Interleukin 2 modulates thymic-derived regulatory T cell epigenetic landscape

Chorro, Laurent; Suzuki, Masako; Chin, Shu Shien; Williams, Tere; Snapp, Erik L.; Odagiu, Livia; Labrecque, Nathalie; Lauvau, Grégoire

doi:10.1038/s41467-018-07806-6

Cited by 29 publications

(23 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SATB1 is predominantly expressed in the thymus and highly associated with thymocyte differentiation. It is thought to induce lymphopoiesis and regulate the expression of various genes during lymphocyte especially T cell development, so SATB1 is thought to be correlated to the development of ALL [18–22, 28, 31, 35–40]. SATB1 regulates many genes involved in HSC lineage decisions and development, but evidence that supports the role of SATB1 in AML remained elusive [41, 42].…”

Section: Discussionmentioning

confidence: 99%

Decreased SATB1 expression promotes AML cell proliferation through NF-κB activation

Luo

et al. 2019

Cancer Cell Int

View full text Add to dashboard Cite

Background Special AT-rich sequence-binding protein 1 (SATB1) is a chromatin-remodeling protein that regulates gene expressions in different types of cancer. Up-regulation of SATB1 is linked with progression of tumors. Our previous study showed that SATB1 expression was decreased in T cell leukemia/lymphoma. The contrary roles of SATB1 in solid organ tumors and hematology malignancy may provide hints to study the function of SATB1. Methods To characterize SATB1 mRNA and protein expression in acute myeloid leukemia (AML), we performed qRT-PCR and Western blot on bone marrow mononuclear cells from 52 newly diagnosed AML patients. Stable HL-60 cell lines with knockdown of SATB1 by shRNAs sequences (HL-60 SATB1-shRNA1 and HL-60 SATB1-shRNA2) were established. Cell proliferation, cell cycle and cell invasiveness were analyzed. Murine model was established using HL-60 SATB1-shRNAs treated nude mice and tumorigenicity was compared to study the role of SATB1 in vivo. Global gene expression profiles were analyzed in HL-60 cells with SATB1 knockdown to investigate the mechanisms underlying the regulation of AML cell growth by SATB1. Results We found that SATB1 expression was significantly decreased in patients with AML compared to normal control, and was increased after complete remission of AML. Knockdown of SATB1 enhanced the proliferation of HL-60 cells and accelerated S phase entry in vitro, and promoted the tumor growth in vivo. Global gene expression profiles were analyzed in HL-60 cells with SATB1 knockdown and the differentially expressed genes were involved in NF-κB, MAPK and PI3 K/Akt signaling pathways. Nuclear NF-κB p65 levels were significantly increased in SATB1 depleted HL-60 cells. Conclusions Decreased SATB1 expression promotes AML cell proliferation through NF-κB activation. SATB1 could be a predictor for better response to treatment in AML.

show abstract

Section: Discussionmentioning

confidence: 99%

Decreased SATB1 expression promotes AML cell proliferation through NF-κB activation

Luo

et al. 2019

Cancer Cell Int

View full text Add to dashboard Cite

show abstract

“…Whether a 129‐derived passenger mutation, a mutation in the ESC clone used for Ackr4 −/− generation or a spontaneous mutation acquired in a subcolony of Ackr4 −/− mice is responsible for the unexplained phenotype remains elusive. For all three scenarios, examples have been reported for other transgenic mice …”

Section: Discussionmentioning

confidence: 79%

B cell hyperactivation in an Ackr4-deficient mouse strain is not caused by lack of ACKR4 expression

Eckert

Werth

Willenzon

et al. 2019

Journal of Leukocyte Biology

View full text Add to dashboard Cite

The majority of genetically modified C57BL/6 mice contain congenic passenger DNA around the targeted gene locus as they were generated from 129‐derived embryonic stem cells (ESCs) with subsequent backcrossing to the C57BL/6 genetic background. When studying the role of atypical chemokine receptor 4 (ACKR4) in the immune system, we realized that the two available Ackr4‐deficient mouse strains (Ackr4−/− and Ackr4GFP/GFP) show profoundly different phenotypes: Compared to wild‐type and Ackr4GFP/GFP mice, Ackr4−/− mice show a strong accumulation of plasma blasts in mesenteric lymph node and spleen as well as increased B cell proliferation after in vitro activation. This phenotype was maintained after further backcrossing to C57BL/6 mice and was even present in heterozygous Ackr4+/− animals, suggesting that a gene variant on the targeted chromosome might cause this phenotype. Exome sequencing revealed that a region of approximately 20 Mbp around the Ackr4 locus on chromosome 9 still originates from the 129 background based on high variant density observed. In activated Ackr4−/− and Ackr4GFP/GFP B cells, transcripts of genes around the Ackr4 locus were equally deregulated compared to C57BL/6 B cells, whereas increased expression of IL‐6 was selectively observed in B cells of Ackr4−/− mice. Because the gene encoding for IL‐6 is placed on chromosome 5 these findings suggest that passenger DNA around the Ackr4 locus has an indirect effect on B cell activation and IL‐6 production. Results of the present study should not only lead to the reinterpretation of data from earlier studies using Ackr4−/− mice but should remind the scientific community about the limitations of mouse models using mice created by gene‐targeting of nonsyngeneic ESCs.

show abstract

“…We detected a larger amount of distal genes ( n = 319) compared with local genes ( n = 35), including 148 distal genes exclusively regulated by distal functional SNPs ( Figure 5A and Supplemental Table 7 ). These exclusive distal genes included many known immunologic genes, such as CD37 ( 45 ), CD28 ( 46 ), IL7 ( 47 ), IL12RB1 ( 48 ), or IL2RA ( 49 ). Previous functional assays have demonstrated that some distal immune-relevant genes could be regulated by distal enhancers in immune cell types, such as IL2RA ( 50 ), CD58 ( 51 ), IRF1 ( 52 ), or IRF5 ( 20 ), indicating the important roles of long-range regulation on autoimmune diseases.…”

Section: Resultsmentioning

confidence: 99%

Multiomics dissection of molecular regulatory mechanisms underlying autoimmune-associated noncoding SNPs

Chen¹,

Guo²,

Duan³

et al. 2020

JCI Insight

View full text Add to dashboard Cite

More than 90% of autoimmune-associated variants are located in noncoding regions, leading to challenges in deciphering the underlying causal roles of functional variants and genes and biological mechanisms. Therefore, to reduce the gap between traditional genetic findings and mechanistic understanding of disease etiologies and clinical drug development, it is important to translate systematically the regulatory mechanisms underlying noncoding variants. Here, we prioritized functional noncoding SNPs with regulatory gene targets associated with 19 autoimmune diseases by incorporating hundreds of immune cell–specific multiomics data. The prioritized SNPs are associated with transcription factor (TF) binding, histone modification, or chromatin accessibility, indicating their allele-specific regulatory roles. Their target genes are significantly enriched in immunologically related pathways and other known immunologically related functions. We found that 90.1% of target genes are regulated by distal SNPs involving several TFs (e.g., the DNA-binding protein CCCTC-binding factor [CTCF]), suggesting the importance of long-range chromatin interaction in autoimmune diseases. Moreover, we predicted potential drug targets for autoimmune diseases, including 2 genes ( NFKB1 and SH2B3 ) with known drug indications on other diseases, highlighting their potential drug repurposing opportunities. Taken together, these findings may provide useful information for future experimental follow-up and drug applications on autoimmune diseases.

show abstract

Interleukin 2 modulates thymic-derived regulatory T cell epigenetic landscape

Cited by 29 publications

References 62 publications

Decreased SATB1 expression promotes AML cell proliferation through NF-κB activation

Decreased SATB1 expression promotes AML cell proliferation through NF-κB activation

B cell hyperactivation in an Ackr4-deficient mouse strain is not caused by lack of ACKR4 expression

Multiomics dissection of molecular regulatory mechanisms underlying autoimmune-associated noncoding SNPs

Contact Info

Product

Resources

About