Downregulation of miR-200a-3p, Targeting CtBP2 Complex, Is Involved in the Hypoproduction of IL-2 in Systemic Lupus Erythematosus–Derived T Cells

Katsuyama, Eri; Yan, Minglu; Watanabe, Koichi; Narazaki, Mariko; Matsushima, Syun; Yamamura, Yuriko; Hiramatsu, Shinichi; Ohashi, Keiji; Watanabe, Hirotaka; Katsuyama, Takayuki; Zeggar, Sonia; Yoshida, Norimitsu; Moulton, Vaishali R.; Tsokos, George C.; Sada, Ken‐ei; Wada, Jun

doi:10.4049/jimmunol.1601705

Cited by 31 publications

(16 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SRSF1 levels are decreased in T cells from SLE patients, and overexpression of SRSF1 into SLE T cells, rescues IL-2 production ( 34 ). It was demonstrated that increased expression of miR-200a-3p is associated with the decreased production of IL-2 through zinc finger E-box binding homeobox–C-terminal binding protein 2 in MRL/lpr mice ( 216 ).…”

Section: Cytokine Signalingmentioning

confidence: 99%

Aberrant T Cell Signaling and Subsets in Systemic Lupus Erythematosus

2018

Self Cite

View full text Add to dashboard Cite

Systemic lupus erythematosus (SLE) is a chronic multi-organ debilitating autoimmune disease, which mainly afflicts women in the reproductive years. A complex interaction of genetics, environmental factors and hormones result in the breakdown of immune tolerance to “self” leading to damage and destruction of multiple organs, such as the skin, joints, kidneys, heart and brain. Both innate and adaptive immune systems are critically involved in the misguided immune response against self-antigens. Dendritic cells, neutrophils, and innate lymphoid cells are important in initiating antigen presentation and propagating inflammation at lymphoid and peripheral tissue sites. Autoantibodies produced by B lymphocytes and immune complex deposition in vital organs contribute to tissue damage. T lymphocytes are increasingly being recognized as key contributors to disease pathogenesis. CD4 T follicular helper cells enable autoantibody production, inflammatory Th17 subsets promote inflammation, while defects in regulatory T cells lead to unchecked immune responses. A better understanding of the molecular defects including signaling events and gene regulation underlying the dysfunctional T cells in SLE is necessary to pave the path for better management, therapy, and perhaps prevention of this complex disease. In this review, we focus on the aberrations in T cell signaling in SLE and highlight therapeutic advances in this field.

show abstract

Section: Cytokine Signalingmentioning

confidence: 99%

Aberrant T Cell Signaling and Subsets in Systemic Lupus Erythematosus

2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…The zinc finger E-box binding homeobox 1 gene, ZEB1, P SKAT.corr < 1.00E-03 and P burden.test.corr < 1.00E-03, OR enrich = 2.03 and CI 95%.enrich = (1.35, 3.05), acts as a transcriptional repressor inhibiting interleukin-2 (IL-2) gene expression. Note that IL-2 plays a critical role in immune tolerance, and insufficient IL-2 production upon stimulation has been recognized in SLE pathogenesis, particularly it has been described a new epigenetic pathway in the control of IL-2 production in SLE whereby low levels of miR-200a-3p accumulate the binding of the ZEB1-CtBP2 complex to the IL-2 promoter and suppresses IL-2 production (50). The role of CCR3 [P SKAT.corr = 0.00838 and P burden.test.corr < 1.00E-03, OR burden.test = 3.74 and CI 95%.burden.test = (1.74, 8.02)] in inflammation is widely known (OMIM * 601268).…”

Section: Discussionmentioning

confidence: 99%

Exploring Impact of Rare Variation in Systemic Lupus Erythematosus by a Genome Wide Imputation Approach

Martínez-Bueno¹,

Alarcón‐Riquelme²

2019

Front. Immunol.

View full text Add to dashboard Cite

The importance of low frequency and rare variation in complex disease genetics is difficult to estimate in patient populations. Genome-wide association studies are therefore, underpowered to detect rare variation. We have used a combined approach of genome-wide-based imputation with a highly stringent sequence kernel association (SKAT) test and a case-control burden test. We identified 98 candidate genes containing rare variation that in aggregate show association with SLE many of which have recognized immunological function, but also function and expression related to relevant tissues such as the joints, skin, blood or central nervous system. In addition we also find that there is a significant enrichment of genes annotated for disease-causing mutations in the OMIM database, suggesting that in complex diseases such as SLE, such mutations may be involved in subtle or combined phenotypes or could accelerate specific organ abnormalities found in the disease. We here provide an important resource of candidate genes for SLE.

show abstract

“…Illumina TruSeq ChIP Sample Prep Kit was used for the construction of sequencing libraries, and they were subjected to sequencing using Illumina HiSeq. The previously published mRNA sequencing data 10 appeared in Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) under the accession number GSE87219 was analyzed with Cuffdiff program, and integrated with genome wide DNA methylation profiling data (GSE102421). In brief, significant methylation peaks in B6 and MRL mice were identified with model-based analysis of ChIP-Seq (MACS 1.4.2) using parameters bandwidth = 300, mfold = 10,30, and gzise = 1870000000 50 , mapped to genome, differentially methylated regions (DRMs) between B6 and MRL mice identified, and duplicate reads removed.…”

Section: Methodsmentioning

confidence: 99%

“…We previously demonstrated that hypomethylation of a CpG within cAMP response element (CRE) motif links to increased expression of PP2Acα in T cells derived from the patients with SLE 9 . We also performed global miRNA and mRNA profiling in CD4+ T cells purified from spleen of MRL/lpr lupus-prone mice (MRL) and compared with the C57BL/6 (B6) and isolated miR-200a-3p, which is involved in the hypoproduction of IL-2 in T cells by targeting CtBP2 complex 10 . To identify the putative methylation-sensitive genes involved in the pathogenesis of SLE, we performed the integration analysis of genome-wide DNA methylation and global mRNA profiling in CD4+ T cells purified from spleen of MRL and compared with B6 mice.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Cathepsin E gene expression by the transcription factor Kaiso in MRL/lpr mice derived CD4+ T cells

Hiramatsu

Watanabe

Zeggar

et al. 2019

Sci Rep

Self Cite

View full text Add to dashboard Cite

Global DNA hypomethylation in CD4+ cells in systemic lupus erythematosus (SLE) was suggested to play a key role in the pathogenesis. To identify new methylation-sensitive genes, we integrated genome-wide DNA methylation and mRNA profiling data in CD4+ cells of MRL/lpr (MRL) and C57BL6/J (B6) mice. We identified Cathepsin E ( Ctse ), in which 13 methyl-CpGs within 583 bp region of intron 1 were hypomethylated, and Ctse mRNA upregulated in MRL compared with B6 mice. One of methyl-CpGs, mCGCG was 93.3 ± 2.05% methylated in B6 mice, while 80.0 ± 6.2% methylated and mutated to CGGG in MRL mice. Kaiso is known to bind to mCGCG and we hypothesized that it represses expression of Ctse in B6 mice. The binding of Kaiso to mCGCG site in B6 mice was reduced in MRL mice revealed by ChIP-PCR. EL4 cells treated with 5-azaC and/or Trichostatin A showed the suppression of binding of Kaiso to mCGCG motif by ChIP-PCR and the overexpression of Ctse was demonstrated by qPCR. Ctse gene silencing by siRNA in EL4 cells resulted in reduction of IL-10 secretion. The hypomethylation of mCGCG motif, reduced recruitment of Kaiso, and increased expression of Ctse and Il-10 in CD4+ cells may be involved in the pathogenesis of SLE.

show abstract

Downregulation of miR-200a-3p, Targeting CtBP2 Complex, Is Involved in the Hypoproduction of IL-2 in Systemic Lupus Erythematosus–Derived T Cells

Cited by 31 publications

References 45 publications

Aberrant T Cell Signaling and Subsets in Systemic Lupus Erythematosus

Aberrant T Cell Signaling and Subsets in Systemic Lupus Erythematosus

Exploring Impact of Rare Variation in Systemic Lupus Erythematosus by a Genome Wide Imputation Approach

Regulation of Cathepsin E gene expression by the transcription factor Kaiso in MRL/lpr mice derived CD4+ T cells

Contact Info

Product

Resources

About