Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell Identities

doi:10.1016/J.MOLCEL.2010.05.004

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Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell Identities

Journal Article•DOI•

Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell Identities

Sven Heinz¹, Christopher Benner¹, Nathanael J. Spann¹, Eric Bertolino², Yin C. Lin¹, Peter Laslo³, Jason X. Cheng², Cornelis Murre¹, Harinder Singh⁴, Harinder Singh², Christopher K. Glass¹ - Show less +7 more•Institutions (4)

University of California, San Diego¹, University of Chicago², University of Leeds³, Genentech⁴

28 May 2010-Molecular Cell (NIH Public Access)-Vol. 38, Iss: 4, pp 576-589

TL;DR: It is demonstrated in macrophages and B cells that collaborative interactions of the common factor PU.1 with small sets of macrophage- or B cell lineage-determining transcription factors establish cell-specific binding sites that are associated with the majority of promoter-distal H3K4me1-marked genomic regions.

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About: This article is published in Molecular Cell.The article was published on 2010-05-28 and is currently open access. It has received 9620 citations till now. The article focuses on the topics: Pioneer factor & General transcription factor.

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Posted Content•DOI•

Temporal scaling in developmental gene networks by epigenetic timing control

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Phuc H.B. Nguyen¹, Nicholas A. Pease¹, Blythe Irwin¹, Kenneth K.N. Ng¹, Hao Yuan Kueh¹ - Show less +1 more•Institutions (1)

University of Washington¹

05 Sep 2019-bioRxiv

TL;DR: This work elucidates the mechanism of a polycomb-based epigenetic timer, that delays activation of the T-cell commitment regulator Bcl11b to facilitate progenitor expansion and enables progenitors to set scalable temporal schedules for flexible size control.

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Abstract: During development, progenitors follow defined temporal schedules for differentiation, to form organs and body plans with precise sizes and proportions. Across diverse contexts, these developmental schedules are encoded by autonomous timekeeping mechanisms in single cells. These autonomous timers not only operate robustly over many cell generations, but can also operate at different speeds in different species, enabling proportional scaling of temporal schedules and population sizes. By combining mathematical modeling with live-cell measurements, we elucidate the mechanism of a polycomb-based epigenetic timer, that delays activation of the T-cell commitment regulator Bcl11b to facilitate progenitor expansion. This mechanism generates activation delays that are independent of cell cycle duration, and are tunably controlled by transcription factors and epigenetic modifiers. When incorporated into regulatory gene networks, this epigenetic timer enables progenitors to set scalable temporal schedules for flexible size control. These findings illuminate how evolution may set and adjust developmental speed in multicellular organisms.

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2 citations

Cites background from "Simple Combinations of Lineage-Dete..."

...We note that this magnitude perturbation is consistent with observed length scales for histone modification clearance around the vicinity of transcription factor binding, as measured by next generation sequencing (Hass et al., 2015; Heinz et al., 2010)....
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Posted Content•DOI•

Chromatin remodeler Brahma safeguards canalization in cardiac mesoderm differentiation

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Swetansu K. Hota¹, Swetansu K. Hota², Andrew P. Blair², Kavitha S. Rao², Kevin So², Aaron M. Blotnick², Ravi V. Desai², Leor S. Weinberger², Leor S. Weinberger¹, Irfan S. Kathiriya², Irfan S. Kathiriya³, Benoit G. Bruneau - Show less +8 more•Institutions (3)

University of California, Berkeley¹, Gladstone Institutes², University of California, San Francisco³

04 Jun 2020-bioRxiv

TL;DR: The results reveal BRM as a compensable safeguard for fidelity of mesoderm chromatin states, and support a model in which developmental canalization is not a rigid irreversible path, but a highly plastic trajectory that must be safeguarded, with implications in development and disease.

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Abstract: SUMMARY Differentiation proceeds along a continuum of increasingly fate-restricted intermediates, referred to as canalization1–4. Canalization is essential for stabilizing cell fate, but the mechanisms underlying robust canalization are unclear. Here we show that deletion of the BRG1/BRM-associated factor (BAF) chromatin remodeling complex ATPase gene Brm (encoding Brahma) results in a radical identity switch during directed cardiogenesis of mouse embryonic stem cells (ESCs). Despite establishment of well-differentiated precardiac mesoderm, Brm-null cells subsequently shifted identities, predominantly becoming neural precursors, violating germ layer assignment. Trajectory inference showed sudden acquisition of non-mesodermal identity in Brm-null cells, consistent with a new transition state inducing a fate switch referred to as a saddle-node bifurcation3,4. Mechanistically, loss of Brm prevented de novo accessibility of cardiac enhancers while increasing expression of the neurogenic factor POU3F1 and preventing expression of the neural suppressor REST. Brm mutant identity switch was overcome by increasing BMP4 levels during mesoderm induction, repressing Pou3f1 and re-establishing a cardiogenic chromatin landscape. Our results reveal BRM as a compensable safeguard for fidelity of mesoderm chromatin states, and support a model in which developmental canalization is not a rigid irreversible path, but a highly plastic trajectory that must be safeguarded, with implications in development and disease.

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2 citations

Posted Content•DOI•

HIV-specific CD8 T cells from elite controllers have an epigenetic imprint that preserves effector functions

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A. B. Frias¹, Rachel L. Rutishauser², Ashish Sharma³, Tian Mi¹, Caitlin C. Zebley¹, C. M. Constantz², H. A. Abdelsamed⁴, Mars Stone, Michael P. Busch, Steven G. Deeks², Rafick Pierre Sekaly³, Ben Youngblood¹ - Show less +8 more•Institutions (4)

St. Jude Children's Research Hospital¹, University of California, San Francisco², Emory University³, University of Pittsburgh⁴

28 Sep 2021-bioRxiv

TL;DR: In this paper, the authors performed genome-wide transcriptional and DNA methylation analysis of MHC Class I multimer+ CD8 T cells sorted from aviremic elite controllers compared to non-controllers on suppressive ART.

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Abstract: Several lines of evidence support a central role for CD8 T cells as key determinants in the control of HIV, particularly in rare "elite controllers" who control the virus to undetectable levels in the blood in the absence of antiretroviral therapy (ART). While HIV-specific CD8 T cells isolated from elite controllers have enhanced antiviral cytokine production and proliferative capacity in response to antigen stimulation when compared to cells isolated from viremic or even aviremic ART-suppressed non-controllers, the cell-intrinsic mechanisms underlying the enhanced T cell memory-like function of HIV-specific CD8 T cells in elite controllers remain largely undefined. To identify the transcriptional and epigenetic pathways that regulate functional capacity in HIV-specific CD8 T cells in elite controllers, we performed genome-wide transcriptional and DNA methylation analysis of MHC Class I multimer+ CD8 T cells sorted from aviremic elite controllers compared to aviremic non-controllers on suppressive ART. Co-omics analysis revealed enrichment for gene signatures that support a multipotent differentiation state, cell survival, and a long-lived effector cell fate in HIV-specific CD8 T cells from elite controllers. Specifically, we observed DNA methylation programs at the transcription factor binding sites of the stem-associated factors TCF-1 and LEF1 that delineate HIV-specific CD8 T cells from elite controllers versus ART-treated individuals. HIV-specific CD8 T cells in elite controllers also maintain T cell receptor and IL-12/STAT4 pathway signaling and have suppressed pro-apoptotic TNF pathway signaling. These findings show that HIV-specific CD8 T cells from elite controllers have enhanced expression and DNA methylation programs that maintain developmental potential and in turn promote long-term survival, proliferative potential, and effector capacity. These data also provide new insights into the relationship between stem-associated transcription factors and stable epigenetic restriction of T cell developmental capacity.

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2 citations

Journal Article•DOI•

BRCA1-BARD1 regulates transcription through modulating topoisomerase IIβ

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Heeyoun Bunch¹, Jaehyeon Jeong¹, Keunsoo Kang², Doo Sin Jo¹, Anh T. Q. Cong³, Deukyeong Kim¹, Donguk Kim¹, Dong-Hyung Cho¹, You Mie Lee¹, Benjamin P C Chen⁴, Matthew J. Schellenberg³, Stuart K. Calderwood⁵ - Show less +8 more•Institutions (5)

Kyungpook National University¹, UPRRP College of Natural Sciences², Mayo Clinic³, University of Texas Southwestern Medical Center⁴, Beth Israel Deaconess Medical Center⁵

06 Oct 2021-Open Biology

TL;DR: RNARNA polymerase II (Pol II)-dependent transcription in stimulus-inducible genes requires topoisomerase IIβ (TOP2B)-mediated DNA strand break and the activation of DNA damage response signalling in h...

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Abstract: RNA polymerase II (Pol II)-dependent transcription in stimulus-inducible genes requires topoisomerase IIβ (TOP2B)-mediated DNA strand break and the activation of DNA damage response signalling in h...

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2 citations

Journal Article•DOI•

Multiomics landscape of the autosomal dominant osteopetrosis type II disease-specific induced pluripotent stem cells

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Chunhong Li¹, Yu Shangguan², Peng Zhu², Weier Dai³, Donge Tang², Minglin Ou¹, Yong Dai² - Show less +3 more•Institutions (3)

Guilin Medical University¹, Southern University of Science and Technology², University of Texas at Austin³

27 Oct 2021-Hereditas

TL;DR: Wang et al. as discussed by the authors performed a multi-omics profiling from the autosomal dominant osteopetrosis type II iPSCs (ADO2-iPSCs) using whole genome re-sequencing, DNA methylation and N6-methyladenosine (m6A) analysis in this study.

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Abstract: BACKGROUND Autosomal dominant osteopetrosis type II (ADO2) is a genetically and phenotypically metabolic bone disease, caused by osteoclast abnormalities. The pathways dysregulated in ADO2 could lead to the defects in osteoclast formation and function. However, the mechanism remains elusive. MATERIALS AND METHODS To systematically explore the molecular characterization of ADO2, we performed a multi-omics profiling from the autosomal dominant osteopetrosis type II iPSCs (ADO2-iPSCs) and healthy normal control iPSCs (NC-iPSCs) using whole genome re-sequencing, DNA methylation and N6-methyladenosine (m6A) analysis in this study. RESULTS Totally, we detected 7,095,817 single nucleotide polymorphisms (SNPs) and 1,179,573 insertion and deletions (InDels), 1,001,943 differentially methylated regions (DMRs) and 2984 differential m6A peaks, and the comprehensive multi-omics profile was generated from the two cells. Interestingly, the ISG15 m6A level in ADO2-iPSCs is higher than NC-iPSCs by IGV software, and the differentially expressed m6A-modified genes (DEMGs) were highly enriched in the osteoclast differentiation and p53 signaling pathway, which associated with the development of osteopetrosis. In addition, combining our previously published transcriptome and proteome datasets, we found that the change in DNA methylation levels correlates inversely with some gene expression levels. CONCLUSION Our results indicate that the global multi-omics landscape not only provides a high-quality data resource but also reveals a dynamic pattern of gene expression, and found that the pathogenesis of ADO2 may begin early in life.

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2 citations

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References

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Journal Article•DOI•

High-resolution profiling of histone methylations in the human genome.

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Artem Barski¹, Suresh Cuddapah¹, Kairong Cui¹, Tae-Young Roh¹, Dustin E. Schones¹, Zhibin Wang¹, Gang Wei¹, Iouri Chepelev², Keji Zhao¹ - Show less +5 more•Institutions (2)

National Institutes of Health¹, University of California, Los Angeles²

18 May 2007-Cell

TL;DR: High-resolution maps for the genome-wide distribution of 20 histone lysine and arginine methylations as well as histone variant H2A.Z, RNA polymerase II, and the insulator binding protein CTCF across the human genome using the Solexa 1G sequencing technology are generated.

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6,488 citations

"Simple Combinations of Lineage-Dete..." refers background or methods in this paper

...…positions, DNase hypersensitivity, and mononucleosomal ChIP-Seq for a wide range of histone modifications are available, allowing precise determination of nucleosome positions, chromatin accessibility, and histone modifications (Barski et al., 2007; Boyle et al., 2008; Schones et al., 2008)....
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...In this cell type, genome-wide data for nucleosome positions, DNase hypersensitivity, and mononucleosomal ChIP-Seq for a wide range of histone modifications are available, allowing precise determination of nucleosome positions, chromatin accessibility, and histone modifications (Barski et al., 2007; Boyle et al., 2008; Schones et al., 2008)....
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...1 Binding Programs in Macrophages and B Cells We initially performed chromatin immunoprecipitation-coupled deep sequencing (ChIP-Seq) (Barski et al., 2007) to define the PU....
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..., 2008), human CD4 T cells (Barski et al., 2007), and CD36 erythrocyte precursors (Cui et al....
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...…other cell types, we performed de novo motif analysis on H3K4me1/H3K4me3 ChIP-Seq data sets from mouse embryonic stem cells (Meissner et al., 2008; Mikkelsen et al., 2007), liver (Wederell et al., 2008), human CD4+ T cells (Barski et al., 2007), and CD36+ erythrocyte precursors (Cui et al., 2009)....
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Journal Article•DOI•

Genome-wide maps of chromatin state in pluripotent and lineage-committed cells

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Tarjei S. Mikkelsen¹, Manching Ku¹, Manching Ku², David B. Jaffe¹, Biju Issac¹, Biju Issac², Erez Lieberman Aiden¹, Erez Lieberman Aiden³, Georgia Giannoukos¹, Pablo Alvarez¹, William Brockman¹, Tae Kyung Kim⁴, Richard Koche², Richard Koche¹, Richard Koche³, William Lee¹, Eric M. Mendenhall¹, Eric M. Mendenhall², Aisling O'Donovan², Aviva Presser¹, Carsten Russ¹, Xiaohui Xie¹, Alexander Meissner³, Marius Wernig³, Rudolf Jaenisch³, Chad Nusbaum¹, Eric S. Lander¹, Eric S. Lander³, Bradley E. Bernstein¹, Bradley E. Bernstein² - Show less +26 more•Institutions (4)

Broad Institute¹, Harvard University², Massachusetts Institute of Technology³, Boston Children's Hospital⁴

02 Aug 2007-Nature

TL;DR: The application of single-molecule-based sequencing technology for high-throughput profiling of histone modifications in mammalian cells is reported and it is shown that chromatin state can be read in an allele-specific manner by using single nucleotide polymorphisms.

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Abstract: We report the application of single-molecule-based sequencing technology for high-throughput profiling of histone modifications in mammalian cells By obtaining over four billion bases of sequence from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of mouse embryonic stem cells, neural progenitor cells and embryonic fibroblasts We find that lysine 4 and lysine 27 trimethylation effectively discriminates genes that are expressed, poised for expression, or stably repressed, and therefore reflect cell state and lineage potential Lysine 36 trimethylation marks primary coding and non-coding transcripts, facilitating gene annotation Trimethylation of lysine 9 and lysine 20 is detected at satellite, telomeric and active long-terminal repeats, and can spread into proximal unique sequences Lysine 4 and lysine 9 trimethylation marks imprinting control regions Finally, we show that chromatin state can be read in an allele-specific manner by using single nucleotide polymorphisms This study provides a framework for the application of comprehensive chromatin profiling towards characterization of diverse mammalian cell populations

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4,166 citations

"Simple Combinations of Lineage-Dete..." refers methods in this paper

...To determine whether there is an analogous relationship between promoter-distal H3K4me1 and binding sites for transcription factors in other cell types, we performed de novo motif analysis on H3K4me1/H3K4me3 ChIP-Seq data sets from mouse embryonic stem cells (Meissner et al., 2008; Mikkelsen et al., 2007), liver (Wederell et al....
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...…other cell types, we performed de novo motif analysis on H3K4me1/H3K4me3 ChIP-Seq data sets from mouse embryonic stem cells (Meissner et al., 2008; Mikkelsen et al., 2007), liver (Wederell et al., 2008), human CD4+ T cells (Barski et al., 2007), and CD36+ erythrocyte precursors (Cui et al., 2009)....
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Journal Article•DOI•

RAG-1-deficient mice have no mature B and T lymphocytes

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Peter Mombaerts¹, John Iacomini¹, Randall S. Johnson², Karl Herrup, Susumu Tonegawa¹, Virginia E. Papaioannou³ - Show less +2 more•Institutions (3)

Massachusetts Institute of Technology¹, Harvard University², Tufts University³

06 Mar 1992-Cell

TL;DR: The introduction of a mutation in RAG-1 into the germline of mice via gene targeting in embryonic stem cells is described and it is shown that this mutation either activates or catalyzes the V(D)J recombination reaction of immunoglobulin and T cell receptor genes.

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2,821 citations

"Simple Combinations of Lineage-Dete..." refers background in this paper

...…in B lineage progenitors devoid of both E2A and EBF (E2A / ), EBF only (EBF / ), or control cells that express both factors (Rag1 / ), which are arrested at successive stages in B cell development (Dias et al., 2008; Ikawa et al., 2004; Lin and Grosschedl, 1995; Mombaerts et al., 1992) (Figure 1A)....
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...We addressed this question in B lineage progenitors devoid of both E2A and EBF (E2A / ), EBF only (EBF / ), or control cells that express both factors (Rag1 / ), which are arrested at successive stages in B cell development (Dias et al., 2008; Ikawa et al., 2004; Lin and Grosschedl, 1995; Mombaerts et al., 1992) (Figure 1A)....
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Journal Article•DOI•

Integration of External Signaling Pathways with the Core Transcriptional Network in Embryonic Stem Cells

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Xi Chen¹, Han Xu¹, Ping Yuan¹, Fang Fang¹, Fang Fang², Mikael Huss¹, Vinsensius B. Vega¹, Eleanor Wong¹, Yuriy L. Orlov¹, Weiwei Zhang², Weiwei Zhang¹, Jianming Jiang², Jianming Jiang¹, Yuin-Han Loh¹, Yuin-Han Loh², Hock Chuan Yeo¹, Zhen Xuan Yeo¹, Vipin Narang¹, Kunde R Govindarajan¹, Bernard Leong¹, Atif Shahab¹, Yijun Ruan¹, Guillaume Bourque¹, Wing-Kin Sung¹, Neil D. Clarke¹, Chia-Lin Wei¹, Huck-Hui Ng², Huck-Hui Ng¹ - Show less +24 more•Institutions (2)

Genome Institute of Singapore¹, National University of Singapore²

13 Jun 2008-Cell

TL;DR: This study uses chromatin immunoprecipitation coupled with ultra-high-throughput DNA sequencing to map the locations of TF-binding sites and identifies important features of the transcriptional regulatory networks that define ES-cell identity.

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2,519 citations

"Simple Combinations of Lineage-Dete..." refers background in this paper

...This model offers an explanation for the extensive genome-wide and cell typespecific colocalization of transcription factors observed in various previous studies (Chen et al., 2008; MacArthur et al., 2009) and provides insights into how simple combinations of lineage-restricted transcription factors on a genome-wide scale can specify promoter-distal cis-regulatory elements ultimately responsible for both cell identity and cell type-specific responses to diverse signaling inputs....
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...…an explanation for the extensive genome-wide and cell typespecific colocalization of transcription factors observed in various previous studies (Chen et al., 2008; MacArthur et al., 2009) and provides insights into how simple combinations of lineage-restricted transcription factors on a…...
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...Comparisons of the genome-wide binding patterns of different transcription factors in a variety of species and cell types have generated two major insights regarding transcription factor binding patterns: (1) different factors in the same cell type tend to colocalize on a genome-wide scale (Chen et al., 2008; MacArthur et al., 2009), and (2) the same factor in different cell types or at different stages of development exhibits different genome-wide binding patterns (Lupien et al....
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...…insights regarding transcription factor binding patterns: (1) different factors in the same cell type tend to colocalize on a genome-wide scale (Chen et al., 2008; MacArthur et al., 2009), and (2) the same factor in different cell types or at different stages of development exhibits different…...
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Journal Article•DOI•

Genome-scale DNA methylation maps of pluripotent and differentiated cells

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Alexander Meissner¹, Tarjei S. Mikkelsen², Tarjei S. Mikkelsen¹, Hongcang Gu², Marius Wernig¹, Jacob H. Hanna¹, Andrey Sivachenko², Xiaolan Zhang², Bradley E. Bernstein³, Bradley E. Bernstein², Chad Nusbaum², David B. Jaffe², Andreas Gnirke², Rudolf Jaenisch¹, Eric S. Lander - Show less +11 more•Institutions (3)

Massachusetts Institute of Technology¹, Broad Institute², Harvard University³

07 Aug 2008-Nature

TL;DR: Low-throughput reduced representation bisulphite sequencing is established as a powerful technology for epigenetic profiling of cell populations relevant to developmental biology, cancer and regenerative medicine.

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Abstract: DNA methylation is essential for normal development and has been implicated in many pathologies including cancer. Our knowledge about the genome-wide distribution of DNA methylation, how it changes during cellular differentiation and how it relates to histone methylation and other chromatin modifications in mammals remains limited. Here we report the generation and analysis of genome-scale DNA methylation profiles at nucleotide resolution in mammalian cells. Using high-throughput reduced representation bisulphite sequencing and single-molecule-based sequencing, we generated DNA methylation maps covering most CpG islands, and a representative sampling of conserved non-coding elements, transposons and other genomic features, for mouse embryonic stem cells, embryonic-stem-cell-derived and primary neural cells, and eight other primary tissues. Several key findings emerge from the data. First, DNA methylation patterns are better correlated with histone methylation patterns than with the underlying genome sequence context. Second, methylation of CpGs are dynamic epigenetic marks that undergo extensive changes during cellular differentiation, particularly in regulatory regions outside of core promoters. Third, analysis of embryonic-stem-cell-derived and primary cells reveals that 'weak' CpG islands associated with a specific set of developmentally regulated genes undergo aberrant hypermethylation during extended proliferation in vitro, in a pattern reminiscent of that reported in some primary tumours. More generally, the results establish reduced representation bisulphite sequencing as a powerful technology for epigenetic profiling of cell populations relevant to developmental biology, cancer and regenerative medicine.

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2,482 citations

"Simple Combinations of Lineage-Dete..." refers methods in this paper

...To determine whether there is an analogous relationship between promoter-distal H3K4me1 and binding sites for transcription factors in other cell types, we performed de novo motif analysis on H3K4me1/H3K4me3 ChIP-Seq data sets from mouse embryonic stem cells (Meissner et al., 2008; Mikkelsen et al., 2007), liver (Wederell et al....
[...]
...…factors in other cell types, we performed de novo motif analysis on H3K4me1/H3K4me3 ChIP-Seq data sets from mouse embryonic stem cells (Meissner et al., 2008; Mikkelsen et al., 2007), liver (Wederell et al., 2008), human CD4+ T cells (Barski et al., 2007), and CD36+ erythrocyte…...
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