Evidence for Epigenetic Maintenance of <i>Ly49a</i> Monoallelic Gene Expression

Rouhi, A. Maureen; Gagnier, Liane; Takei, Fumio; Mager, Dixie L.

doi:10.4049/jimmunol.176.5.2991

Cited by 42 publications

(49 citation statements)

References 52 publications

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“…The association with combined epigenetic modifications and transcription of NKG2A described in this work are remarkably similar to our results for Ly-49A (21). We have shown previously that both DNA hypomethylation and histone acetylation of an intragenic region are associated with transcriptional activity of Ly-49A.…”

Section: Discussionsupporting

confidence: 92%

“…It appears that the whole KIR gene cluster is in an open chromatin conformation with acetylated histones, and expression of individual alleles is associated with hypomethylated clusters of CpG dinucleotides in the promoter region, whereas methylated promoters correlate with lack of expression. Previous work in our laboratory has shown that both DNA hypomethylation and histone acetylation correlate with expression of Ly-49A on ex vivo NK cells (21). In this study, we show for the first time a role for epigenetic mechanisms in regulating expression of NKG2A both in developing and mature adult NK cells.…”

Section: N Atural Killer Cells Play An Important Role In the Immunesupporting

confidence: 63%

“…However, in contrast to Ly-49, in which we have shown previously that both DNA methylation and unacetylated histones are associated with gene silencing (21), it is believed that DNA methylation status alone is the primary mechanism determining the expression of KIR genes in adult NK cells (13,20). This difference may arise from the different CpG distribution observed between the gene families.…”

Section: Discussionmentioning

confidence: 66%

“…Bisulfite conversion of DNA was performed using the EZ DNA methylation kit (Zymo Research), according to the manufacturer's protocol, with minor modifications (21). Treated DNA was cleaned and eluted to 15 l following the manufacturer's instructions.…”

Section: Bisulfite Conversionmentioning

confidence: 99%

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A Role for DNA Hypomethylation and Histone Acetylation in Maintaining Allele-Specific Expression of Mouse NKG2A in Developing and Mature NK Cells

Rogers

Rouhi

Takei

et al. 2006

The Journal of Immunology

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The repertoire of receptors that is expressed by NK cells is critical for their ability to kill virally infected or transformed cells. However, the molecular mechanisms that determine whether and when NK receptor genes are transcribed during hemopoiesis remain unclear. In this study, we show that hypomethylation of a CpG-rich region in the mouse NKG2A gene is associated with transcription of NKG2A in ex vivo NK cells and NK cell lines. This observation was extended to various developmental stages of NK cells sorted from bone marrow, in which we demonstrate that the CpGs are methylated in the NKG2A-negative stages (hemopoietic stem cells, NK progenitors, and NKG2A-negative NK cells), and hypomethylated specifically in the NKG2A-positive NK cells. Furthermore, we provide evidence that DNA methylation is important in maintaining the allele-specific expression of NKG2A. Finally, we show that acetylated histones are associated with the CpG-rich region in NKG2A positive, but not negative, cell lines, and that treatment with the histone deacetylase inhibitor trichostatin A alone is sufficient to induce NKG2A expression. Treatment with the methyltransferase inhibitor 5-azacytidine only is insufficient to induce transcription, but cotreatment with both drugs resulted in a significantly greater induction, suggesting a cooperative role for DNA methylation and histone acetylation status in regulating gene expression. These results enhance our understanding of the formation and maintenance of NK receptor repertoires in developing and mature NK cells.

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Section: Discussionsupporting

confidence: 92%

Section: N Atural Killer Cells Play An Important Role In the Immunesupporting

confidence: 63%

Section: Discussionmentioning

confidence: 66%

Section: Bisulfite Conversionmentioning

confidence: 99%

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A Role for DNA Hypomethylation and Histone Acetylation in Maintaining Allele-Specific Expression of Mouse NKG2A in Developing and Mature NK Cells

Rogers

Rouhi

Takei

et al. 2006

The Journal of Immunology

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“…Genomic DNA was modified with sodium bisulfite as described (29). Converted DNA was used as a template in the following first round of PCR amplifying the MEIS1 promoter region with forward and reverse flanking bisulfite primers.…”

Section: Dna Methylation Analysis Of the Meis1 Promoter Regionmentioning

confidence: 99%

Identification of E74-like factor 1 (ELF1) as a transcriptional regulator of the Hox cofactor MEIS1

Xiang

Argiropoulos

et al. 2010

Experimental Hematology

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Objective-MEIS1 is a Hox cofactor known for its role in development and strongly linked to normal and leukemic hematopoiesis. Although previous studies have focused on identifying protein partners of MEIS1 and its transcriptionaly regulated targets, little is known about the upstream transcriptional regulators of this tightly regulated gene. Understanding the regulation of MEIS1 is important toward the understanding of normal hematopoiesis and leukemogenesis.Materials and Methods-Here we describe our studies focusing on the evolutionary conserved putative MEIS1 promoter region. Phylogenetic sequence analysis followed and reporter assays in MEIS1 expressing (K562) and non-expressing (HL60) leukemic cell line models were used to identify key regulatory regions and potential transcription factor binding sites within the candidate promoter region followed by functional and expression studies of one identified regulator in both cell lines and primary human cord blood and leukemia samples. Results-The chromatin status of MEIS1 promoter region is associated with MEIS1 expression.Truncation and mutation studies coupled with reporter assays revealed that a conserved ETS family member binding site located 289bp upstream of the annotated human MEIS1 transcription start site (AHTSS) is required for promoter activity. Of the three ETS family members tested, only ELF1 was enriched on the MEIS1 promoter as assessed by both electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) experiments in K562. This finding was confirmed in MEIS1 expressing primary human samples. Moreover, siRNA -mediated knockdown of ELF1 in K562 cells was associated with a decreased MEIS1 expression.Conclusions-We conclude that the ETS transcription factor ELF1 is an important positive regulator of MEIS1 expression.

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High allelic polymorphism, moderate sequence diversity and diversifying selection for B-NK but not B-lec, the pair of lectin-like receptor genes in the chicken MHC

Rogers

Kaufman

2008

Immunogenetics

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We previously characterised the C-type lectin-like receptor genes B-NK and B-lec, located next to each other in opposite orientations in the chicken major histocompatibility complex (MHC). We showed that B-NK is an inhibitory receptor expressed on natural killer cells, whereas B-lec is an activation-induced receptor with a broader expression pattern. It is interesting to note that the chicken MHC has been linked with resistance or susceptibility to Marek's disease virus (MDV), an oncogenic herpes virus. Recent reports show that the C-type lectin-like receptors in mouse and rat (Ly49H, NKR-P1 and Clr) are associated with resistance to another herpesvirus, cytomegalovirus (CMV). Therefore, B-NK and B-lec are potential candidate genes for the MHC-mediated resistance to MDV. In this paper, we report that both genes encode glycosylated type II membrane proteins that form disulphide-linked homodimers. The gene sequences from nine lines of domestic chicken representing seven haplotypes show that B-lec is well conserved between the different haplotypes, apparently under purifying selection. In contrast, B-NK has high allelic polymorphism and moderate sequence diversity, with 21 nucleotide changes in the complementary deoxyribonucleic acids (cDNAs) resulting in 20 amino acid substitutions. The allelic variations include substitutions, an indel and loss/gain of three predicted N-linked glycosylation sites. Strikingly, there is as much as 7% divergence between protein sequences of B-NK from different haplotypes, greater than the difference observed between the highly polymorphic human KIR NK receptors. Analysis of ds and dn reveal evidence of strong positive selection for B-NK to be polymorphic at the protein level, and modelling demonstrates significant variation between haplotypes in the predicted ligand binding face of B-NK.

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Evidence for Epigenetic Maintenance of Ly49a Monoallelic Gene Expression

Cited by 42 publications

References 52 publications

A Role for DNA Hypomethylation and Histone Acetylation in Maintaining Allele-Specific Expression of Mouse NKG2A in Developing and Mature NK Cells

A Role for DNA Hypomethylation and Histone Acetylation in Maintaining Allele-Specific Expression of Mouse NKG2A in Developing and Mature NK Cells

Identification of E74-like factor 1 (ELF1) as a transcriptional regulator of the Hox cofactor MEIS1

High allelic polymorphism, moderate sequence diversity and diversifying selection for B-NK but not B-lec, the pair of lectin-like receptor genes in the chicken MHC

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