Tet Proteins Regulate Neutrophil Granulation in Zebrafish through Demethylation of socs3b mRNA

Banks, Kelly M.; Lan, Yahui; Evans, Todd

doi:10.1016/j.celrep.2020.108632

Cited by 16 publications

(8 citation statements)

References 57 publications

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“…Indeed, by examining the causal genes for immunodeficiency that were upregulated in myeloid phagocytes, we found TET2 and WAS upregulated in bone marrow, and ATP6AP1 and NCKAP1L upregulated in spleen. Intriguingly, all four disease genes are known to participate in signaling pathways associated with myeloid-phagocytes–mediated immunity (Banks et al, 2021; Brunetti et al, 2022; Stahnke et al, 2021; Suwankitwat et al, 2021; Yang et al, 2020). These findings suggest that disease genes that are upregulated in the receptor-bearing cell type might be involved in a downstream signaling pathway.…”

Section: Resultsmentioning

confidence: 99%

“…For instance, owing to upregulation of IFNGR1 gene, which encodes an immunodeficiency-associated receptor, we found myeloid phagocytes as affected by this disease. Then, we found three additional disease genes that were upregulated in myeloid phagocytes and were all associated with myeloid-phagocytes–mediated immune response (Banks et al, 2021; Cabral-Marques et al, 2017; Ellis & Beaman, 2004; Eshleman et al, 2020; Stahnke et al, 2021; Suwankitwat et al, 2021; Yang et al, 2020). Thus, exploring disease genes in appropriate cellular context can enhance the mechanistic understanding of disease emergence.…”

Section: Discussionmentioning

confidence: 96%

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Affected cell types for hundreds of Mendelian diseases revealed by analysis of human and mouse single-cell data

Hekselman

Vital

Ziv-Agam

et al. 2022

Preprint

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Hereditary diseases manifest clinically in certain tissues, however their affected cell types typically remain elusive. Single-cell expression studies showed that overexpression of disease-associated genes may point to the affected cell types. Here, we developed a method that infers disease-affected cell types from the preferential expression of disease-associated genes in cell types (PrEDiCT). We applied PrEDiCT to single-cell expression data of six human tissues, to infer the cell types affected in 1,113 hereditary diseases. Overall, we identified 110 cell types affected by 714 diseases. We corroborated our findings by literature text-mining and recapitulation in mouse corresponding tissues. Based on these findings, we explored features of disease-affected cell types and cell classes, highlighted cell types affected by mitochondrial diseases and heritable cancers, and identified diseases that perturb intercellular communication. This study expands our understanding of disease mechanisms and cellular vulnerability.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

Affected cell types for hundreds of Mendelian diseases revealed by analysis of human and mouse single-cell data

Hekselman

Vital

Ziv-Agam

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…This is consistent with the neutrophilia observed in Socs3 knockout mice, which included infiltration into multiple organs ( 4 ). Moreover, elevated socs3b mRNA levels observed in zebrafish Tet mutants correlated with defective neutrophil maturation ( 60 ) identifying Socs3b as a crucial regulator of neutrophil production. Signaling by G-CSFR plays a key role in this process ( 33 ), with Socs3 knockout mice being hypersensitive to G-CSF stimulation ( 4 , 13 ), suggesting unrestrained G-CSFR signaling as the underlying cause of the neutrophilia in these animals.…”

Section: Discussionmentioning

confidence: 99%

Socs3b regulates the development and function of innate immune cells in zebrafish

Sobah

Scott²,

Laird³

et al. 2023

Front. Immunol.

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IntroductionSuppressor of cytokine signaling 3 (SOCS3) is a critical component of the negative feedback regulation that controls signaling by cytokines and other factors thereby ensuring that important processes such as hematopoiesis and inflammation occur at appropriate levels.MethodsTo gain further insights into SOCS3 function, the zebrafish socs3b gene was investigated through analysis of a knockout line generated using CRISPR/Cas9-mediated genome editing.ResultsZebrafish socs3b knockout embryos displayed elevated numbers of neutrophils during primitive and definitive hematopoiesis but macrophage numbers were not altered. However, the absence of socs3b reduced neutrophil functionality but enhanced macrophage responses. Adult socs3b knockout zebrafish displayed reduced survival that correlated with an eye pathology involving extensive infiltration of neutrophils and macrophages along with immune cell dysregulation in other tissues.DiscussionThese findings identify a conserved role for Socs3b in the regulation of neutrophil production and macrophage activation.

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“…Naturally, it does not mean that TET2 cannot catalyse demethylation in this process. It may also function by affecting the methylation of mRNA [50] or other cis-acting elements like enhancer [35].…”

Section: Discussionmentioning

confidence: 99%

A novel epigenetic marker, TET2, is identified in the intractable epileptic brain and regulates ABCB1 in the blood-brain barrier

Kong

Lang

Zhang

et al. 2021

Preprint

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BackgroundDrug-resistant epilepsy (DRE) is a chronic condition derived from spontaneous changes and regulatory effects in the epileptic brain. DNA methylation, an inheritable but reversible epigenetic change, may participate in this complicated regulatory network. As demethylation factors, ten-eleven translocation (TET) family members have become a focus in recent studies of neurological disorders. Thus, we aimed to unravel their role in DRE and their function related to the possible refractory factor ABCB1 in a blood-brain barrier (BBB) model.MethodsWe quantified and localized TET1, TET2 and 5-hydroxymethylcytosine (5-hmC) in the temporal lobe cortex of DRE patients (n = 27) and traumatic brain haemorrhage controls (n = 10) by immunochemical staining. TET2 and ABCB1 expression patterns were determined in the temporal cortex and isolated brain capillaries of DRE patients using immunohistological detection and Western blot analysis, respectively. A BBB model constructed with hCMEC/D3 cells was used to verify the demethylation and regulatory effects of TET2 on ABCB1.ResultsTET2 expression was significantly increased in the temporal cortical tissue of DRE patients with or without hippocampal sclerosis (HS) compared to control patients, while TET1 and 5-hmC showed differences in expression. We also discovered that the vascular endothelium of DRE patients has a strong affinity for TET2. ABCB1 and TET2 have identical densities in the DRE temporal cortex, and they both have evidently higher expression in the vascular endothelium from the neocortex of DRE patients. In the BBB, TET2 depletion can cause attenuated expression and function of ABCB1, as well as a pattern of higher methylation in CpG islands of the ABCB1 promoter.ConclusionsThrough a cohort study performed on the temporal cortex and brain vessels of DRE patients, we identified a novel epigenetic marker, TET2. Data from experiments in a BBB model suggest that TET2 has a specific regulatory effect on ABCB1, which may serve as a potential mechanism and target in DRE and requires further research.

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Tet Proteins Regulate Neutrophil Granulation in Zebrafish through Demethylation of socs3b mRNA

Cited by 16 publications

References 57 publications

Affected cell types for hundreds of Mendelian diseases revealed by analysis of human and mouse single-cell data

Affected cell types for hundreds of Mendelian diseases revealed by analysis of human and mouse single-cell data

Socs3b regulates the development and function of innate immune cells in zebrafish

A novel epigenetic marker, TET2, is identified in the intractable epileptic brain and regulates ABCB1 in the blood-brain barrier

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