Presetting of chromatin structure and transcription factor binding poise the human GADD45 gene for rapid transcriptional up-regulation

Intrauterine growth restriction (IUGR) increases the risk of serious adult morbidities such as hypertension. In an IUGR rat model of hypertension, we reported a persistent decrease in kidney 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) mRNA and protein levels from birth through postnatal (P) day 21. This enzyme deficiency can lead to hypertension by limiting renal glucocorticoid deactivation. In the present study, we hypothesized that IUGR affects renal 11β-HSD2 epigenetic determinants of chromatin structure and alters key transcription factor binding to the 11β-HSD2 promoter in association with persistent downregulation of its mRNA expression. To test this hypothesis, we performed bilateral uterine artery ligation on embryonic day 19.5 pregnant rats and harvested kidneys at day 0 (P0) and P21. Key transcription factors that can affect 11β-HSD2 expression include transcriptional enhancers specificity protein 1 (SP1) and NF-κB p65 and transcriptional repressors early growth response factor (Egr-1) and NF-κB p50. Our most important findings were as follows: 1) IUGR significantly decreased SP1 and NF-κB (p65) binding to the 11β-HSD2 promoter in males, while it increased Egr-1 binding in females and NF-κB (p50) binding in males; 2) IUGR increased CpG methylation status, as well as modified the pattern of methylation in several CpG sites of 11β-HSD2 promoter at P0 also in a sex-specific manner; and 3) IUGR decreased trimethylation of H3K36 in exon 5 of 11β-HSD2 at P0 and P21 in both genders. We conclude that IUGR is associated with altered transcriptional repressor/activator binding in connection with increased methylation in the 11β-HSD2 promoter region in a sex-specific manner, possibly leading to decreased transcriptional activity. Furthermore, IUGR decreased trimethylation of H3K36 of the 11β-HSD2 gene in both genders, which is associated with decreased transcriptional elongation. We speculate that alterations in transcription factor binding and chromatin structure play a role in in utero reprogramming.

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Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding

Leukemia ◽

10.1038/leu.2012.49 ◽

2012 ◽

Vol 26 (8) ◽

pp. 1829-1841 ◽

Cited By ~ 103

Author(s):

A Ptasinska ◽

S A Assi ◽

D Mannari ◽

S R James ◽

D Williamson ◽

...

Keyword(s):

Transcription Factor ◽

Chromatin Structure ◽

Transcription Factor Binding ◽

Factor Binding ◽

Genome Wide

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Mechanisms for ATP-dependent chromatin remodelling

Biochemical Society Transactions ◽

10.1042/bst0280376 ◽

2000 ◽

Vol 28 (4) ◽

pp. 376-379 ◽

Cited By ~ 4

Author(s):

I. Whitehouse ◽

A. Flaus ◽

K. Havas ◽

T. Owen-Hughes

Keyword(s):

Gene Regulation ◽

Transcription Factor ◽

Chromatin Structure ◽

General Feature ◽

Transcription Factor Binding ◽

Model System ◽

Chromatin Remodelling ◽

Factor Binding ◽

Founding Member ◽

Hydrolysis Of

Gene regulation involves the generation of a local chromatin topology that is conducive to transcription. Several classes of chromatin remodelling activity have been shown to play a role in this process. ATP-dependent chromatin-remodelling activities use energy derived from the hydrolysis of ATP to alter the structure of chromatin, making it more accessible for transcription factor binding. The yeast SWI-SWF complex is the founding member of this family of ATP-dependent chromatin-remodelling activities. We have developed a model system to study the ability of the SWI-SWF complex to alter chromatin structure. Using this system, we find that SWI-SWF is able to alter the position of nucleosomes along the DNA. This is consistent with recent reports that other ATP-dependent chromatin-remodelling activities can alter the positions of nucleosomes along DNA. This suggests that nucleosome mobilization may be a general feature of the activity of ATP-dependent chromatin-remodelling activities. Some of the mechanisms by which nucleosomes may be moved along DNA are discussed.

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Analyzing Chromatin Structure and Transcription Factor Binding in Yeast

Methods ◽

10.1006/meth.1998.0633 ◽

1998 ◽

Vol 15 (4) ◽

pp. 295-302 ◽

Cited By ~ 8

Author(s):

Philip D. Gregory ◽

Slobodan Barbaric ◽

Wolfram Hörz

Keyword(s):

Transcription Factor ◽

Chromatin Structure ◽

Transcription Factor Binding ◽

Factor Binding

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Chromatin structure modulates transcription factor binding to the mouse mammary tumor virus (MMTV) promoter

The Journal of Steroid Biochemistry and Molecular Biology ◽

10.1016/0960-0760(93)90051-w ◽

1993 ◽

Vol 47 (1-6) ◽

pp. 1-10 ◽

Cited By ~ 19

Author(s):

Mathias Truss ◽

Jörg Bartsch ◽

Robert S.G. Hache ◽

Miguel Beato

Keyword(s):

Transcription Factor ◽

Mammary Tumor ◽

Chromatin Structure ◽

Mouse Mammary Tumor Virus ◽

Transcription Factor Binding ◽

Mammary Tumor Virus ◽

Factor Binding ◽

Mouse Mammary Tumor ◽

Tumor Virus ◽

Mmtv Promoter

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Dynamic reorganization of chromatin structure and selective DNA demethylation prior to stable enhancer complex formation during differentiation of primary hematopoietic cells in vitro

Blood ◽

10.1182/blood-2003-09-3323 ◽

2004 ◽

Vol 103 (8) ◽

pp. 2950-2955 ◽

Cited By ~ 45

Author(s):

Hiromi Tagoh ◽

Svitlana Melnik ◽

Pascal Lefevre ◽

Suyinn Chong ◽

Arthur D. Riggs ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Cell Differentiation ◽

Chromatin Structure ◽

Molecular Mechanisms ◽

Transcription Factor Binding ◽

Dna Demethylation ◽

Mouse Bone Marrow ◽

Cell Fate Decisions ◽

Factor Binding

Abstract In order to gain insights in the true molecular mechanisms involved in cell fate decisions, it is important to study the molecular details of gene activation where such decisions occur, which is at the level of the chromatin structure of individual genes. In the study presented here we addressed this issue and examined the dynamic development of an active chromatin structure at the chicken lysozyme locus during the differentiation of primary myeloid cells from transgenic mouse bone marrow. Using in vivo footprinting we found that stable enhancer complex assembly and high-level gene expression are late events in cell differentiation. However, even before the onset of gene expression and stable transcription factor binding, specific chromatin alterations are observed. This includes changes in DNA topology and the selective demethylation of CpG dinucleotides located in the cores of critical transcription factor binding sites, but not in flanking DNA. These results firmly support the idea that epigenetic programs guiding blood cell differentiation are engraved into the chromatin of lineage-specific genes and that such chromatin changes are implemented before cell lineage specification. (Blood. 2004;103:2950-2955)

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Aberrant silencing of the CpG island-containing human O6-methylguanine DNA methyltransferase gene is associated with the loss of nucleosome-like positioning.

Molecular and Cellular Biology ◽

10.1128/mcb.17.10.5813 ◽

1997 ◽

Vol 17 (10) ◽

pp. 5813-5822 ◽

Cited By ~ 36

Author(s):

S A Patel ◽

D M Graunke ◽

R O Pieper

Keyword(s):

Transcription Factor ◽

Chromatin Structure ◽

Dna Methyltransferase ◽

Cytosine Methylation ◽

Cpg Island ◽

Cpg Islands ◽

Transcription Factor Binding ◽

Open Chromatin ◽

Factor Binding ◽

Methylguanine Dna Methyltransferase

Tumor-associated aberrant silencing of CpG island-containing genes has been correlated with increased cytosine methylation, a "closed" chromatin structure, and exclusion of transcription factor binding in the CpG island/promoter regions of affected genes. Given the lack of understanding of what constitutes a closed chromatin structure in CpG islands, however, it has been difficult to assess the relationship among cytosine methylation, chromatin structure, and inappropriate gene silencing. In this study, nuclease accessibility analysis was used to more clearly define the chromatin structure in the CpG island of the human O6-methylguanine DNA methyltransferase (MGMT) gene. Chromatin structure was then related to in vivo DNA-protein interactions and cytosine methylation status of the MGMT CpG island in human glioma cells varying in MGMT expression. The results of these studies indicated that the "open" chromatin structure associated with the MGMT CpG island in MGMT+ cells consisted of an approximately 250-bp transcription factor-binding, nuclease-accessible, nucleosome-free region of DNA, whose formation was associated with at least four flanking, precisely positioned nucleosome-like structures. In MGMT- cells, this precise nucleosomal array was lost and was replaced by randomly positioned nucleosomes (i.e., the closed chromatin structure), regardless of whether methylation of the CpG island was spread over the entire island or limited to regions outside the transcription factor binding region. These results suggest that CpG islands facilitate the expression of housekeeping genes by facilitating nucleosomal positioning and that the conditions that alter the formation of this array (such as perhaps methylation) may indirectly affect CpG island-containing gene expression.

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