Regulation of Mouse Mammary Tumor Virus<i>env</i>Transcriptional Activator Initiated Mammary Tumor Virus Superantigen Transcripts in Lymphomas of SJL/J Mice: Role of Ikaros, Demethylation, and Chromatin Structural Change in the Transcriptional Activation of Mammary Tumor Virus Superantigen

Thomas, Robin; Haleem, Kamran; Siddique, Abu Bakar; Simmons, William J.; Sen, Namita; Zhang, Dajun; Tsiagbe, V. K.

doi:10.4049/jimmunol.170.1.218

Cited by 4 publications

(2 citation statements)

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“…Ikaros, a lymphocyte-specific zinc finger DNA-binding protein required for the development of all lymphoid lineages (34,36), is a component of several chromatin remodeling and methylation complexes, including the NURD, Sin3, and CtBP corepressors (35,45,46). Ikaros has been shown to negatively regulate G 1 -to-S phase progression in mature T cells (59), and it acts as a tumor suppressor in both T and B lymphocytes (38,59,60). These activities led us to test whether Ikaros might be involved in the regulation of chromatin structure and transcription at the IL2 gene.…”

Section: Discussionmentioning

confidence: 99%

Ikaros Enforces the Costimulatory Requirement for IL2 Gene Expression and Is Required for Anergy Induction in CD4+ T Lymphocytes

Thomas

Chunder

Chen

et al. 2007

The Journal of Immunology

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125

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T cell activation results in dynamic remodeling of the chromatin at the IL2 promoter and induction of IL2 gene transcription. These processes are each dependent upon CD28 costimulation, but the molecular basis for this requirement is not clear. The IL2 promoter contains consensus-binding elements for Ikaros, a lymphocyte-specific zinc-finger DNA-binding protein that can regulate gene expression by recruiting chromatin-remodeling complexes. We find that native Ikaros in CD4+ T cells exhibits sequence-specific binding to these elements in vitro, and interacts with the endogenous IL2 promoter in vivo, in a manner dependent upon its DNA-binding domain. This binding has important consequences on the regulation of the IL2 gene, because CD4+ T cells with reduced Ikaros DNA-binding activity no longer require signals from the TCR or CD28 for histone acetylation at the endogenous IL2 promoter, and no longer require CD28 costimulation for expression of the IL2 gene. Furthermore, CD4+ T cells with reduced Ikaros activity are resistant to clonal anergy induced by TCR ligation in the absence of either CD28 or IL-2R signals. These results establish Ikaros as a transcriptional repressor of the IL2 gene that functions through modulation of chromatin structure and has an obligate role in the induction of anergy.

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Section: Discussionmentioning

confidence: 99%

Ikaros Enforces the Costimulatory Requirement for IL2 Gene Expression and Is Required for Anergy Induction in CD4+ T Lymphocytes

Thomas

Chunder

Chen

et al. 2007

The Journal of Immunology

Self Cite

125

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“…The nuclei were subsequently washed in the respective digestion buffer (without CaCl 2 ). DNase I, micrococcal nuclease (MNase, NEB, Frankfurt, Germany), was performed as previously described [ 14 , 15 ]. A control without the MNase was included for all samples.…”

Section: Methodsmentioning

confidence: 99%

NFKB1 Promoter DNA from nt+402 to nt+99 Is Hypomethylated in Different Human Immune Cells

et al. 2016

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Sepsis, with a persistently high 90-day mortality of about 46%, is the third most frequent cause of death in intensive care units worldwide. Further understanding of the inflammatory signaling pathways occurring in sepsis is important for new efficient treatment options. Key regulator of the inflammatory response is the transcription factor NFκB. As we have recently shown, the -94 Ins/Del NFKB1 promoter polymorphism influences sepsis mortality. However, a molecular explanation is still missing. Thus, promoter activity might be varying depending on the NFKB1 genotype, explaining the genotype dependent mortality from sepsis, and one likely mechanism is the degree of promoter methylation. Therefore, we tested the hypothesis that NFκB mRNA expression is regulated by promoter methylation in human cell lines and primary immune cell cultures. First, we examined the methylation of the NFKB1 promoter in U937, REH and HL-60 cells. In the promoter region of nt+99/+229 methylation in all analyzed cell lines was below 1%. Following incubation with bacterial cell wall components, no significant changes in the frequency of promoter methylation in U937 and REH cells were measured and the methylation frequency was under 1%. However, NFκB1 mRNA expression was two-fold increased in U937 cells after 24 h incubation with LPS. By contrast, demethylation by 5-Aza-2′-deoxycytidine incubation enhanced NFκB1 expression significantly. In addition, we analyzed NFKB1 promoter methylation in primary cells from healthy volunteers depending on the NFKB1–94 Ins/Del genotype. Methylation in the promoter region from nt+402 to nt+99 was below 1%. Genotype dependent differences occurred in neutrophil cells, where DD-genotype was significantly more methylated compared to II genotype at nt+284/+402. Besides in the promoter region from nt-227/-8 in ID-genotypes methylation of neutrophils was significantly decreased compared to lymphocytes and in II-genotypes methylation in neutrophils was significantly decreased compared to lymphocytes and monocytes. In addition, CHART-PCR showed that the hypomethylated promoter regions are highly accessible. Therefore we assume that the demethylated regions are very important for NFKB1 promoter activity.

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Mouse

Percy¹,

Barthold

2007

Pathology of Laboratory Rodents and Rabbits

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The laboratory mouse is an artificial creation, and there is no true "wildtype" laboratory mouse. Furthermore, there is no such thing as "normal" microflora, since laboratory mice are maintained in microbially pristine environments devoid of pathogens and opportunistic pathogens, as well as other commensal flora/fauna. House mice, from which laboratory mice originated, are represented by several species and subspecies native to the Old World. Laboratory mice are largely derived from domesticated "fancy mice" that arose from many years of trading of mouse variants among fanciers in Europe, Asia, North America, and Australia. The laboratory mouse genome, including its retroelements, is a mosaic derived from different subspecies of the Mus musculus complex, including M.m. domesticus, M.m. musculus, M.m. castaneus, M.m. molossinus (a natural hybrid of M.m. musculus and M.m. castaneus), and M. bactrianus.The genome of M.m. domesticus is the predominant contributor to most strains of mice, but many inbred strains share a common "Eve" with a mitochondrial genome of M.m. musculus origin, and a common "Adam" that contributed their Y chromosome from Asian mice. In addition, there is evidence that other Mus species, outside of the M. musculus complex, may have contributed to the genome of some laboratory mouse strains. The C57BL mouse genome contains a contribution from M. spretus. The 1st inbred mouse (DBA), and other strains with DBA genetic contributions, was partially derived from Japanese waltzing mice with M. bactrianus parentage. Perhaps the only laboratory mouse that is derived from a single species (subspecies), M.m. domesticus, is the "Swiss" mouse, but there is a high likelihood that several Swiss stocks and strains have been genetically corrupted.There are over 450 inbred strains of laboratory mice that have arisen during the last century, and these strains, which were selectively inbred to pan-genomic homozygosity for purposes entirely unrelated to modern research, are the foundation upon which literally thousands of spontaneous mutants and GEMs have been built. Additional inbred strains have been developed from wild mice (M.m. castaneus, M. spretus, etc.). Furthermore, "outbred" mice (mostly Swiss mice) are highly homozygous and nearly inbred. There is no such thing as an outbred laboratory mouse with a fully heterozygous genome representative of wildtype M. musculus, and there is no wild mouse genetic counterpart of the laboratory mouse. When working with mice, the pathologist must also become facile with hybrids,

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Regulation of Mouse Mammary Tumor VirusenvTranscriptional Activator Initiated Mammary Tumor Virus Superantigen Transcripts in Lymphomas of SJL/J Mice: Role of Ikaros, Demethylation, and Chromatin Structural Change in the Transcriptional Activation of Mammary Tumor Virus Superantigen

Cited by 4 publications

References 51 publications

Ikaros Enforces the Costimulatory Requirement for IL2 Gene Expression and Is Required for Anergy Induction in CD4+ T Lymphocytes

Ikaros Enforces the Costimulatory Requirement for IL2 Gene Expression and Is Required for Anergy Induction in CD4+ T Lymphocytes

NFKB1 Promoter DNA from nt+402 to nt+99 Is Hypomethylated in Different Human Immune Cells

Mouse

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