An Epigenetic Switch Between Differentiation and Proliferation in Hepatoblastoma

Transforming growth factor-β signaling (TGF-β) maintains a balanced physiological function including cell growth, differentiation, and proliferation and regulation of immune system by modulating either SMAD2/3 and SMAD7 (SMAD-dependent) or SMAD-independent signaling pathways under normal conditions. Increased production of TGF-β promotes immunosuppression in Human Immunodeficiency Virus (HIV)/Simian Immunodeficiency Virus (SIV) infection. However, the cellular source and downstream events of increased TGF-β production that attributes to its pathological manifestations remain unknown. Here, we have shown increased production of TGF-β in a majority of intestinal CD3−CD20−CD68+ cells from acute and chronically SIV infected rhesus macaques, which negatively correlated with the frequency of jejunum CD4+ T cells. No significant changes in intestinal TGF-β receptor II expression were observed but increased production of the pSMAD2/3 protein and SMAD3 gene expression in jejunum tissues that were accompanied by a downregulation of SMAD7 protein and gene expression. Enhanced TGF-β production by intestinal CD3−CD20−CD68+ cells and increased TGF-β/SMAD-dependent signaling might be due to a disruption of a negative feedback loop mediated by SMAD7. This suggests that SIV infection impacts the SMAD-dependent signaling pathway of TGF-β and provides a potential framework for further study to understand the role of viral factor(s) in modulating TGF-β production and downregulating SMAD7 expression in SIV. Regulation of mucosal TGF-β expression by therapeutic TGF-β blockers may help to create effective antiviral mucosal immune responses.

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Genetic Studies of mei-P26 Reveal a Link Between the Processes That Control Germ Cell Proliferation in Both Sexes and Those That Control Meiotic Exchange in Drosophila

Genetics ◽

10.1093/genetics/155.4.1757 ◽

2000 ◽

Vol 155 (4) ◽

pp. 1757-1772 ◽

Cited By ~ 7

Author(s):

Scott L Page ◽

Kim S McKim ◽

Benjamin Deneen ◽

Tajia L Van Hook ◽

R Scott Hawley

Keyword(s):

Meiotic Recombination ◽

Double Mutant ◽

P Element ◽

Genetic Studies ◽

Germline Differentiation ◽

Males And Females ◽

Bag Of Marbles ◽

Differentiation And Proliferation

Abstract We present the cloning and characterization of mei-P26, a novel P-element-induced exchange-defective female meiotic mutant in Drosophila melanogaster. Meiotic exchange in females homozygous for mei-P261 is reduced in a polar fashion, such that distal chromosomal regions are the most severely affected. Additional alleles generated by duplication of the P element reveal that mei-P26 is also necessary for germline differentiation in both females and males. To further assess the role of mei-P26 in germline differentiation, we tested double mutant combinations of mei-P26 and bag-of-marbles (bam), a gene necessary for the control of germline differentiation and proliferation in both sexes. A null mutation at the bam locus was found to act as a dominant enhancer of mei-P26 in both males and females. Interestingly, meiotic exchange in mei-P261; bamΔ86/+ females is also severely decreased in comparison to mei-P261 homozygotes, indicating that bam affects the meiotic phenotype as well. These data suggest that the pathways controlling germline differentiation and meiotic exchange are related and that factors involved in the mitotic divisions of the germline may regulate meiotic recombination.

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KDM6A Lysine Demethylase Directs Epigenetic Polarity of MDSCs during Murine Sepsis

Journal of Innate Immunity ◽

10.1159/000517407 ◽

2021 ◽

pp. 1-12

Author(s):

Isatou Bah ◽

Tuqa Alkhateeb ◽

Dima Youssef ◽

Zhi Q. Yao ◽

Charles E. McCall ◽

...

Keyword(s):

Suppressor Cells ◽

Transcription Activation ◽

Myeloid Derived Suppressor Cells ◽

Molecular Processes ◽

Epigenetic Switch ◽

Translation Research ◽

Non Coding Rna ◽

Genetic Deletion ◽

Lysine Demethylase ◽

Long Non Coding Rna

Sepsis-induced myeloid-derived suppressor cells (MDSCs) increase mortality risk. We previously identified that long non-coding RNA Hotairm1 supports myeloid precursor shifts to Gr1<sup>+</sup>CD11b<sup>+</sup> MDSCs during mouse sepsis. A major unanswered question is what molecular processes control Hotairm1 expression. In this study, we found by a genetic deletion that a specific PU.1-binding site is indispensable in controlling Hotairm1 transcription. We then identified H3K4me3 and H3K27me3 at the PU.1 site on the Hotairm1 promoter. Controlling an epigenetic switch of Hotairm1 transcription by PU.1 was histone KDM6A demethylase for H3K27me3 that derepressed its transcription with possible contributions from Ezh2 methyltransferase for H3K27me3. KDM6A knockdown in MDSCs increased H3K27me3, decreased H3K4me3, and inhibited Hotairm1 transcription activation by PU.1. These results enlighten clinical translation research of PU.1 epigenetic regulation as a potential sepsis immune-checkpoint treatment site.

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The Role of Cadherin, β-Catenin, and AP-1 in Retinoid-regulated Carcinoma Cell Differentiation and Proliferation

Journal of Biological Chemistry ◽

10.1074/jbc.m203158200 ◽

2002 ◽

Vol 277 (28) ◽

pp. 25313-25322 ◽

Cited By ~ 38

Author(s):

Salimuddin Shah ◽

Michael J. Pishvaian ◽

Vijayasurian Easwaran ◽

Powell H. Brown ◽

Stephen W. Byers

Keyword(s):

Cell Differentiation ◽

Carcinoma Cell ◽

Differentiation And Proliferation

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RNA viruses and the mitogenic Raf/MEK/ERK signal transduction cascade

Biological Chemistry ◽

10.1515/bc.2008.145 ◽

2008 ◽

Vol 389 (10) ◽

Cited By ~ 64

Author(s):

Stephan Pleschka

Keyword(s):

Signal Transduction ◽

Rna Viruses ◽

Rna Virus ◽

Cell Metabolism ◽

Mitogen Activated Protein Kinase ◽

Erk Signaling ◽

Control Center ◽

Signal Transduction Cascade ◽

Host Interaction ◽

Differentiation And Proliferation

AbstractThe Raf/MEK/ERK signal transduction cascade belongs to the mitogen-activated protein kinase (MAPK) cascades. Raf/MEK/ERK signaling leads to stimulus-specific changes in gene expression, alterations in cell metabolism or induction of programmed cell death (apoptosis), and thus controls cell differentiation and proliferation. It is induced by extracellular agents, including pathogens such as RNA viruses. Many DNA viruses are known to induce cellular signaling via this pathway. As these pathogens partly use the DNA synthesis machinery for their replication, they aim to drive cells into a proliferative state. In contrast, the consequences of RNA virus-induced Raf/MEK/ERK signaling were less clear for a long time, but since the turn of the century the number of publications on this topic has rapidly increased. Research on this virus/host-interaction will broaden our understanding of its relevance in viral replication. This important control center of cellular responses is differently employed to support the replication of several important human pathogenic RNA viruses including influenza, Ebola, hepatitis C and SARS corona viruses.

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