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Experimental Eye Research Aug 2021Age is a major risk factor for cataract (ARC). However, the influence of aging on the lens transcriptome is under studied. Lens epithelial (LEC) and fiber cells (LFC)...
Age is a major risk factor for cataract (ARC). However, the influence of aging on the lens transcriptome is under studied. Lens epithelial (LEC) and fiber cells (LFC) were isolated from young (3 month old) and aged (24 month old) C57BL/6J mice, and the transcriptome elucidated via RNAseq. EdgeR estimated differential gene expression in pairwise contrasts, and Advaita's Ipathway guide and custom R scripts were used to evaluate the potential biological significance of differentially expressed genes (DEGs). This analysis revealed age-dependent decreases in lens differentiation marker expression in both LECs and LFCs, with gamma crystallin transcripts downregulating nearly 50 fold in aged LFCs. The expression of the transcription factors Hsf4 and Maf, which are known to activate lens fiber cell preferred genes, are downregulated, while FoxE3, which represses gamma crystallin expression, is upregulated in aged fibers. Aged LECs upregulate genes controlling the immune response, complement pathways, and cellular stress responses, including glutathione peroxidase 3 (Gpx3). Aged LFCs exhibit broad changes in the expression of genes regulating cell communication, and upregulate genes involved in antigen processing/presentation and cholesterol metabolism, while changes in the expression of mitochondrial respiratory chain genes are consistent with mitochondrial stress, including upregulation of NDufa4l2, which encodes an alternate electron transport chain protein. However, age did not profoundly affect the response of LECs to injury as both young and aged LECs upregulate inflammatory gene signatures at 24 h post injury to similar extents. These RNAseq profiles provide a rich data set that can be mined to understand the genetic regulation of lens aging and how this impinges on the pathophysiology of age related cataract.
Topics: Aging; Animals; Cataract; Disease Models, Animal; Female; Forkhead Transcription Factors; Gene Expression Regulation; Heat Shock Transcription Factors; Heat-Shock Proteins; Lens, Crystalline; Male; Mice; Mice, Inbred C57BL; Proto-Oncogene Proteins c-maf; RNA; Transcriptome; gamma-Crystallins
PubMed: 34119483
DOI: 10.1016/j.exer.2021.108663 -
Experimental Animals Jan 2020The transcription factor MafB regulates macrophage differentiation. However, studies on the phenotype of Mafb-deficient macrophages are still limited. Recently, it was... (Review)
Review
The transcription factor MafB regulates macrophage differentiation. However, studies on the phenotype of Mafb-deficient macrophages are still limited. Recently, it was shown that the specific expression of MafB permits macrophages to be distinguished from dendritic cells. In addition, MafB has been reported to be involved in various diseases related to macrophages. Studies using macrophage-specific Mafb-deficient mice show that MafB is linked to atherosclerosis, autoimmunity, obesity, and ischemic stroke, all of which exhibit macrophage abnormality. Therefore, MafB is hypothesized to be indispensable for the regulation of macrophages to maintain systemic homeostasis and may serve as an innovative target for treating macrophage-related diseases.
Topics: Atherosclerosis; Autoimmunity; Homeostasis; Macrophages; MafB Transcription Factor; Obesity; Stroke
PubMed: 31582643
DOI: 10.1538/expanim.19-0076 -
Nature Immunology May 2024Intestinal immune responses to microbes are controlled by the cytokine IL-10 to avoid immune pathology. Here, we use single-cell RNA sequencing of colon lamina propria...
Intestinal immune responses to microbes are controlled by the cytokine IL-10 to avoid immune pathology. Here, we use single-cell RNA sequencing of colon lamina propria leukocytes (LPLs) along with RNA-seq and ATAC-seq of purified CD4 T cells to show that the transcription factors Blimp-1 (encoded by Prdm1) and c-Maf co-dominantly regulate Il10 while negatively regulating proinflammatory cytokines in effector T cells. Double-deficient Prdm1MafCd4 mice infected with Helicobacter hepaticus developed severe colitis with an increase in T1/NK/ILC1 effector genes in LPLs, while Prdm1Cd4 and MafCd4 mice exhibited moderate pathology and a less-marked type 1 effector response. LPLs from infected MafCd4 mice had increased type 17 responses with increased Il17a and Il22 expression and an increase in granulocytes and myeloid cell numbers, resulting in increased T cell-myeloid-neutrophil interactions. Genes over-expressed in human inflammatory bowel disease showed differential expression in LPLs from infected mice in the absence of Prdm1 or Maf, revealing potential mechanisms of human disease.
Topics: Animals; Positive Regulatory Domain I-Binding Factor 1; Mice; Proto-Oncogene Proteins c-maf; Colitis; Mice, Knockout; Humans; Helicobacter hepaticus; Helicobacter Infections; Mice, Inbred C57BL; Intestinal Mucosa; Inflammatory Bowel Diseases; Gene Expression Regulation; Disease Models, Animal
PubMed: 38609547
DOI: 10.1038/s41590-024-01814-z -
Nature Communications Apr 2021High myopia is a leading cause of blindness worldwide. Myopia progression may lead to pathological changes of lens and affect the outcome of lens surgery, but the...
High myopia is a leading cause of blindness worldwide. Myopia progression may lead to pathological changes of lens and affect the outcome of lens surgery, but the underlying mechanism remains unclear. Here, we find an increased lens size in highly myopic eyes associated with up-regulation of β/γ-crystallin expressions. Similar findings are replicated in two independent mouse models of high myopia. Mechanistic studies show that the transcription factor MAF plays an essential role in up-regulating β/γ-crystallins in high myopia, by direct activation of the crystallin gene promoters and by activation of TGF-β1-Smad signaling. Our results establish lens morphological and molecular changes as a characteristic feature of high myopia, and point to the dysregulation of the MAF-TGF-β1-crystallin axis as an underlying mechanism, providing an insight for therapeutic interventions.
Topics: Animals; Female; Humans; Lens, Crystalline; Maf Transcription Factors; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myopia, Degenerative; Promoter Regions, Genetic; Smad Proteins; Transforming Growth Factor beta1; Up-Regulation; beta-Crystallins; gamma-Crystallins
PubMed: 33833231
DOI: 10.1038/s41467-021-22041-2 -
Frontiers in Immunology 2020Beyond its well-admitted role in development and organogenesis, it is now clear that the transcription factor c-Maf has owned its place in the realm of immune-related... (Review)
Review
Beyond its well-admitted role in development and organogenesis, it is now clear that the transcription factor c-Maf has owned its place in the realm of immune-related transcription factors. Formerly introduced solely as a Th2 transcription factor, the role attributed to c-Maf has gradually broadened over the years and has extended to most, if not all, known immune cell types. The influence of c-Maf is particularly prominent among T cell subsets, where c-Maf regulates the differentiation as well as the function of multiple subsets of CD4 and CD8 T cells, lending it a crucial position in adaptive immunity and anti-tumoral responsiveness. Recent research has also revealed the role of c-Maf in controlling Th17 responses in the intestine, positioning it as an essential factor in intestinal homeostasis. This review aims to present and discuss the recent advances highlighting the particular role played by c-Maf in T lymphocyte differentiation, function, and homeostasis.
Topics: Cell Differentiation; Humans; Immune Tolerance; Interleukin-10; Intestines; Nuclear Receptor Subfamily 1, Group F, Member 3; Proto-Oncogene Proteins c-maf; T-Lymphocytes
PubMed: 32117317
DOI: 10.3389/fimmu.2020.00206 -
The Journal of Biological Chemistry May 2023MafA and c-Maf are close members of the Maf transcription factor family and indicators of poor prognosis of multiple myeloma (MM). Our previous study finds that the...
MafA and c-Maf are close members of the Maf transcription factor family and indicators of poor prognosis of multiple myeloma (MM). Our previous study finds that the ubiquitin ligase HERC4 induces c-Maf degradation but stabilizes MafA, and the mechanism is elusive. In the present study, we find that HERC4 interacts with MafA and mediates its K63-linked polyubiquitination at K33. Moreover, HERC4 inhibits MafA phosphorylation and its transcriptional activity triggered by glycogen synthase kinase 3β (GSK3β). The K33R MafA variant prevents HERC4 from inhibiting MafA phosphorylation and increases MafA transcriptional activity. Further analyses reveal that MafA can also activate the STAT3 signaling, but it is suppressed by HERC4. Lastly, we demonstrate that lithium chloride, a GSK3β inhibitor, can upregulate HERC4 and synergizes dexamethasone, a typical anti-MM drug, in inhibiting MM cell proliferation and xenograft growth in nude mice. These findings thus highlight a novel regulation of MafA oncogenic activity in MM and provide the rationale by targeting HERC4/GSK3β/MafA for the treatment of MM.
Topics: Animals; Humans; Mice; Cell Proliferation; Dexamethasone; Glycogen Synthase Kinase 3 beta; Lithium Chloride; Maf Transcription Factors, Large; Mice, Nude; Multiple Myeloma; Phosphorylation; Polyubiquitin; STAT3 Transcription Factor; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitination; Xenograft Model Antitumor Assays
PubMed: 37028761
DOI: 10.1016/j.jbc.2023.104675 -
Neurobiology of Aging Mar 2022The genetic locus containing the WWOX and MAF genes was implicated as a clinical Alzheimer's disease (AD) risk locus in two recent large meta-analytic genome wide...
The genetic locus containing the WWOX and MAF genes was implicated as a clinical Alzheimer's disease (AD) risk locus in two recent large meta-analytic genome wide association studies (GWAS). In a prior GWAS, we identified a variant in WWOX as a suggestive risk allele for hippocampal sclerosis. We hypothesized that the WWOX/MAF locus may be preferentially associated with non-plaque- and non-tau-related neuropathological changes (NC). Data from research participants with GWAS and autopsy measures from the National Alzheimer's Coordinating Center and the Religious Orders Study and the Rush Memory and Aging Project were meta-analyzed. Notably, no variants in the locus were significantly associated with ADNC. However, several WWOX/MAF variants had significant adjusted associations with limbic-predominant age-related TDP-43 encephalopathy NC (LATE-NC), HS, and brain arteriolosclerosis. These associations remained largely unchanged after adjustment for ADNC (operationalized with standard semiquantitative staging), suggesting that these associations are independent of ADNC. Thus, WWOX genetic variants were associated pathologically with LATE-NC, not ADNC.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Dementia; Female; Genetic Variation; Genome-Wide Association Study; Humans; Male; Phenotype; Proto-Oncogene Proteins c-maf; TDP-43 Proteinopathies; Tumor Suppressor Proteins; WW Domain-Containing Oxidoreductase
PubMed: 34852950
DOI: 10.1016/j.neurobiolaging.2021.10.011 -
Cell Reports Apr 2023Corticospinal tract (CST) neurons innervate the deep spinal dorsal horn to sustain chronic neuropathic pain. The majority of neurons targeted by the CST are interneurons...
Corticospinal tract (CST) neurons innervate the deep spinal dorsal horn to sustain chronic neuropathic pain. The majority of neurons targeted by the CST are interneurons expressing the transcription factor c-Maf. Here, we used intersectional genetics to decipher the function of these neurons in dorsal horn sensory circuits. We find that excitatory c-Maf (c-Maf) neurons receive sensory input mainly from myelinated fibers and target deep dorsal horn parabrachial projection neurons and superficial dorsal horn neurons, thereby connecting non-nociceptive input to nociceptive output structures. Silencing c-Maf neurons has little effect in healthy mice but alleviates mechanical hypersensitivity in neuropathic mice. c-Maf neurons also receive input from inhibitory c-Maf and parvalbumin neurons, and compromising inhibition by these neurons caused mechanical hypersensitivity and spontaneous aversive behaviors reminiscent of c-Maf neuron activation. Our study identifies c-Maf neurons as normally silent second-order nociceptors that become engaged in pathological pain signaling upon loss of inhibitory control.
Topics: Animals; Mice; Spinal Cord Dorsal Horn; Spinal Cord; Posterior Horn Cells; Neuralgia; Synaptic Transmission; Interneurons; Proto-Oncogene Proteins c-maf
PubMed: 36947543
DOI: 10.1016/j.celrep.2023.112295 -
Biomolecules Mar 2022β-cells are insulin-producing cells in the pancreas that maintain euglycemic conditions. Pancreatic β-cell maturity and function are regulated by a variety of... (Review)
Review
β-cells are insulin-producing cells in the pancreas that maintain euglycemic conditions. Pancreatic β-cell maturity and function are regulated by a variety of transcription factors that enable the adequate expression of the cellular machinery involved in nutrient sensing and commensurate insulin secretion. One of the key factors in this regulation is MAF bZIP transcription factor A (MafA). MafA expression is decreased in type 2 diabetes, contributing to β-cell dysfunction and disease progression. The molecular biology underlying MafA is complex, with numerous transcriptional and post-translational regulatory nodes. Understanding these complexities may uncover potential therapeutic targets to ameliorate β-cell dysfunction. This article will summarize the role of MafA in normal β-cell function and disease, with a special focus on known transcriptional and post-translational regulators of MafA expression.
Topics: Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Maf Transcription Factors, Large
PubMed: 35454124
DOI: 10.3390/biom12040535 -
Biomedical Papers of the Medical... Sep 2019The aim of this paper was to summarise knowledge of IL-22 involvement in multiple sclerosis (MS) and the possible link between IL-22 and two transcription factors - AHR... (Review)
Review
The aim of this paper was to summarise knowledge of IL-22 involvement in multiple sclerosis (MS) and the possible link between IL-22 and two transcription factors - AHR and c-Maf. The conclusion is that despite numerous studies, the exact role of IL-22 in the pathogenesis of MS is still unknown. The expression and function of c-Maf in MS have not been studied. It seems that the functions of c-Maf and AHR are at least partly connected with IL-22, as both directly or indirectly influence the regulation of IL-22 expression. This possible connection has never been studied in MS.
Topics: Adaptor Proteins, Signal Transducing; Basic Helix-Loop-Helix Transcription Factors; Humans; Interleukins; Multiple Sclerosis; Receptors, Aryl Hydrocarbon; Transcription Factors; Interleukin-22
PubMed: 31162488
DOI: 10.5507/bp.2019.024