Restraint of IFN-γ expression through a distal silencer CNS–28 for tissue homeostasis

Cui, Kairong; Chen, Zuojia; Yun, Cao; Liu, Shuai; Ren, Gang; Hu, Gangqing; Fang, Difeng; Wei, Danping; Liu, Chengyu; Zhu, Jinfang; Wu, Chuan; Zhao, Keji

doi:10.1016/j.immuni.2023.03.006

Cited by 11 publications

(5 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, in Kmt2d KO models lymphopeniadriven memory skewing could occur due to their severely reduced overall T-cell counts. A preliminary study described Kmt2d KO in CD8 + T-cells impacts survival (12), whereas another shows Kmt2d KO suppresses IFNg (11); however, both of these studies were performed in Kmt2d KO mice, which we now report Kmt2d KO mice are lymphopenic. As lymphopenia can drive homeostatic proliferation, future studies regarding peripheral T-cells in Kmt2d haploinsufficient models would be necessary to understand these shifts removing the confounding influence of lymphopenia.…”

Section: Discussionmentioning

confidence: 70%

“…Kmt2d KO model, which removes exons 16-19 instead of exons 50-51 were assessed at a bulk level (GEO accession: GSE204946 [CD4 + ] and NCBI SRA: PRJNA541991 [CD8 + ]) and then more in depth at a sc level (GEO accession: GSE217656) for relative expression changes before and after stimulation (11,12). When examined, the presented T-cell figures within the source articles for the Kmt2d -exon16-19fl/fl KO aligned with our own Kmt2d -SET-fl/fl KO peripheral The following mouse lines are displayed as splenic cells (or as listed: thymocytes or peripheral blood [E]) from individual mice (n = 3-30; from two or more independent experiments) on the graphs: Kmt2d +/bgeo ( +/+ black diamonds/ +/bgeo gray diamonds), Lck-Cre Mar ; Kmt2d -SET-fl/fl (Creblue circles/ Cre + yellow squares), CD4-Cre; Kmt2d -SET-fl/fl (Creblack up-right triangles/Cre + red inverted triangles), and peripheral blood Vav1-iCre; Kmt2d -SETfl/fl (Creblack stars/Cre + green asterisks).…”

Section: Integrin Expression In Peripheral T-cells Is Required For Lo...mentioning

confidence: 99%

“…Kmt2d -SET-fl/fl (also known as Mll4 -SET-fl/fl mice), a kind gift from Dr. Kai Ge (NIH) that have been previously described (20,21), were crossed with Cre recombinase (Cre) under various promoters. This mouse strain is not the same as the publicly available Kmt2d tm1.1Kaig/J (also known as Mll4 fl/fl ) mouse from Jackson Laboratories (Strain #032152), which we refer to in this document (referencing some prior Kmt2d literature (11)(12)(13) and scRNA analyses [GSE217656] as Kmt2d -exon16-19-fl/fl to differentiate it from Kmt2d -SET-fl/fl . Briefly, Kmt2d -SET-fl/fl mice harbor LoxP sites around Kmt2d exons 50 and 51 and disrupt the SET domain through a frameshift causing a stop codon at exon 52 upon exposure to Cre, which leads to a truncated protein (276 amino acid truncation at the carboxyterminal end).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

KMT2D regulates activation, localization, and integrin expression by T-cells

Potter,

Zhang,

Kotliar

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

Individuals with Kabuki syndrome present with immunodeficiency; however, how pathogenic variants in the gene encoding the histone-modifying enzyme lysine methyltransferase 2D (KMT2D) lead to immune alterations remain poorly understood. Following up on our prior report of KMT2D-altered integrin expression in B-cells, we performed targeted analyses of KMT2D’s influence on integrin expression in T-cells throughout development (thymocytes through peripheral T-cells) in murine cells with constitutive- and conditional-targeted Kmt2d deletion. Using high-throughput RNA-sequencing and flow cytometry, we reveal decreased expression (both at the transcriptional and translational levels) of a cluster of leukocyte-specific integrins, which perturb aspects of T-cell activation, maturation, adhesion/localization, and effector function. H3K4me3 ChIP-PCR suggests that these evolutionary similar integrins are under direct control of KMT2D. KMT2D loss also alters multiple downstream programming/signaling pathways, including integrin-based localization, which can influence T-cell populations. We further demonstrated that KMT2D deficiency is associated with the accumulation of murine CD8+ single-positive (SP) thymocytes and shifts in both human and murine peripheral T-cell populations, including the reduction of the CD4+ recent thymic emigrant (RTE) population. Together, these data show that the targeted loss of Kmt2d in the T-cell lineage recapitulates several distinct features of Kabuki syndrome-associated immune deficiency and implicates epigenetic mechanisms in the regulation of integrin signaling.

show abstract

Section: Discussionmentioning

confidence: 70%

Section: Integrin Expression In Peripheral T-cells Is Required For Lo...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

KMT2D regulates activation, localization, and integrin expression by T-cells

Potter,

Zhang,

Kotliar

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…For all analyses, we utilized the mouse reference genome mm10 and annotations from GENCODE (M21) 68 . The RNA-seq data and ChIP–seq data generated in this study were pre-processed from raw reads to expression level, differentially expressed genes analysis, mapped reads or tracks (bigWig files) following the procedures outlined in our previous studies 69 , 70 .…”

Section: Methodsmentioning

confidence: 99%

Three-dimensional chromatin reorganization regulates B cell development during ageing

Ma,

Cao,

et al. 2024

Nat Cell Biol

Self Cite

View full text Add to dashboard Cite

The contribution of three-dimensional genome organization to physiological ageing is not well known. Here we show that large-scale chromatin reorganization distinguishes young and old bone marrow progenitor (pro-) B cells. These changes result in increased interactions at the compartment level and reduced interactions within topologically associated domains (TADs). The gene encoding Ebf1, a key B cell regulator, switches from compartment A to B with age. Genetically reducing Ebf1 recapitulates some features of old pro-B cells. TADs that are most reduced with age contain genes important for B cell development, including the immunoglobulin heavy chain (Igh) locus. Weaker intra-TAD interactions at Igh correlate with altered variable (V), diversity (D) and joining (J) gene recombination. Our observations implicate three-dimensional chromatin reorganization as a major driver of pro-B cell phenotypes that impair B lymphopoiesis with age.

show abstract

“…Notably, GAS is present in the promoter IRF1 ( 20 , 21 ), STAT1, IFNGR, and IFN-γ ( 22 ), imposing positive feedback and self-sustained inflammation ( 3 , 19 ). The most recent report identified the interaction between GATA3 and CNS-28 silencer as a restrainer of IFN-y mRNA transcription by diminishing enhancer-promoter interactions within the gene locus ( 23 ).…”

Section: Ifn-γ In Tumormentioning

confidence: 99%

Dysregulation in IFN-γ signaling and response: the barricade to tumor immunotherapy

Han

Liu

2023

Front. Immunol.

View full text Add to dashboard Cite

Interferon-gamma (IFN-γ) has been identified as a crucial factor in determining the responsiveness to immunotherapy. Produced primarily by natural killer (NK) and T cells, IFN-γ promotes activation, maturation, proliferation, cytokine expression, and effector function in immune cells, while simultaneously inducing antigen presentation, growth arrest, and apoptosis in tumor cells. However, tumor cells can hijack the IFN-γ signaling pathway to mount IFN-γ resistance: rather than increasing antigenicity and succumbing to death, tumor cells acquire stemness characteristics and express immunosuppressive molecules to defend against antitumor immunity. In this review, we summarize the potential mechanisms of IFN-γ resistance occurring at two critical stages: disrupted signal transduction along the IFNG/IFNGR/JAK/STAT pathway, or preferential expression of specific interferon-stimulated genes (ISGs). Elucidating the molecular mechanisms through which tumor cells develop IFN-γ resistance help identify promising therapeutic targets to improve immunotherapy, with broad application value in conjugation with targeted, antibody or cellular therapies.

show abstract

Restraint of IFN-γ expression through a distal silencer CNS–28 for tissue homeostasis

Cited by 11 publications

References 76 publications

KMT2D regulates activation, localization, and integrin expression by T-cells

KMT2D regulates activation, localization, and integrin expression by T-cells

Three-dimensional chromatin reorganization regulates B cell development during ageing

Dysregulation in IFN-γ signaling and response: the barricade to tumor immunotherapy

Contact Info

Product

Resources

About