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•

Comprehensive Integration of Single-Cell Data.

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Tim Stuart, Andrew Butler¹, Paul J. Hoffman, Christoph Hafemeister, Efthymia Papalexi¹, William M. Mauck¹, Yuhan Hao¹, Marlon Stoeckius², Peter Smibert², Rahul Satija¹ - Show less +6 more•Institutions (2)

New York University¹, Harvard University²

13 Jun 2019-Cell

TL;DR: A strategy to "anchor" diverse datasets together, enabling us to integrate single-cell measurements not only across scRNA-seq technologies, but also across different modalities.

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7,892 citations

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

...We searched for overrepresented DNA sequence motifs in accessible regions using the Homer package [Heinz et al., 2010], using the findMotifsGenome....
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...10 Heinz et al., 2010 http://homer.ucsd.edu/homer/ R R Core https://www.r-project.org/ Python Python Software Foundation https://www.python.org/...
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...We searched for overrepresented DNA sequence motifs in accessible regions using the Homer package [Heinz et al., 2010], using the findMotifsGenome.pl program with default parameters, and the mm9 genome....
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Journal Article•DOI•

deepTools2: a next generation web server for deep-sequencing data analysis

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Fidel Ramírez¹, Devon Ryan¹, Björn Grüning², Vivek Bhardwaj¹, Fabian Kilpert¹, Andreas S. Richter¹, Steffen Heyne¹, Friederike Dündar³, Thomas Manke¹ - Show less +5 more•Institutions (3)

Max Planck Society¹, University of Freiburg², Cornell University³

08 Jul 2016-Nucleic Acids Research

TL;DR: An update to the Galaxy-based web server deepTools, which allows users to perform complete bioinformatic workflows ranging from quality controls and normalizations of aligned reads to integrative analyses, including clustering and visualization approaches, is presented.

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Abstract: We present an update to our Galaxy-based web server for processing and visualizing deeply sequenced data. Its core tool set, deepTools, allows users to perform complete bioinformatic workflows ranging from quality controls and normalizations of aligned reads to integrative analyses, including clustering and visualization approaches. Since we first described our deepTools Galaxy server in 2014, we have implemented new solutions for many requests from the community and our users. Here, we introduce significant enhancements and new tools to further improve data visualization and interpretation. deepTools continue to be open to all users and freely available as a web service at deeptools.ie-freiburg.mpg.de The new deepTools2 suite can be easily deployed within any Galaxy framework via the toolshed repository, and we also provide source code for command line usage under Linux and Mac OS X. A public and documented API for access to deepTools functionality is also available.

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4,359 citations

Additional excerpts

...The rapidly increasing diversity of experimental assays using high-throughput sequencing has led to a concomitant increase in the number of analysis packages that allow for insightful visualization and downstream analyses (e.g. ChAsE (1), the ChIP-seq web server (http://ccg. vital-it.ch/chipseq), Genomation (2), Homer (3), ngs.plot (4))....
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...ch/chipseq), Genomation (2), Homer (3), ngs....
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Journal Article•DOI•

Histone H3K27ac separates active from poised enhancers and predicts developmental state

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Menno P. Creyghton¹, Albert W. Cheng, G. Grant Welstead, Tristan Kooistra, Bryce W. Carey, Eveline J. Steine, Jacob H. Hanna, Michael A. Lodato, Garrett M. Frampton, Phillip A. Sharp, Laurie A. Boyer, Richard A. Young, Rudolf Jaenisch - Show less +9 more•Institutions (1)

Massachusetts Institute of Technology¹

14 Dec 2010-Proceedings of the National Academy of Sciences of the United States of America

TL;DR: The epigenetic landscape of enhancer elements in embryonic stem cells and several adult tissues in the mouse is interrogated and it is found that histone H3K27ac distinguishes active enhancers from inactive/poised enhancers and poised enhancer networks provide clues to unrealized developmental programs.

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Abstract: Developmental programs are controlled by transcription factors and chromatin regulators, which maintain specific gene expression programs through epigenetic modification of the genome. These regulatory events at enhancers contribute to the specific gene expression programs that determine cell state and the potential for differentiation into new cell types. Although enhancer elements are known to be associated with certain histone modifications and transcription factors, the relationship of these modifications to gene expression and developmental state has not been clearly defined. Here we interrogate the epigenetic landscape of enhancer elements in embryonic stem cells and several adult tissues in the mouse. We find that histone H3K27ac distinguishes active enhancers from inactive/poised enhancer elements containing H3K4me1 alone. This indicates that the amount of actively used enhancers is lower than previously anticipated. Furthermore, poised enhancer networks provide clues to unrealized developmental programs. Finally, we show that enhancers are reset during nuclear reprogramming.

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3,541 citations

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

...Examination of ChIP-Seq data (7, 24) confirmed that both Foxa2 and PU....
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Journal Article•DOI•

Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes

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Warren A. Whyte¹, David A. Orlando¹, Denes Hnisz¹, Brian J. Abraham¹, Charles Y. Lin¹, Charles Y. Lin², Michael H. Kagey¹, Peter B. Rahl¹, Tong Ihn Lee¹, Richard A. Young¹ - Show less +6 more•Institutions (2)

Massachusetts Institute of Technology¹, Harvard University²

11 Apr 2013-Cell

TL;DR: In this article, the ESC master transcription factors form unusual enhancer domains at most genes that control the pluripotent state, called super-enhancers, which consist of clusters of enhancers that are densely occupied by the master regulators and Mediator.

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2,978 citations

Journal Article•DOI•

Regulatory T Cells: Mechanisms of Differentiation and Function

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Steven Z. Josefowicz¹, Li-Fan Lu², Alexander Y. Rudensky³•Institutions (3)

Howard Hughes Medical Institute¹, Rockefeller University², University of California, San Diego³

26 Mar 2012-Annual Review of Immunology

TL;DR: Cellular and molecular mechanisms in the differentiation and function of regulatory T cells and their role in autoimmune and autoinflammatory disorders, allergy, acute and chronic infections, cancer, and metabolic inflammation are discussed.

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Abstract: The immune system has evolved to mount an effective defense against pathogens and to minimize deleterious immune-mediated inflammation caused by commensal microorganisms, immune responses against self and environmental antigens, and metabolic inflammatory disorders. Regulatory T (Treg) cell–mediated suppression serves as a vital mechanism of negative regulation of immune-mediated inflammation and features prominently in autoimmune and autoinflammatory disorders, allergy, acute and chronic infections, cancer, and metabolic inflammation. The discovery that Foxp3 is the transcription factor that specifies the Treg cell lineage facilitated recent progress in understanding the biology of regulatory T cells. In this review, we discuss cellular and molecular mechanisms in the differentiation and function of these cells.

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2,356 citations

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

...1 is required for the maintenance of cell type– specific regulatory chromatin characteristics following macrophage and B cell differentiation (153, 154)....
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References

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Journal Article•DOI•

Identification and Characterization of Enhancers Controlling the Inflammatory Gene Expression Program in Macrophages

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Serena Ghisletti¹, Iros Barozzi¹, Flore Mietton¹, Sara Polletti¹, Francesca De Santa¹, Elisa Venturini, Lorna Gregory², Lorne Lonie², Adeline Chew³, Chia-Lin Wei³, Jiannis Ragoussis², Gioacchino Natoli¹ - Show less +8 more•Institutions (3)

European Institute of Oncology¹, Wellcome Trust Centre for Human Genetics², Genome Institute of Singapore³

26 Mar 2010-Immunity

TL;DR: The combinatorial assembly of tissue- and signal-specific transcription factors determines the activity of a distinct group of enhancers and it is suggested that this may represent a general paradigm in tissue-restricted and stimulus-responsive gene regulation.

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608 citations

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

...Absolute , 20,481 total, 1,274 with p300; PU.1 and C/EBPb, 13,874 total, 4,230 with ata for resting bone marrow-derived macrophages (Ghisletti et al., 2010)....
[...]
...…play a role in shaping the transcriptional response to inflammatory stimuli such as lipopolysaccharide (LPS), likely by generating cell type-specific regions of open chromatin that serve as beacons for the recruitment of transcriptional coactivators in response to stimuli (Ghisletti et al., 2010)....
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...1 and C/EBPb, 13,874 total, 4,230 with ata for resting bone marrow-derived macrophages (Ghisletti et al., 2010)....
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...Of note, analysis of the genome-wide location of p300 in resting macrophages (Ghisletti et al., 2010) indicates marked enrichment at genomic locations cobound by PU.1 and C/EBPb (Figure 4G)....
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...Of note, analysis of the genome-wide location of p300 in resting macrophages (Ghisletti et al., 2010) indicates marked enrichment at genomic locations cobound by PU....
[...]

Journal Article•DOI•

Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb

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Bo Feng¹, Jianming Jiang¹, Jianming Jiang², Petra Kraus¹, Jia-Hui Ng¹, Jian-Chien Dominic Heng², Jian-Chien Dominic Heng¹, Yun-Shen Chan², Yun-Shen Chan¹, Lai-Ping Yaw¹, Weiwei Zhang¹, Weiwei Zhang², Yuin-Han Loh¹, Yuin-Han Loh², Jianyong Han¹, Vinsensius B. Vega¹, Valere Cacheux-Rataboul¹, Bing Lim³, Bing Lim¹, Thomas Lufkin¹, Huck-Hui Ng², Huck-Hui Ng¹ - Show less +18 more•Institutions (3)

Genome Institute of Singapore¹, National University of Singapore², Harvard University³

11 Jan 2009-Nature Cell Biology

TL;DR: This work shows that the orphan nuclear receptor Esrrb functions in conjunction with Oct4 and Sox2 to mediate reprogramming of mouse embryonic fibroblasts (MEFs) to iPS cells, and indicates that it is possible to reprogram MEFs without exogenous Klf transcription factors and link a nuclear receptor to somatic cell reprograming.

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Abstract: The dominant effect of transcription factors in imparting expanded potency is best exemplified by the reprogramming of fibroblasts to pluripotent cells using retrovirus-mediated transduction of defined transcription factors. In the murine system, Oct4, Sox2, c-Myc and Klf4 are sufficient to convert fibroblasts to induced pluripotent stem (iPS) cells that have many characteristics of embryonic stem (ES) cells. Here we show that the orphan nuclear receptor Esrrb functions in conjunction with Oct4 and Sox2 to mediate reprogramming of mouse embryonic fibroblasts (MEFs) to iPS cells. Esrrb-reprogrammed cells share similar expression and epigenetic signatures as ES cells. These cells are also pluripotent and can differentiate in vitro and in vivo into the three major embryonic cell lineages. Furthermore, these cells contribute to mouse chimaeras and are germline transmissible. In ES cells, Esrrb targets many genes involved in self-renewal and pluripotency. This suggests that Esrrb may mediate reprogramming through the upregulation of ES-cell-specific genes. Our findings also indicate that it is possible to reprogram MEFs without exogenous Klf transcription factors and link a nuclear receptor to somatic cell reprogramming.

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518 citations

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

...For example, H3K4me1-marked promoter-distal regions in ES cells were significantly enriched for motifs recognized by KLF4, OCT4, SOX2, and Esrrb, factors that, in combination, are sufficient to reprogram somatic cells into induced pluripotent stem cells (Feng et al., 2009)....
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Journal Article•DOI•

Transcriptional control of granulocyte and monocyte development.

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Alan D. Friedman¹•Institutions (1)

Johns Hopkins University¹

15 Oct 2007-Oncogene

TL;DR: PU.1 directs the hematopoietic stem cell to the lymphoid-myeloid progenitor (LMP) and interacts with GATA-binding protein 1 to inhibit commitment to the megakaryocyte-erythroid progenitors (GMP) stage, while inhibiting lymphoid development via cross-inhibition of Pax5 and potentially other regulators.

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Abstract: PU.1 directs the hematopoietic stem cell to the lymphoid-myeloid progenitor (LMP) and interacts with GATA-binding protein 1 to inhibit commitment to the megakaryocyte-erythroid progenitor. The CCAAT/enhancer-binding protein (C/EBP)alpha then directs the LMP to the granulocyte-monocyte progenitor (GMP) stage, while inhibiting lymphoid development via cross-inhibition of Pax5 and potentially other regulators. Increased PU.1 activity favors monocytic commitment of the GMP. Induction of PU.1 by C/EBPalpha and interaction of PU.1 with c-Jun elevates PU.1 activity. Zippering of C/EBPalpha with c-Jun or c-Fos also contributes to monocyte lineage specification. An additional factor, potentially an Id1-regulated basic helix-loop-helix protein, may be required for the GMP to commit to the granulocyte lineage. Egr-1, Egr-2, Vitamin D Receptor, MafB/c: Fos and PU.1:interferon regulatory factor 8 complexes direct further monocytic maturation, while retinoic acid receptor (RAR) and C/EBPepsilon direct granulopoiesis. Both C/EBPalpha and RARs induce C/EBPepsilon, and PU.1 is also required, albeit at lower levels, for granulocytic maturation. HoxA10 and CAAT displacement protein act as transcriptional repressors to delay expression of terminal differentiation. Gfi-1 and Egr-1,2/Nab2 complexes repress each other to maintain myeloid lineage fidelity. NF-kappaB directly binds and cooperates with C/EBPbeta to induce the inflammatory response in mature myeloid cells and potentially also cooperates with C/EBPalpha to regulate early myelopoiesis.

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412 citations

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

...Of these, AP-1 and C/EBP family factors are required for macrophage development and function (Friedman, 2007), whereas E2A, EBF1, Pax5, and Oct-2 play important roles in the development and function of B cells (Medina and Singh, 2005)....
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Journal Article•DOI•

Developmental roles of 21 Drosophila transcription factors are determined by quantitative differences in binding to an overlapping set of thousands of genomic regions

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Stewart MacArthur¹, Stewart MacArthur², Xiao-Yong Li², Xiao-Yong Li³, Jingyi Li³, James B. Brown³, Hou Cheng Chu², Lucy Zeng², Brandi P Grondona², Aaron Hechmer², Lisa Simirenko², Soile V.E. Keranen², David W. Knowles², Mark Stapleton², Peter J. Bickel³, Mark D. Biggin², Michael B. Eisen², Michael B. Eisen³ - Show less +14 more•Institutions (3)

University of Cambridge¹, Lawrence Berkeley National Laboratory², University of California, Berkeley³

23 Jul 2009-Genome Biology

TL;DR: It is suggested that most animal transcription factors will be found to show a similar broad overlapping pattern of binding in vivo, with specificity achieved by modulating the amount, rather than the identity, of bound factor.

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Abstract: We previously established that six sequence-specific transcription factors that initiate anterior/posterior patterning in Drosophila bind to overlapping sets of thousands of genomic regions in blastoderm embryos. While regions bound at high levels include known and probable functional targets, more poorly bound regions are preferentially associated with housekeeping genes and/or genes not transcribed in the blastoderm, and are frequently found in protein coding sequences or in less conserved non-coding DNA, suggesting that many are likely non-functional. Here we show that an additional 15 transcription factors that regulate other aspects of embryo patterning show a similar quantitative continuum of function and binding to thousands of genomic regions in vivo. Collectively, the 21 regulators show a surprisingly high overlap in the regions they bind given that they belong to 11 DNA binding domain families, specify distinct developmental fates, and can act via different cis-regulatory modules. We demonstrate, however, that quantitative differences in relative levels of binding to shared targets correlate with the known biological and transcriptional regulatory specificities of these factors. It is likely that the overlap in binding of biochemically and functionally unrelated transcription factors arises from the high concentrations of these proteins in nuclei, which, coupled with their broad DNA binding specificities, directs them to regions of open chromatin. We suggest that most animal transcription factors will be found to show a similar broad overlapping pattern of binding in vivo, with specificity achieved by modulating the amount, rather than the identity, of bound factor.

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367 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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...…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…...
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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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...…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…...
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Journal Article•DOI•

PU.1 recruits a second nuclear factor to a site important for immunoglobulin kappa 3' enhancer activity.

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Jm. R. Pongubala¹, Sujatha Nagulapalli¹, M. J. Klemsz¹, S. R. Mckercher¹, R. A. Maki¹, Michael L. Atchison¹ - Show less +2 more•Institutions (1)

University of Pennsylvania¹

01 Jan 1992-Molecular and Cellular Biology

TL;DR: UV-crosslinking studies and elution from sodium dodecyl sulfate-polyacrylamide gels indicate that NF-EM5 is a protein of approximately 46 kDa, and site-directed mutagenesis studies of the PU.1- and EM5-binding sites indicate that these sites play important roles in kappa E3' enhancer activity.

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Abstract: PU.1 is a B-cell- and macrophage-specific transcription factor. By an electrophoretic mobility shift assay and dimethyl sulfate methylation interference assays, we show that PU.1 binds to DNA sequences within the immunoglobulin kappa 3' enhancer (kappa E3'). Binding of PU.1 to the kappa E3' enhancer assists the binding of a second tissue-restricted factor, NF-EM5, to an adjacent site. Binding of NF-EM5 to kappa E3' DNA sequences requires protein-protein interaction with PU.1 as well as specific protein-DNA interactions. This is the first known instance of PU.1 interacting with another cellular protein. NF-EM5 does not cofractionate with PU.1, suggesting that it is a distinct protein and is not a posttranslational modification of PU.1. UV-crosslinking studies and elution from sodium dodecyl sulfate-polyacrylamide gels indicate that NF-EM5 is a protein of approximately 46 kDa. Site-directed mutagenesis studies of the PU.1- and EM5-binding sites indicate that these sites play important roles in kappa E3' enhancer activity. By using a series of PU.1 deletion constructs, we have identified a region in PU.1 that is necessary for interaction with NF-EM5. This segment encompasses a 43-amino-acid region with PEST sequence homology, i.e., one that is rich in proline (P), glutamic acid (E), serine (S), and threonine (T).

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356 citations

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

...Both promoter-proximal and promoter-distal commonly PU.1-bound regions exhibited enrichment for a PU.1:IRF composite, consistent with the ability of PU.1 and IRF4/8 to form a ternary complex on this class of composite sites in both cell types (Eisenbeis et al., 1993; Pongubala et al., 1992)....
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...1 and IRF4/8 to form a ternary complex on this class of composite sites in both cell types (Eisenbeis et al., 1993; Pongubala et al., 1992)....
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