Publications by authors named "Rebecca F Lowdon"

16 Publications

  • Page 1 of 1

Epigenetic dynamics shaping melanophore and iridophore cell fate in zebrafish.

Genome Biol 2021 10 4;22(1):282. Epub 2021 Oct 4.

Department of Genetics, Washington University School of Medicine, St Louis, MO, USA.

Background: Zebrafish pigment cell differentiation provides an attractive model for studying cell fate progression as a neural crest progenitor engenders diverse cell types, including two morphologically distinct pigment cells: black melanophores and reflective iridophores. Nontrivial classical genetic and transcriptomic approaches have revealed essential molecular mechanisms and gene regulatory circuits that drive neural crest-derived cell fate decisions. However, how the epigenetic landscape contributes to pigment cell differentiation, especially in the context of iridophore cell fate, is poorly understood.

Results: We chart the global changes in the epigenetic landscape, including DNA methylation and chromatin accessibility, during neural crest differentiation into melanophores and iridophores to identify epigenetic determinants shaping cell type-specific gene expression. Motif enrichment in the epigenetically dynamic regions reveals putative transcription factors that might be responsible for driving pigment cell identity. Through this effort, in the relatively uncharacterized iridophores, we validate alx4a as a necessary and sufficient transcription factor for iridophore differentiation and present evidence on alx4a's potential regulatory role in guanine synthesis pathway.

Conclusions: Pigment cell fate is marked by substantial DNA demethylation events coupled with dynamic chromatin accessibility to potentiate gene regulation through cis-regulatory control. Here, we provide a multi-omic resource for neural crest differentiation into melanophores and iridophores. This work led to the discovery and validation of iridophore-specific alx4a transcription factor.
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http://dx.doi.org/10.1186/s13059-021-02493-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489059PMC
October 2021

Human placental cytotrophoblast epigenome dynamics over gestation and alterations in placental disease.

Dev Cell 2021 05 22;56(9):1238-1252.e5. Epub 2021 Apr 22.

Ely and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94115, USA; Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94115, USA; Division of Maternal-Fetal Medicine, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Anatomy, University of California, San Francisco, San Francisco, CA 94122, USA. Electronic address:

The human placenta and its specialized cytotrophoblasts rapidly develop, have a compressed lifespan, govern pregnancy outcomes, and program the offspring's health. Understanding the molecular underpinnings of these behaviors informs development and disease. Profiling the extraembryonic epigenome and transcriptome during the 2nd and 3rd trimesters revealed H3K9 trimethylation overlapping deeply DNA hypomethylated domains with reduced gene expression and compartment-specific patterns that illuminated their functions. Cytotrophoblast DNA methylation increased, and several key histone modifications decreased across the genome as pregnancy advanced. Cytotrophoblasts from severe preeclampsia had substantially increased H3K27 acetylation globally and at genes that are normally downregulated at term but upregulated in this syndrome. In addition, some cases had an immature pattern of H3K27ac peaks, and others showed evidence of accelerated aging, suggesting subtype-specific alterations in severe preeclampsia. Thus, the cytotrophoblast epigenome dramatically reprograms during pregnancy, placental disease is associated with failures in this process, and H3K27 hyperacetylation is a feature of severe preeclampsia.
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http://dx.doi.org/10.1016/j.devcel.2021.04.001DOI Listing
May 2021

Tissue-specific DNA methylation is conserved across human, mouse, and rat, and driven by primary sequence conservation.

BMC Genomics 2017 Sep 12;18(1):724. Epub 2017 Sep 12.

Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA.

Background: Uncovering mechanisms of epigenome evolution is an essential step towards understanding the evolution of different cellular phenotypes. While studies have confirmed DNA methylation as a conserved epigenetic mechanism in mammalian development, little is known about the conservation of tissue-specific genome-wide DNA methylation patterns.

Results: Using a comparative epigenomics approach, we identified and compared the tissue-specific DNA methylation patterns of rat against those of mouse and human across three shared tissue types. We confirmed that tissue-specific differentially methylated regions are strongly associated with tissue-specific regulatory elements. Comparisons between species revealed that at a minimum 11-37% of tissue-specific DNA methylation patterns are conserved, a phenomenon that we define as epigenetic conservation. Conserved DNA methylation is accompanied by conservation of other epigenetic marks including histone modifications. Although a significant amount of locus-specific methylation is epigenetically conserved, the majority of tissue-specific DNA methylation is not conserved across the species and tissue types that we investigated. Examination of the genetic underpinning of epigenetic conservation suggests that primary sequence conservation is a driving force behind epigenetic conservation. In contrast, evolutionary dynamics of tissue-specific DNA methylation are best explained by the maintenance or turnover of binding sites for important transcription factors.

Conclusions: Our study extends the limited literature of comparative epigenomics and suggests a new paradigm for epigenetic conservation without genetic conservation through analysis of transcription factor binding sites.
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http://dx.doi.org/10.1186/s12864-017-4115-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596466PMC
September 2017

Epigenomic annotation of noncoding mutations identifies mutated pathways in primary liver cancer.

PLoS One 2017 23;12(3):e0174032. Epub 2017 Mar 23.

Center for Genome Sciences and Systems Biology, Department of Genetics, Washington University in St. Louis, Saint Louis, Missouri, United States of America.

Evidence that noncoding mutation can result in cancer driver events is mounting. However, it is more difficult to assign molecular biological consequences to noncoding mutations than to coding mutations, and a typical cancer genome contains many more noncoding mutations than protein-coding mutations. Accordingly, parsing functional noncoding mutation signal from noise remains an important challenge. Here we use an empirical approach to identify putatively functional noncoding somatic single nucleotide variants (SNVs) from liver cancer genomes. Annotation of candidate variants by publicly available epigenome datasets finds that 40.5% of SNVs fall in regulatory elements. When assigned to specific regulatory elements, we find that the distribution of regulatory element mutation mirrors that of nonsynonymous coding mutation, where few regulatory elements are recurrently mutated in a patient population but many are singly mutated. We find potential gain-of-binding site events among candidate SNVs, suggesting a mechanism of action for these variants. When aggregating noncoding somatic mutation in promoters, we find that genes in the ERBB signaling and MAPK signaling pathways are significantly enriched for promoter mutations. Altogether, our results suggest that functional somatic SNVs in cancer are sporadic, but occasionally occur in regulatory elements and may affect phenotype by creating binding sites for transcriptional regulators. Accordingly, we propose that noncoding mutation should be formally accounted for when determining gene- and pathway-mutation burden in cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174032PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363827PMC
August 2017

Evolution of Epigenetic Regulation in Vertebrate Genomes.

Trends Genet 2016 05 12;32(5):269-283. Epub 2016 Apr 12.

Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

Empirical models of sequence evolution have spurred progress in the field of evolutionary genetics for decades. We are now realizing the importance and complexity of the eukaryotic epigenome. While epigenome analysis has been applied to genomes from single-cell eukaryotes to human, comparative analyses are still relatively few and computational algorithms to quantify epigenome evolution remain scarce. Accordingly, a quantitative model of epigenome evolution remains to be established. We review here the comparative epigenomics literature and synthesize its overarching themes. We also suggest one mechanism, transcription factor binding site (TFBS) turnover, which relates sequence evolution to epigenetic conservation or divergence. Lastly, we propose a framework for how the field can move forward to build a coherent quantitative model of epigenome evolution.
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http://dx.doi.org/10.1016/j.tig.2016.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4842087PMC
May 2016

Developmental enhancers revealed by extensive DNA methylome maps of zebrafish early embryos.

Nat Commun 2015 Feb 20;6:6315. Epub 2015 Feb 20.

1] Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63108, USA [2] Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, Missouri 63108, USA.

DNA methylation undergoes dynamic changes during development and cell differentiation. Recent genome-wide studies discovered that tissue-specific differentially methylated regions (DMRs) often overlap tissue-specific distal cis-regulatory elements. However, developmental DNA methylation dynamics of the majority of the genomic CpGs outside gene promoters and CpG islands has not been extensively characterized. Here, we generate and compare comprehensive DNA methylome maps of zebrafish developing embryos. From these maps, we identify thousands of developmental stage-specific DMRs (dsDMRs) across zebrafish developmental stages. The dsDMRs contain evolutionarily conserved sequences, are associated with developmental genes and are marked with active enhancer histone posttranslational modifications. Their methylation pattern correlates much stronger than promoter methylation with expression of putative target genes. When tested in vivo using a transgenic zebrafish assay, 20 out of 20 selected candidate dsDMRs exhibit functional enhancer activities. Our data suggest that developmental enhancers are a major target of DNA methylation changes during embryogenesis.
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http://dx.doi.org/10.1038/ncomms7315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4339225PMC
February 2015

Regulatory network decoded from epigenomes of surface ectoderm-derived cell types.

Nat Commun 2014 Nov 25;5:5442. Epub 2014 Nov 25.

Department of Dermatology, University of California, San Francisco, San Francisco, California 94143, USA.

Developmental history shapes the epigenome and biological function of differentiated cells. Epigenomic patterns have been broadly attributed to the three embryonic germ layers. Here we investigate how developmental origin influences epigenomes. We compare key epigenomes of cell types derived from surface ectoderm (SE), including keratinocytes and breast luminal and myoepithelial cells, against neural crest-derived melanocytes and mesoderm-derived dermal fibroblasts, to identify SE differentially methylated regions (SE-DMRs). DNA methylomes of neonatal keratinocytes share many more DMRs with adult breast luminal and myoepithelial cells than with melanocytes and fibroblasts from the same neonatal skin. This suggests that SE origin contributes to DNA methylation patterning, while shared skin tissue environment has limited effect on epidermal keratinocytes. Hypomethylated SE-DMRs are in proximity to genes with SE relevant functions. They are also enriched for enhancer- and promoter-associated histone modifications in SE-derived cells, and for binding motifs of transcription factors important in keratinocyte and mammary gland biology. Thus, epigenomic analysis of cell types with common developmental origin reveals an epigenetic signature that underlies a shared gene regulatory network.
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http://dx.doi.org/10.1038/ncomms6442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385735PMC
November 2014

A comparative encyclopedia of DNA elements in the mouse genome.

Nature 2014 Nov;515(7527):355-64

Bioinformatics and Genomics, Centre for Genomic Regulation (CRG) and UPF, Doctor Aiguader, 88, 08003 Barcelona, Catalonia, Spain.

The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, yet the two mammals differ in significant ways. To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types. By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization. Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases.
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http://dx.doi.org/10.1038/nature13992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266106PMC
November 2014

Comparative DNA methylome analysis of endometrial carcinoma reveals complex and distinct deregulation of cancer promoters and enhancers.

BMC Genomics 2014 Oct 6;15:868. Epub 2014 Oct 6.

Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St, Louis MO 63108, USA.

Background: Aberrant DNA methylation is a hallmark of many cancers. Classically there are two types of endometrial cancer, endometrioid adenocarcinoma (EAC), or Type I, and uterine papillary serous carcinoma (UPSC), or Type II. However, the whole genome DNA methylation changes in these two classical types of endometrial cancer is still unknown.

Results: Here we described complete genome-wide DNA methylome maps of EAC, UPSC, and normal endometrium by applying a combined strategy of methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylation-sensitive restriction enzyme digestion sequencing (MRE-seq). We discovered distinct genome-wide DNA methylation patterns in EAC and UPSC: 27,009 and 15,676 recurrent differentially methylated regions (DMRs) were identified respectively, compared with normal endometrium. Over 80% of DMRs were in intergenic and intronic regions. The majority of these DMRs were not interrogated on the commonly used Infinium 450K array platform. Large-scale demethylation of chromosome X was detected in UPSC, accompanied by decreased XIST expression. Importantly, we discovered that the majority of the DMRs harbored promoter or enhancer functions and are specifically associated with genes related to uterine development and disease. Among these, abnormal methylation of transposable elements (TEs) may provide a novel mechanism to deregulate normal endometrium-specific enhancers derived from specific TEs.

Conclusions: DNA methylation changes are an important signature of endometrial cancer and regulate gene expression by affecting not only proximal promoters but also distal enhancers.
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http://dx.doi.org/10.1186/1471-2164-15-868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4198682PMC
October 2014

methylC Track: visual integration of single-base resolution DNA methylation data on the WashU EpiGenome Browser.

Bioinformatics 2014 Aug 10;30(15):2206-7. Epub 2014 Apr 10.

Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63108, USA and Department of Neurosurgery, Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.

Summary: We present methylC track, an efficient mechanism for visualizing single-base resolution DNA methylation data on a genome browser. The methylC track dynamically integrates the level of methylation, the position and context of the methylated cytosine (i.e. CG, CHG and CHH), strand and confidence level (e.g. read coverage depth in the case of whole-genome bisulfite sequencing data). Investigators can access and integrate these information visually at specific locus or at the genome-wide level on the WashU EpiGenome Browser in the context of other rich epigenomic datasets.

Availability And Implementation: The methylC track is part of the WashU EpiGenome Browser, which is open source and freely available at http://epigenomegateway.wustl.edu/browser/. The most up-to-date instructions and tools for preparing methylC track are available at http://epigenomegateway.wustl.edu/+/cmtk.

Contact: [email protected]

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btu191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103599PMC
August 2014

Functional DNA methylation differences between tissues, cell types, and across individuals discovered using the M&M algorithm.

Genome Res 2013 Sep 26;23(9):1522-40. Epub 2013 Jun 26.

Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri 63108, USA.

DNA methylation plays key roles in diverse biological processes such as X chromosome inactivation, transposable element repression, genomic imprinting, and tissue-specific gene expression. Sequencing-based DNA methylation profiling provides an unprecedented opportunity to map and compare complete DNA methylomes. This includes one of the most widely applied technologies for measuring DNA methylation: methylated DNA immunoprecipitation followed by sequencing (MeDIP-seq), coupled with a complementary method, methylation-sensitive restriction enzyme sequencing (MRE-seq). A computational approach that integrates data from these two different but complementary assays and predicts methylation differences between samples has been unavailable. Here, we present a novel integrative statistical framework M&M (for integration of MeDIP-seq and MRE-seq) that dynamically scales, normalizes, and combines MeDIP-seq and MRE-seq data to detect differentially methylated regions. Using sample-matched whole-genome bisulfite sequencing (WGBS) as a gold standard, we demonstrate superior accuracy and reproducibility of M&M compared to existing analytical methods for MeDIP-seq data alone. M&M leverages the complementary nature of MeDIP-seq and MRE-seq data to allow rapid comparative analysis between whole methylomes at a fraction of the cost of WGBS. Comprehensive analysis of nineteen human DNA methylomes with M&M reveals distinct DNA methylation patterns among different tissue types, cell types, and individuals, potentially underscoring divergent epigenetic regulation at different scales of phenotypic diversity. We find that differential DNA methylation at enhancer elements, with concurrent changes in histone modifications and transcription factor binding, is common at the cell, tissue, and individual levels, whereas promoter methylation is more prominent in reinforcing fundamental tissue identities.
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http://dx.doi.org/10.1101/gr.156539.113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759728PMC
September 2013

DNA hypomethylation within specific transposable element families associates with tissue-specific enhancer landscape.

Nat Genet 2013 Jul 26;45(7):836-41. Epub 2013 May 26.

Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA.

Transposable element (TE)-derived sequences comprise half of the human genome and DNA methylome and are presumed to be densely methylated and inactive. Examination of genome-wide DNA methylation status within 928 TE subfamilies in human embryonic and adult tissues identified unexpected tissue-specific and subfamily-specific hypomethylation signatures. Genes proximal to tissue-specific hypomethylated TE sequences were enriched for functions important for the relevant tissue type, and their expression correlated strongly with hypomethylation within the TEs. When hypomethylated, these TE sequences gained tissue-specific enhancer marks, including monomethylation of histone H3 at lysine 4 (H3K4me1) and occupancy by p300, and a majority exhibited enhancer activity in reporter gene assays. Many such TEs also harbored binding sites for transcription factors that are important for tissue-specific functions and showed evidence of evolutionary selection. These data suggest that sequences derived from TEs may be responsible for wiring tissue type-specific regulatory networks and may have acquired tissue-specific epigenetic regulation.
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http://dx.doi.org/10.1038/ng.2649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3695047PMC
July 2013

An encyclopedia of mouse DNA elements (Mouse ENCODE).

Genome Biol 2012 Aug 13;13(8):418. Epub 2012 Aug 13.

To complement the human Encyclopedia of DNA Elements (ENCODE) project and to enable a broad range of mouse genomics efforts, the Mouse ENCODE Consortium is applying the same experimental pipelines developed for human ENCODE to annotate the mouse genome.
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http://dx.doi.org/10.1186/gb-2012-13-8-418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491367PMC
August 2012

Integrative analysis of the Caenorhabditis elegans genome by the modENCODE project.

Science 2010 Dec 22;330(6012):1775-87. Epub 2010 Dec 22.

Program in Computational Biology and Bioinformatics, Yale University, Bass 432, 266 Whitney Avenue, New Haven, CT 06520, USA.

We systematically generated large-scale data sets to improve genome annotation for the nematode Caenorhabditis elegans, a key model organism. These data sets include transcriptome profiling across a developmental time course, genome-wide identification of transcription factor-binding sites, and maps of chromatin organization. From this, we created more complete and accurate gene models, including alternative splice forms and candidate noncoding RNAs. We constructed hierarchical networks of transcription factor-binding and microRNA interactions and discovered chromosomal locations bound by an unusually large number of transcription factors. Different patterns of chromatin composition and histone modification were revealed between chromosome arms and centers, with similarly prominent differences between autosomes and the X chromosome. Integrating data types, we built statistical models relating chromatin, transcription factor binding, and gene expression. Overall, our analyses ascribed putative functions to most of the conserved genome.
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http://dx.doi.org/10.1126/science.1196914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3142569PMC
December 2010
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