scholarly journals Endogenous retroviruses drive KRAB zinc-finger protein family expression for tumor suppression

2020 ◽  
Vol 6 (43) ◽  
pp. eabc3020 ◽  
Author(s):  
Jumpei Ito ◽  
Izumi Kimura ◽  
Andrew Soper ◽  
Alexandre Coudray ◽  
Yoshio Koyanagi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Zinc Finger ◽  
Tumor Suppression ◽  
Zinc Finger Protein ◽  
Global Gene Expression ◽  
Endogenous Retroviruses ◽  
Cellular Growth ◽  
Migration And Invasion ◽  
Cell Matrix ◽  
Expression Of Genes

Gene expression aberration is a hallmark of cancers, but the mechanisms underlying such aberrations remain unclear. Human endogenous retroviruses (HERVs) are genomic repetitive elements that potentially function as enhancers. Since numerous HERVs are epigenetically activated in tumors, their activation could cause global gene expression aberrations in tumors. Here, we show that HERV activation in tumors leads to the up-regulation of hundreds of transcriptional suppressors, namely, Krüppel-associated box domain–containing zinc-finger family proteins (KZFPs). KZFP genes are preferentially encoded nearby the activated HERVs in tumors and transcriptionally regulated by these adjacent HERVs. Increased HERV and KZFP expression in tumors was associated with better disease conditions. Increased KZFP expression in cancer cells altered the expression of genes related to the cell cycle and cell-matrix adhesion and suppressed cellular growth, migration, and invasion abilities. Our data suggest that HERV activation in tumors drives the synchronized elevation of KZFP expression, presumably leading to tumor suppression.

scholarly journals Endogenous retroviruses drive KRAB zinc-finger family protein expression for tumor suppression

2020 ◽  
Author(s):  
Jumpei Ito ◽  
Izumi Kimura ◽  
Andrew Soper ◽  
Alexandre Coudray ◽  
Yoshio Koyanagi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Zinc Finger ◽  
Tumor Suppression ◽  
Endogenous Retroviruses ◽  
Tumor Characteristics ◽  
Human Endogenous Retroviruses ◽  
Cell Matrix ◽  
Family Protein ◽  
Cell Matrix Adhesion

AbstractNumerous genes are aberrantly expressed in tumors, but its cause remains unclear. Human endogenous retroviruses (HERVs) are repetitive elements in the genome and have a potential to work as enhancers modulating adjacent genes. Since numerous HERVs are activated epigenetically in tumors, their activation could alter gene expression globally in tumors and change the tumor characteristics. Here, we show the HERV activation in tumors is associated with the upregulation of hundreds of transcriptional suppressors, Krüppel-associated box domain-containing zinc-finger family proteins (KZFPs). KZFP genes are preferentially encoded nearby the activated HERVs in tumors and transcriptionally regulated by the adjacent HERVs. Increased HERV and KZFP expression in tumors was associated with better disease conditions. Many KZFPs could suppress the progressive characteristics of cancer cells by downregulating genes related to the cell cycle and cell-matrix adhesion. Our data suggest that HERV activation in tumors drives the concerted expression of KZFP genes for tumor suppression.

scholarly journals Ectopic targeting of CG DNA methylation in Arabidopsis with the bacterial SssI methyltransferase

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wanlu Liu ◽  
Javier Gallego-Bartolomé ◽  
Yuxing Zhou ◽  
Zhenhui Zhong ◽  
Ming Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Basic Research ◽  
Crop Plant ◽  
Open Chromatin ◽  
Histone Marks ◽  
It Impacts ◽  
Finger Protein

AbstractThe ability to target epigenetic marks like DNA methylation to specific loci is important in both basic research and in crop plant engineering. However, heritability of targeted DNA methylation, how it impacts gene expression, and which epigenetic features are required for proper establishment are mostly unknown. Here, we show that targeting the CG-specific methyltransferase M.SssI with an artificial zinc finger protein can establish heritable CG methylation and silencing of a targeted locus in Arabidopsis. In addition, we observe highly heritable widespread ectopic CG methylation mainly over euchromatic regions. This hypermethylation shows little effect on transcription while it triggers a mild but significant reduction in the accumulation of H2A.Z and H3K27me3. Moreover, ectopic methylation occurs preferentially at less open chromatin that lacks positive histone marks. These results outline general principles of the heritability and interaction of CG methylation with other epigenomic features that should help guide future efforts to engineer epigenomes.

ming is expressed in neuroblast sublineages and regulates gene expression in the Drosophila central nervous system

Development ◽  
1992 ◽  
Vol 116 (4) ◽  
pp. 943-952 ◽  
Author(s):  
X. Cui ◽  
C.Q. Doe
Keyword(s):  
Gene Expression ◽  
Central Nervous System ◽  
Nervous System ◽  
Cell Fate ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Cell Lineage ◽  
Cell Lineages ◽  
Finger Protein ◽  
Cell Diversity

Cell diversity in the Drosophila central nervous system (CNS) is primarily generated by the invariant lineage of neural precursors called neuroblasts. We used an enhancer trap screen to identify the ming gene, which is transiently expressed in a subset of neuroblasts at reproducible points in their cell lineage (i.e. in neuroblast ‘sublineages’), suggesting that neuroblast identity can be altered during its cell lineage. ming encodes a predicted zinc finger protein and loss of ming function results in precise alterations in CNS gene expression, defects in axonogenesis and embryonic lethality. We propose that ming controls cell fate within neuroblast cell lineages.

scholarly journals Global impacts of chromosomal imbalance on gene expression in Arabidopsis and other taxa

2018 ◽  
Vol 115 (48) ◽  
pp. E11321-E11330 ◽  
Author(s):  
Jie Hou ◽  
Xiaowen Shi ◽  
Chen Chen ◽  
Md. Soliman Islam ◽  
Adam F. Johnson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Transcription Factors ◽  
Leaf Tissue ◽  
Global Gene Expression ◽  
Published Data ◽  
Chromosomal Imbalance ◽  
Regulatory Processes ◽  
Expression Of Genes ◽  
Global Impacts

Changes in dosage of part of the genome (aneuploidy) have long been known to produce much more severe phenotypic consequences than changes in the number of whole genomes (ploidy). To examine the basis of these differences, global gene expression in mature leaf tissue for all five trisomies and in diploids, triploids, and tetraploids of Arabidopsis thaliana was studied. The trisomies displayed a greater spread of expression modulation than the ploidy series. In general, expression of genes on the varied chromosome ranged from compensation to dosage effect, whereas genes from the remainder of the genome ranged from no effect to reduced expression approaching the inverse level of chromosomal imbalance (2/3). Genome-wide DNA methylation was examined in each genotype and found to shift most prominently with trisomy 4 but otherwise exhibited little change, indicating that genetic imbalance is generally mechanistically unrelated to DNA methylation. Independent analysis of gene functional classes demonstrated that ribosomal, proteasomal, and gene body methylated genes were less modulated compared with all classes of genes, whereas transcription factors, signal transduction components, and organelle-targeted protein genes were more tightly inversely affected. Comparing transcription factors and their targets in the trisomies and in expression networks revealed considerable discordance, illustrating that altered regulatory stoichiometry is a major contributor to genetic imbalance. Reanalysis of published data on gene expression in disomic yeast and trisomic mouse cells detected similar stoichiometric effects across broad phylogenetic taxa, and indicated that these effects reflect normal gene regulatory processes.

scholarly journals The Cardiac Tissue-Restricted Homeobox Protein Csx/Nkx2.5 Physically Associates with the Zinc Finger Protein GATA4 and Cooperatively Activates Atrial Natriuretic Factor Gene Expression

1998 ◽  
Vol 18 (6) ◽  
pp. 3120-3129 ◽  
Author(s):  
Youngsook Lee ◽  
Tetsuo Shioi ◽  
Hideko Kasahara ◽  
Shawn M. Jobe ◽  
Russell J. Wiese ◽  
...  
Keyword(s):  
Gene Expression ◽  
Zinc Finger ◽  
Protein Interaction ◽  
Binding Sites ◽  
Atrial Natriuretic Factor ◽  
Target Gene ◽  
Cardiac Tissue ◽  
Zinc Finger Protein ◽  
Finger Protein ◽  
Homeobox Protein

ABSTRACT Specification and differentiation of the cardiac muscle lineage appear to require a combinatorial network of many factors. The cardiac muscle-restricted homeobox protein Csx/Nkx2.5 (Csx) is expressed in the precardiac mesoderm as well as the embryonic and adult heart. Targeted disruption of Csx causes embryonic lethality due to abnormal heart morphogenesis. The zinc finger transcription factor GATA4 is also expressed in the heart and has been shown to be essential for heart tube formation. GATA4 is known to activate many cardiac tissue-restricted genes. In this study, we tested whether Csx and GATA4 physically associate and cooperatively activate transcription of a target gene. Coimmunoprecipitation experiments demonstrate that Csx and GATA4 associate intracellularly. Interestingly, in vitro protein-protein interaction studies indicate that helix III of the homeodomain of Csx is required to interact with GATA4 and that the carboxy-terminal zinc finger of GATA4 is necessary to associate with Csx. Both regions are known to directly contact the cognate DNA sequences. The promoter-enhancer region of the atrial natriuretic factor (ANF) contains several putative Csx binding sites and consensus GATA4 binding sites. Transient-transfection assays indicate that Csx can activate ANF reporter gene expression to the same extent that GATA4 does in a DNA binding site-dependent manner. Coexpression of Csx and GATA4 synergistically activates ANF reporter gene expression. Mutational analyses suggest that this synergy requires both factors to fully retain their transcriptional activities, including the cofactor binding activity. These results demonstrate the first example of homeoprotein and zinc finger protein interaction in vertebrates to cooperatively regulate target gene expression. Such synergistic interaction among tissue-restricted transcription factors may be an important mechanism to reinforce tissue-specific developmental pathways.

scholarly journals Global transcriptome analysis of rat hypothalamic arcuate nucleus demonstrates reversal of hypothalamic gliosis following surgically and diet induced weight loss

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Pernille Barkholt ◽  
Kristoffer T. G. Rigbolt ◽  
Mechthilde Falkenhahn ◽  
Thomas Hübschle ◽  
Uwe Schwahn ◽  
...  
Keyword(s):  
Gene Expression ◽  
Weight Loss ◽  
Molecular Mechanisms ◽  
Arcuate Nucleus ◽  
Gene Expression Signature ◽  
Global Gene Expression ◽  
Metabolic Effects ◽  
Expression Of Genes ◽  
Hypothalamic Arcuate Nucleus ◽  
Laser Capture

Abstract The central mechanisms underlying the marked beneficial metabolic effects of bariatric surgery are unclear. Here, we characterized global gene expression in the hypothalamic arcuate nucleus (Arc) in diet-induced obese (DIO) rats following Roux-en-Y gastric bypass (RYGB). 60 days post-RYGB, the Arc was isolated by laser-capture microdissection and global gene expression was assessed by RNA sequencing. RYGB lowered body weight and adiposity as compared to sham-operated DIO rats. Discrete transcriptome changes were observed in the Arc following RYGB, including differential expression of genes associated with inflammation and neuropeptide signaling. RYGB reduced gene expression of glial cell markers, including Gfap, Aif1 and Timp1, confirmed by a lower number of GFAP immunopositive astrocyte profiles in the Arc. Sham-operated weight-matched rats demonstrated a similar glial gene expression signature, suggesting that RYGB and dietary restriction have common effects on hypothalamic gliosis. Considering that RYGB surgery also led to increased orexigenic and decreased anorexigenic gene expression, this may signify increased hunger-associated signaling at the level of the Arc. Hence, induction of counterregulatory molecular mechanisms downstream from the Arc may play an important role in RYGB-induced weight loss.

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