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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Journal Article•DOI•

Transcription factors: from enhancer binding to developmental control.

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François Spitz, Eileen E. M. Furlong

01 Sep 2012-Nature Reviews Genetics

TL;DR: Current knowledge of transcription factor function from genomic and genetic studies is reviewed and how different strategies, including extensive cooperative regulation, progressive priming of regulatory elements, and the integration of activities from multiple enhancers, confer specificity and robustness to transcriptional regulation during development are discussed.

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Abstract: Developmental progression is driven by specific spatiotemporal domains of gene expression, which give rise to stereotypically patterned embryos even in the presence of environmental and genetic variation. Views of how transcription factors regulate gene expression are changing owing to recent genome-wide studies of transcription factor binding and RNA expression. Such studies reveal patterns that, at first glance, seem to contrast with the robustness of the developmental processes they encode. Here, we review our current knowledge of transcription factor function from genomic and genetic studies and discuss how different strategies, including extensive cooperative regulation (both direct and indirect), progressive priming of regulatory elements, and the integration of activities from multiple enhancers, confer specificity and robustness to transcriptional regulation during development.

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1,774 citations

Journal Article•DOI•

Transcriptional regulation of macrophage polarization: enabling diversity with identity.

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Toby Lawrence, Gioacchino Natoli¹•Institutions (1)

European Institute of Oncology¹

01 Nov 2011-Nature Reviews Immunology

TL;DR: This Review summarizes the current knowledge of transcriptional and chromatin-mediated control of macrophage polarization in physiology and disease and describes a complex interplay between microenvironmental signals and a hardwired differentiation programme that determines Macrophage identity.

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Abstract: In terms of both phenotype and function, macrophages have remarkable heterogeneity, which reflects the specialization of tissue-resident macrophages in microenvironments as different as liver, brain and bone. Also, marked changes in the activity and gene expression programmes of macrophages can occur when they come into contact with invading microorganisms or injured tissues. Therefore, the macrophage lineage includes a remarkable diversity of cells with different functions and functional states that are specified by a complex interplay between microenvironmental signals and a hardwired differentiation programme that determines macrophage identity. In this Review, we summarize the current knowledge of transcriptional and chromatin-mediated control of macrophage polarization in physiology and disease.

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1,771 citations

Journal Article•DOI•

Trained immunity: A program of innate immune memory in health and disease

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Mihai G. Netea¹, Leo A. B. Joosten¹, Eicke Latz², Kingston H. G. Mills³, Gioacchino Natoli⁴, Hendrik G. Stunnenberg¹, Luke A. J. O'Neill³, Ramnik J. Xavier⁵ - Show less +4 more•Institutions (5)

Radboud University Nijmegen¹, German Center for Neurodegenerative Diseases², Trinity College, Dublin³, European Institute of Oncology⁴, Harvard University⁵

22 Apr 2016-Science

TL;DR: Proof-of-principle experimental studies support the hypothesis that trained immunity is one of the main immunological processes that mediate the nonspecific protective effects against infections induced by vaccines, such as bacillus Calmette-Guérin or measles vaccination.

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Abstract: The general view that only adaptive immunity can build immunological memory has recently been challenged. In organisms lacking adaptive immunity, as well as in mammals, the innate immune system can mount resistance to reinfection, a phenomenon termed "trained immunity" or "innate immune memory." Trained immunity is orchestrated by epigenetic reprogramming, broadly defined as sustained changes in gene expression and cell physiology that do not involve permanent genetic changes such as mutations and recombination, which are essential for adaptive immunity. The discovery of trained immunity may open the door for novel vaccine approaches, new therapeutic strategies for the treatment of immune deficiency states, and modulation of exaggerated inflammation in autoinflammatory diseases.

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1,690 citations

Journal Article•DOI•

Tissue-Resident Macrophage Enhancer Landscapes Are Shaped by the Local Microenvironment

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Yonit Lavin¹, Deborah R. Winter², Ronnie Blecher-Gonen², Eyal David², Hadas Keren-Shaul², Miriam Merad¹, Steffen Jung², Ido Amit² - Show less +4 more•Institutions (2)

Icahn School of Medicine at Mount Sinai¹, Weizmann Institute of Science²

04 Dec 2014-Cell

TL;DR: A combination of tissue- and lineage-specific transcription factors form the regulatory networks controlling chromatin specification in tissue-resident macrophages, and the environment is capable of shaping the chromatin landscape of transplanted bone marrow precursors, and even differentiated macrophage can be reprogrammed when transferred into a new microenvironment.

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1,628 citations

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

...The orchestration of chromatin modifications is regulated by crosstalk between the environment and ontogeny through a small number of TFs (Heinz et al., 2010)....
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...The cobinding of PU.1 with lineage-specific TFs orchestrates cell-type specificity by regulating expression and establishing the chromatin landscape (Heinz et al., 2010; Laslo et al., 2006)....
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...1 with lineage-specific TFs orchestrates cell-type specificity by regulating expression and establishing the chromatin landscape (Heinz et al., 2010; Laslo et al., 2006)....
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...In macrophages, PU.1 occupies most enhancers, where it is necessary for the maintenance of methylation on the fourth lysine of the H3 subunit (H3K4me1) (Ghisletti et al., 2010; Heinz et al., 2010)....
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...enhancers, on the other hand, tend to be bound by specific sets of TFs that regulate their chromatin states (Ghisletti et al., 2010; Heinz et al., 2010; Lara-Astiaso et al., 2014; Winter and Amit, 2014)....
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Journal Article•DOI•

Genetic and Epigenetic Fine-Mapping of Causal Autoimmune Disease Variants

[...]

Kyle Kai-How Farh¹, Alexander Marson², Jiang Zhu³, Markus Kleinewietfeld⁴, William J. Housley⁴, Samantha Beik⁵, Noam Shoresh⁵, Holly Whitton⁵, Russell J.H. Ryan¹, Alexander A. Shishkin⁶, Meital Hatan⁵, Marlene J. Carrasco-Alfonso⁷, Dita Mayer⁷, C. John Luckey⁷, Nikolaos A. Patsopoulos⁷, Philip L. De Jager⁷, Vijay K. Kuchroo⁷, Charles B. Epstein⁵, Mark J. Daly¹, David A. Hafler⁴, Bradley E. Bernstein³ - Show less +17 more•Institutions (7)

Harvard University¹, University of California, San Francisco², Howard Hughes Medical Institute³, Yale University⁴, Broad Institute⁵, California Institute of Technology⁶, Brigham and Women's Hospital⁷

19 Feb 2015-Nature

TL;DR: A fine-mapping algorithm is developed to identify candidate causal variants for 21 autoimmune diseases from genotyping data, and it is found that most non-coding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models.

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Abstract: Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown. Here we developed a fine-mapping algorithm to identify candidate causal variants for 21 autoimmune diseases from genotyping data. We integrated these predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4(+) T-cell subsets, regulatory T cells, CD8(+) T cells, B cells, and monocytes. We find that ∼90% of causal variants are non-coding, with ∼60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation. Causal variants tend to occur near binding sites for master regulators of immune differentiation and stimulus-dependent gene activation, but only 10-20% directly alter recognizable transcription factor binding motifs. Rather, most non-coding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models.

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1,622 citations

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References

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Open Access

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Journal Article•DOI•

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

[...]

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)....
[...]
...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)....
[...]
...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....
[...]
..., 2008), human CD4 T cells (Barski et al., 2007), and CD36 erythrocyte precursors (Cui et al....
[...]
...…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)....
[...]

Journal Article•DOI•

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

[...]

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.

...read moreread less

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....
[...]
...…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)....
[...]

Journal Article•DOI•

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

[...]

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)....
[...]
...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)....
[...]

Journal Article•DOI•

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

[...]

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....
[...]
...…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…...
[...]
...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....
[...]
...…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

[...]

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.

...read moreread less

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…...
[...]