Role of Positive and Negative Cis-regulatory Elements in the Transcriptional Activation of the Lysozyme Locus in Developing Macrophages of Transgenic Mice

Jägle, Ulrike; Müller, Albrecht; Kohler, Hubertus; Bonifer, Constanze

doi:10.1074/jbc.272.9.5871

Cited by 33 publications

(24 citation statements)

References 37 publications

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“…We have shown previously that the early enhancers and the promoter are activated first at the CFU-GM stage and stay active during macrophage differentiation (30,33). Here we present direct evidence that the Ϫ6.1-kb and Ϫ3.9-kb enhancers are targets for the Ets factor Fli-1 and members of the NF1 family.…”

Section: Discussionsupporting

confidence: 67%

“…The Ϫ6.1-kb enhancer, the Ϫ3.9-kb enhancer, and the promoter are the first elements that are switched on during macrophage differentiation. The presence of the Ϫ6.1-kb enhancer is absolutely required for the correct timing of lysozyme locus activation (33). The binding sites for NF1 family members at the early enhancers at Ϫ6.1 kb and Ϫ3.9 kb are important for enhancer activity in transfection assays (24,45).…”

Section: Resultsmentioning

confidence: 99%

“…Functional experiments in transgenic mice as well as chromatin structure studies have shown that in contrast to the early enhancers and in the presence of the Ϫ2.4-kb silencer, the Ϫ2.7-kb enhancer is activated only late in myelopoiesis (30,33). Transfection experiments in HD11 cells with constructs containing both elements show no enhancer activity, whereas the Ϫ2.7-kb enhancer on its own is active in these cells, indi- cating that the Ϫ2.4-kb element represses the activity of the enhancer (59).…”

Section: Discussionmentioning

confidence: 99%

“…Transcription of the lysozyme gene is initially activated in granulocyte-macrophage precursors (CFU-GM); this process requires the presence of the early-acting enhancers at Ϫ6.1 kb and Ϫ3.9 kb and the promoter. As judged by DNase I-hypersensitive site mapping experiments, a third enhancer at Ϫ2.7 kb becomes active later in development (30,33).…”

mentioning

confidence: 99%

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Developmentally Regulated Recruitment of Transcription Factors and Chromatin Modification Activities to Chicken Lysozyme cis-Regulatory Elements In Vivo

Lefèvre

Melnik

Wilson

et al. 2003

Molecular and Cellular Biology

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Expression of the chicken lysozyme gene is upregulated during macrophage differentiation and reaches its highest level in bacterial lipopolysaccharide (LPS)-stimulated macrophages. This is accompanied by complex alterations in chromatin structure. We have previously shown that chromatin fine-structure alterations precede the onset of gene expression in macrophage precursor cells and mark the lysozyme chromatin domain for expression later in development. To further examine this phenomenon and to investigate the basis for the differentiation-dependent alterations of lysozyme chromatin, we studied the recruitment of transcription factors to the lysozyme locus in vivo at different stages of myeloid differentiation. Factor recruitment occurred in several steps. First, early-acting transcription factors such as NF1 and Fli-1 bound to a subset of enhancer elements and recruited CREB-binding protein. LPS stimulation led to an additional recruitment of C/EBP␤ and a significant change in enhancer and promoter structure. Transcription factor recruitment was accompanied by specific changes in histone modification within the lysozyme chromatin domain. Interestingly, we present evidence for a transient interaction of transcription factors with lysozyme chromatin in lysozymenonexpressing macrophage precursors, which was accompanied by a partial demethylation of CpG sites. This indicates that a partially accessible chromatin structure of lineage-specific genes is a hallmark of hematopoietic progenitor cells.

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Section: Discussionsupporting

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Developmentally Regulated Recruitment of Transcription Factors and Chromatin Modification Activities to Chicken Lysozyme cis-Regulatory Elements In Vivo

Lefèvre

Melnik

Wilson

et al. 2003

Molecular and Cellular Biology

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“…We then asked how the different cis-regulatory elements cooperate during earlier stages of cell differentiation. To this end, we analyzed the time course of transcriptional activation of wild type and mutant lysozyme locus constructs during in vitro differentiation of myeloid precursor cells isolated from the bone marrow of transgenic mice (24). In early macrophage precursor cells the Ϫ6.1 kb and Ϫ3.9-kb enhancers, the promoter, and the silencer element are DNase I-hypersensitive, whereas the Ϫ2.7-kb enhancer is not (6,10,19).…”

Section: The Role Of Positive and Negative Cis-regulatory Elements Inmentioning

confidence: 99%

The Chicken Lysozyme Locus as a Paradigm for the Complex Developmental Regulation of Eukaryotic Gene Loci

Bonifer

Jägle²,

Huber

1997

Journal of Biological Chemistry

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Gene loci of higher organisms have complex structural features. In some cases their coding regions occupy many, even hundreds, of kilobases of DNA. Additionally, the sequences that contain the information for the correct spatial and temporal regulation of a particular gene locus during development often exceed the extensions of the coding region by severalfold.The question of what type of information is encoded in these vast amounts of DNA has puzzled researchers from the beginning.It is now clear that eukaryotic genes are regulated by a number of different cis-regulatory elements distributed over large distances. A convenient way to assay the number and the distribution of cis-regulatory elements has been the mapping of DHS 1 in chromatin. Such local chromatin perturbations are in most cases caused by the binding of transcription factors to their cognate DNA sequences. The pattern of DHS can undergo dramatic developmental changes, indicating a change in the activity of cis-regulatory elements. In addition, the analysis of protein-DNA interactions at a single-nucleotide resolution level in vivo has demonstrated that, depending on the developmental stage, different combinations of transcription factors can occupy the same cis-regulatory element (1, 2). These experiments indicate that the transcriptional activation of a gene locus is achieved by the cooperation of several different cisregulatory elements, which, in turn, assemble transcription factors in a sequential, developmentally controlled fashion. However, the assembly of active transcription factor complexes on natural genes does not occur on naked DNA but in a chromatin context, where nucleosome-DNA interactions have to be counteracted. Hence, the activation of a gene locus requires at least the following steps: the perturbation of chromatin structure by the binding of transcription factors on cis-regulatory elements, the developmentally controlled reorganization of transcription factor complexes, the assembly of the basal transcription machinery and its interaction with upstream regulatory elements, the onset of mRNA synthesis, and, in many cases, the maintenance of an active transcriptional state during multiple rounds of DNA synthesis.How can the molecular basis of locus activation be experimentally studied? While the basal activities of individual cisregulatory elements of particular gene loci can be analyzed by transient and stable transfection experiments, the molecular mechanism of activation of a gene locus from the transcriptionally silent state can only be studied in a developing system, preferentially in transgenic animals. The ideal model locus should be small, thus facilitating the manipulation of individual cis-regulatory elements within the context of an entire genomic locus, and it should be extensively characterized on the molecular level. In addition, to dissect the role of different cis-regulatory elements in the developmental control of gene locus activation, it should be possible to follow cell differentiation experimentally, thus enab...

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Myeloid-specific gene expression

Clarke

Gordon

1998

Journal of Leukocyte Biology

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The mononuclear phagocytes are recruited from bone marrow precursors to most tissues of the body, particularly during inflammation or immune stimulation. This combination of accessibility as stem cells and heterogenity of tissue locations makes the myeloid cell potentially important as a carrier of therapeutic agents. Understanding the regulation of transcription in myeloid cells is necessary for any future design of tissue-specific gene targeting vectors, particularly if there are inherent size limitations. Identified members of the C/EBP, Runt/PEBP2/CBF, and Ets families of transcription factors are critical for myeloid-specific gene expression and may have myeloid-restricted expression or myeloid-specific regulation in the hematopoietic system. AP-1, Sp1, and Myb appear to be important for myeloid-restricted expression in some cases. In addition, factors involved in the up-regulation of the level of gene expression when macrophages are activated by agents such as interferon-gamma and bacterial products have been identified. Some of the sequences to which these transcription factors bind in myeloid-restricted genes have been tested in cell lines and in transgenic mice and it is now possible to make an attempt to describe the characteristics of a myeloid-specific promoter.

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Role of Positive and Negative Cis-regulatory Elements in the Transcriptional Activation of the Lysozyme Locus in Developing Macrophages of Transgenic Mice

Cited by 33 publications

References 37 publications

Developmentally Regulated Recruitment of Transcription Factors and Chromatin Modification Activities to Chicken Lysozyme cis-Regulatory Elements In Vivo

Developmentally Regulated Recruitment of Transcription Factors and Chromatin Modification Activities to Chicken Lysozyme cis-Regulatory Elements In Vivo

The Chicken Lysozyme Locus as a Paradigm for the Complex Developmental Regulation of Eukaryotic Gene Loci

Myeloid-specific gene expression

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