesis upon loss of CpG DNA methylation, and a tendency for smRNAs to direct strand-specific DNA methylation in regions of RNA-DNA homology. Finally, strand-specific mRNA-seq revealed altered transcript abundance of hundreds of genes, transposons, and unannotated intergenic transcripts upon modification of the DNA methylation state.


Nature | 2011

Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells

Ryan Lister; Mattia Pelizzola; Yasuyuki S. Kida; R. David Hawkins; Joseph R. Nery; Gary C. Hon; Jessica Antosiewicz-Bourget; Ronan C. O’Malley; Rosa Castanon; Sarit Klugman; Michael Downes; Ruth T. Yu; Ron Stewart; Bing Ren; James A. Thomson; Ronald M. Evans; Joseph R. Ecker

Induced pluripotent stem cells (iPSCs) offer immense potential for regenerative medicine and studies of disease and development. Somatic cell reprogramming involves epigenomic reconfiguration, conferring iPSCs with characteristics similar to embryonic stem (ES) cells. However, it remains unknown how complete the reestablishment of ES-cell-like DNA methylation patterns is throughout the genome. Here we report the first whole-genome profiles of DNA methylation at single-base resolution in five human iPSC lines, along with methylomes of ES cells, somatic cells, and differentiated iPSCs and ES cells. iPSCs show significant reprogramming variability, including somatic memory and aberrant reprogramming of DNA methylation. iPSCs share megabase-scale differentially methylated regions proximal to centromeres and telomeres that display incomplete reprogramming of non-CG methylation, and differences in CG methylation and histone modifications. Lastly, differentiation of iPSCs into trophoblast cells revealed that errors in reprogramming CG methylation are transmitted at a high frequency, providing an iPSC reprogramming signature that is maintained after differentiation.


Science | 2013

Global Epigenomic Reconfiguration During Mammalian Brain Development

Ryan Lister; Eran A. Mukamel; Joseph R. Nery; Mark A. Urich; Clare A. Puddifoot; Nicholas D. Johnson; Jacinta Lucero; Yun Huang; Andrew J. Dwork; Matthew D. Schultz; Miao Yu; Julian Tonti-Filippini; Holger Heyn; Shijun Hu; Joseph C. Wu; Anjana Rao; Manel Esteller; Chuan He; Fatemeh Haghighi; Terrence J. Sejnowski; M. Margarita Behrens; Joseph R. Ecker

Introduction Several lines of evidence point to a key role for dynamic epigenetic changes during brain development, maturation, and learning. DNA methylation (mC) is a stable covalent modification that persists in post-mitotic cells throughout their lifetime, defining their cellular identity. However, the methylation status at each of the ~1 billion cytosines in the genome is potentially an information-rich and flexible substrate for epigenetic modification that can be altered by cellular activity. Indeed, changes in DNA methylation have been implicated in learning and memory, as well as in age-related cognitive decline. However, little is known about the cell type–specific patterning of DNA methylation and its dynamics during mammalian brain development. The DNA methylation landscape of human and mouse neurons is dynamically reconfigured through development. Base-resolution analysis allowed identification of methylation in the CG and CH context (H = A, C, or T). Unlike other differentiated cell types, neurons accumulate substantial mCH during the early years of life, coinciding with the period of synaptogenesis and brain maturation. Methods We performed genome-wide single-base resolution profiling of the composition, patterning, cell specificity, and dynamics of DNA methylation in the frontal cortex of humans and mice throughout their lifespan (MethylC-Seq). Furthermore, we generated base-resolution maps of 5-hydroxymethylcytosine (hmC) in mammalian brains by TAB-Seq at key developmental stages, accompanied by RNA-Seq transcriptional profiling. Results Extensive methylome reconfiguration occurs during development from fetal to young adult. In this period, coincident with synaptogenesis, highly conserved non-CG methylation (mCH) accumulates in neurons, but not glia, to become the dominant form of methylation in the human neuronal genome. We uncovered surprisingly complex features of brain cell DNA methylation at multiple scales, first by identifying intragenic methylation patterns in neurons and glia that distinguish genes with cell type–specific activity. Second, we report a novel mCH signature that identifies genes escaping X-chromosome inactivation in neurons. Third, we find >100,000 developmentally dynamic and cell type–specific differentially CG-methylated regions that are enriched at putative regulatory regions of the genome. Finally, whole-genome detection of 5-hydroxymethylcytosine (hmC) at single-base resolution revealed that this mark is present in fetal brain cells at locations that lose CG methylation and become activated during development. CG-demethylation at these hmC-poised loci depends on Tet2 activity. Discussion Whole-genome single-base resolution methylcytosine and hydroxymethylcytosine maps revealed profound changes during frontal cortex development in humans and mice. These results extend our knowledge of the unique role of DNA methylation in brain development and function, and offer a new framework for testing the role of the epigenome in healthy function and in pathological disruptions of neural circuits. Overall, brain cell DNA methylation has unique features that are precisely conserved, yet dynamic and cell-type specific. Epigenetic Brainscape Epigenetic modifications and their potential changes during development are of high interest, but few studies have characterized such differences. Lister et al. (1237905, published online 4 July; see the Perspective by Gabel and Greenberg) report whole-genome base-resolution analysis of DNA cytosine modifications and transcriptome analysis in the frontal cortex of human and mouse brains at multiple developmental stages. The high-resolution mapping of DNA cytosine methylation (5mC) and one of its oxidation derivatives (5hmC) at key developmental stages provides a comprehensive resource covering the temporal dynamics of these epigenetic modifications in neurons compared to glia. The data suggest that methylation marks are dynamic during brain development in both humans and mice. A genome-wide map shows that DNA methylation in neurons and glial cells changes during development in humans and mice. [Also see Perspective by Gabel and Greenberg] DNA methylation is implicated in mammalian brain development and plasticity underlying learning and memory. We report the genome-wide composition, patterning, cell specificity, and dynamics of DNA methylation at single-base resolution in human and mouse frontal cortex throughout their lifespan. Widespread methylome reconfiguration occurs during fetal to young adult development, coincident with synaptogenesis. During this period, highly conserved non-CG methylation (mCH) accumulates in neurons, but not glia, to become the dominant form of methylation in the human neuronal genome. Moreover, we found an mCH signature that identifies genes escaping X-chromosome inactivation. Last, whole-genome single-base resolution 5-hydroxymethylcytosine (hmC) maps revealed that hmC marks fetal brain cell genomes at putative regulatory regions that are CG-demethylated and activated in the adult brain and that CG demethylation at these hmC-poised loci depends on Tet2 activity.


Nature | 2011

Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells

William A. Pastor; Utz J. Pape; Yun Huang; Hope R. Henderson; Ryan Lister; Myunggon Ko; Erin M. McLoughlin; Yevgeny Brudno; Sahasransu Mahapatra; Philipp Kapranov; Mamta Tahiliani; George Q. Daley; X. Shirley Liu; Joseph R. Ecker; Patrice M. Milos; Suneet Agarwal; Anjana Rao

5-hydroxymethylcytosine (5hmC) is a modified base present at low levels in diverse cell types in mammals. 5hmC is generated by the TET family of Fe(II) and 2-oxoglutarate-dependent enzymes through oxidation of 5-methylcytosine (5mC). 5hmC and TET proteins have been implicated in stem cell biology and cancer, but information on the genome-wide distribution of 5hmC is limited. Here we describe two novel and specific approaches to profile the genomic localization of 5hmC. The first approach, termed GLIB (glucosylation, periodate oxidation, biotinylation) uses a combination of enzymatic and chemical steps to isolate DNA fragments containing as few as a single 5hmC. The second approach involves conversion of 5hmC to cytosine 5-methylenesulphonate (CMS) by treatment of genomic DNA with sodium bisulphite, followed by immunoprecipitation of CMS-containing DNA with a specific antiserum to CMS. High-throughput sequencing of 5hmC-containing DNA from mouse embryonic stem (ES) cells showed strong enrichment within exons and near transcriptional start sites. 5hmC was especially enriched at the start sites of genes whose promoters bear dual histone 3 lysine 27 trimethylation (H3K27me3) and histone 3 lysine 4 trimethylation (H3K4me3) marks. Our results indicate that 5hmC has a probable role in transcriptional regulation, and suggest a model in which 5hmC contributes to the ‘poised’ chromatin signature found at developmentally-regulated genes in ES cells.


Cell Stem Cell | 2010

Distinct Epigenomic Landscapes of Pluripotent and Lineage-Committed Human Cells

R. David Hawkins; Gary C. Hon; Leonard K. Lee; Queminh Ngo; Ryan Lister; Mattia Pelizzola; Lee Edsall; Samantha Kuan; Ying Luu; Sarit Klugman; Jessica Antosiewicz-Bourget; Zhen Ye; Celso A. Espinoza; Saurabh Agarwahl; Li Shen; Victor Ruotti; Wei Wang; Ron Stewart; James A. Thomson; Joseph R. Ecker; Bing Ren

Human embryonic stem cells (hESCs) share an identical genome with lineage-committed cells, yet possess the remarkable properties of self-renewal and pluripotency. The diverse cellular properties in different cells have been attributed to their distinct epigenomes, but how much epigenomes differ remains unclear. Here, we report that epigenomic landscapes in hESCs and lineage-committed cells are drastically different. By comparing the chromatin-modification profiles and DNA methylomes in hESCs and primary fibroblasts, we find that nearly one-third of the genome differs in chromatin structure. Most changes arise from dramatic redistributions of repressive H3K9me3 and H3K27me3 marks, which form blocks that significantly expand in fibroblasts. A large number of potential regulatory sequences also exhibit a high degree of dynamics in chromatin modifications and DNA methylation. Additionally, we observe novel, context-dependent relationships between DNA methylation and chromatin modifications. Our results provide new insights into epigenetic mechanisms underlying properties of pluripotency and cell fate commitment.


Nature Biotechnology | 2010

Comparison of sequencing-based methods to profile DNA methylation and identification of monoallelic epigenetic modifications

R. Alan Harris; Ting Wang; Cristian Coarfa; Raman P. Nagarajan; Chibo Hong; Sara L. Downey; Brett E. Johnson; Shaun D. Fouse; Allen Delaney; Yongjun Zhao; Adam B. Olshen; Tracy Ballinger; Xin Zhou; Kevin J. Forsberg; Junchen Gu; Lorigail Echipare; Henriette O'Geen; Ryan Lister; Mattia Pelizzola; Yuanxin Xi; Charles B. Epstein; Bradley E. Bernstein; R. David Hawkins; Bing Ren; Wen-Yu Chung; Hongcang Gu; Christoph Bock; Andreas Gnirke; Michael Q. Zhang; David Haussler

Analysis of DNA methylation patterns relies increasingly on sequencing-based profiling methods. The four most frequently used sequencing-based technologies are the bisulfite-based methods MethylC-seq and reduced representation bisulfite sequencing (RRBS), and the enrichment-based techniques methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylated DNA binding domain sequencing (MBD-seq). We applied all four methods to biological replicates of human embryonic stem cells to assess their genome-wide CpG coverage, resolution, cost, concordance and the influence of CpG density and genomic context. The methylation levels assessed by the two bisulfite methods were concordant (their difference did not exceed a given threshold) for 82% for CpGs and 99% of the non-CpG cytosines. Using binary methylation calls, the two enrichment methods were 99% concordant and regions assessed by all four methods were 97% concordant. We combined MeDIP-seq with methylation-sensitive restriction enzyme (MRE-seq) sequencing for comprehensive methylome coverage at lower cost. This, along with RNA-seq and ChIP-seq of the ES cells enabled us to detect regions with allele-specific epigenetic states, identifying most known imprinted regions and new loci with monoallelic epigenetic marks and monoallelic expression.


Proceedings of the National Academy of Sciences of the United States of America | 2012

Widespread dynamic DNA methylation in response to biotic stress

Robert H. Dowen; Mattia Pelizzola; Robert J. Schmitz; Ryan Lister; Jill M. Dowen; Joseph R. Nery; Jack E. Dixon; Joseph R. Ecker

Regulation of gene expression by DNA methylation is crucial for defining cellular identities and coordinating organism-wide developmental programs in many organisms. In plants, modulation of DNA methylation in response to environmental conditions represents a potentially robust mechanism to regulate gene expression networks; however, examples of dynamic DNA methylation are largely limited to gene imprinting. Here we report an unexpected role for DNA methylation in regulation of the Arabidopsis thaliana immune system. Profiling the DNA methylomes of plants exposed to bacterial pathogen, avirulent bacteria, or salicylic acid (SA) hormone revealed numerous stress-induced differentially methylated regions, many of which were intimately associated with differentially expressed genes. In response to SA, transposon-associated differentially methylated regions, which were accompanied by up-regulation of 21-nt siRNAs, were often coupled to transcriptional changes of the transposon and/or the proximal gene. Thus, dynamic DNA methylation changes within repetitive sequences or transposons can regulate neighboring genes in response to SA stress.


Cell | 2013

Epigenomic Analysis of Multilineage Differentiation of Human Embryonic Stem Cells

Wei Xie; Matthew D. Schultz; Ryan Lister; Zhonggang Hou; Nisha Rajagopal; Pradipta Ray; John W. Whitaker; Shulan Tian; R. David Hawkins; Danny Leung; Hongbo Yang; Tao Wang; Ah Young Lee; Scott Swanson; Jiuchun Zhang; Yun Zhu; Audrey Kim; Joseph R. Nery; Mark A. Urich; Samantha Kuan; Chia An Yen; Sarit Klugman; Pengzhi Yu; Kran Suknuntha; Nicholas E. Propson; Huaming Chen; Lee Edsall; Ulrich Wagner; Yan Li; Zhen Ye

Epigenetic mechanisms have been proposed to play crucial roles in mammalian development, but their precise functions are only partially understood. To investigate epigenetic regulation of embryonic development, we differentiated human embryonic stem cells into mesendoderm, neural progenitor cells, trophoblast-like cells, and mesenchymal stem cells and systematically characterized DNA methylation, chromatin modifications, and the transcriptome in each lineage. We found that promoters that are active in early developmental stages tend to be CG rich and mainly engage H3K27me3 upon silencing in nonexpressing lineages. By contrast, promoters for genes expressed preferentially at later stages are often CG poor and primarily employ DNA methylation upon repression. Interestingly, the early developmental regulatory genes are often located in large genomic domains that are generally devoid of DNA methylation in most lineages, which we termed DNA methylation valleys (DMVs). Our results suggest that distinct epigenetic mechanisms regulate early and late stages of ES cell differentiation.


Genome Research | 2012

Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer

Gary C. Hon; R. David Hawkins; Otavia L. Caballero; Christine Lo; Ryan Lister; Mattia Pelizzola; Armand Valsesia; Zhen Ye; Samantha Kuan; Lee Edsall; Anamaria A. Camargo; Brian J. Stevenson; Joseph R. Ecker; Vineet Bafna; Robert L. Strausberg; Andrew J.G. Simpson; Bing Ren

While genetic mutation is a hallmark of cancer, many cancers also acquire epigenetic alterations during tumorigenesis including aberrant DNA hypermethylation of tumor suppressors, as well as changes in chromatin modifications as caused by genetic mutations of the chromatin-modifying machinery. However, the extent of epigenetic alterations in cancer cells has not been fully characterized. Here, we describe complete methylome maps at single nucleotide resolution of a low-passage breast cancer cell line and primary human mammary epithelial cells. We find widespread DNA hypomethylation in the cancer cell, primarily at partially methylated domains (PMDs) in normal breast cells. Unexpectedly, genes within these regions are largely silenced in cancer cells. The loss of DNA methylation in these regions is accompanied by formation of repressive chromatin, with a significant fraction displaying allelic DNA methylation where one allele is DNA methylated while the other allele is occupied by histone modifications H3K9me3 or H3K27me3. Our results show a mutually exclusive relationship between DNA methylation and H3K9me3 or H3K27me3. These results suggest that global DNA hypomethylation in breast cancer is tightly linked to the formation of repressive chromatin domains and gene silencing, thus identifying a potential epigenetic pathway for gene regulation in cancer cells.

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Joseph R. Ecker

Salk Institute for Biological Studies

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A. Harvey Millar

University of Western Australia

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Joseph R. Nery

Salk Institute for Biological Studies

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Ethan Ford

University of Western Australia

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Mattia Pelizzola

Istituto Italiano di Tecnologia

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Bing Ren

Ludwig Institute for Cancer Research

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R. David Hawkins

Ludwig Institute for Cancer Research

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Mark A. Urich

Salk Institute for Biological Studies

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Julian Tonti-Filippini

University of Western Australia

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