Role of Histone Methyltransferase G9a in CpG Methylation of the Prader-Willi Syndrome Imprinting Center

AbstractWhile the significance of acquired genetic abnormalities in the initiation of hepatocellular carcinoma (HCC) has been established, the role of epigenetic modification remains unknown. Here we identified the pivotal role of histone methyltransferase G9a in the DNA damage-triggered initiation of HCC. Using liver-specific G9a-deficient (G9aΔHep) mice, we revealed that loss of G9a significantly attenuated liver tumor initiation caused by diethylnitrosamine (DEN). In addition, pharmacological inhibition of G9a attenuated the DEN-induced initiation of HCC. After treatment with DEN, while the induction of γH2AX and p53 were comparable in the G9aΔHep and wild-type livers, more apoptotic hepatocytes were detected in the G9aΔHep liver. Transcriptome analysis identified Bcl-G, a pro-apoptotic Bcl-2 family member, to be markedly upregulated in the G9aΔHep liver. In human cultured hepatoma cells, a G9a inhibitor, UNC0638, upregulated BCL-G expression and enhanced the apoptotic response after treatment with hydrogen peroxide or irradiation, suggesting an essential role of the G9a-Bcl-G axis in DNA damage response in hepatocytes. The proposed mechanism was that DNA damage stimuli recruited G9a to the p53-responsive element of the Bcl-G gene, resulting in the impaired enrichment of p53 to the region and the attenuation of Bcl-G expression. G9a deletion allowed the recruitment of p53 and upregulated Bcl-G expression. These results demonstrate that G9a allows DNA-damaged hepatocytes to escape p53-induced apoptosis by silencing Bcl-G, which may contribute to the tumor initiation. Therefore, G9a inhibition can be a novel preventive strategy for HCC.

Download Full-text

The Role of the Histone Methyltransferase EZH2 in Liver Inflammation and Fibrosis in STAM NASH Mice

Biology ◽

10.3390/biology9050093 ◽

2020 ◽

Vol 9 (5) ◽

pp. 93 ◽

Cited By ~ 1

Author(s):

Seul Lee ◽

Dong-Cheol Woo ◽

Jeeheon Kang ◽

Moonjin Ra ◽

Ki Hyun Kim ◽

...

Keyword(s):

Liver Disease ◽

Epigenetic Modification ◽

Treatment Options ◽

Histone Methyltransferase ◽

Alcoholic Fatty Liver ◽

Alcoholic Steatohepatitis ◽

Promising Therapeutic Target ◽

Alcoholic Fatty Liver Disease ◽

Potential Therapeutics

Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease, with few biomarkers and treatment options currently available. Non-alcoholic steatohepatitis (NASH), a progressive disease of NAFLD, may lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Epigenetic modification can contribute to the progression of NAFLD causing non-alcoholic steatohepatitis (NASH), in which the exact role of epigenetics remains poorly understood. To identify potential therapeutics for NASH, we tested small-molecule inhibitors of the epigenetic target histone methyltransferase EZH2, Tazemetostat (EPZ-6438), and UNC1999 in STAM NASH mice. The results demonstrate that treatment with EZH2 inhibitors decreased serum TNF-alpha in NASH. In this study, we investigated that inhibition of EZH2 reduced mRNA expression of inflammatory cytokines and fibrosis markers in NASH mice. In conclusion, these results suggest that EZH2 may present a promising therapeutic target in the treatment of NASH.

Download Full-text

The role of CpG methylation in cell type-specific expression of the aquaporin-5 gene

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2006.12.126 ◽

2007 ◽

Vol 353 (4) ◽

pp. 1017-1022 ◽

Cited By ~ 17

Author(s):

Johji Nomura ◽

Akinori Hisatsune ◽

Takeshi Miyata ◽

Yoichiro Isohama

Keyword(s):

Cpg Methylation ◽

Cell Type ◽

Aquaporin 5 ◽

Specific Expression ◽

Cell Type Specific Expression ◽

Cell Type Specific

Download Full-text

Critical Role of c-Myc in Acute Myeloid Leukemia Involving Direct Regulation of miR-26a and Histone Methyltransferase EZH2

Genes & Cancer ◽

10.1177/1947601911416357 ◽

2011 ◽

Vol 2 (5) ◽

pp. 585-592 ◽

Cited By ~ 53

Author(s):

B. Salvatori ◽

I. Iosue ◽

N. Djodji Damas ◽

A. Mangiavacchi ◽

S. Chiaretti ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Critical Role ◽

Histone Methyltransferase ◽

Direct Regulation ◽

Acute Myeloid

Download Full-text

An Unexpected Function of the Prader-Willi Syndrome Imprinting Center in Maternal Imprinting in Mice

PLoS ONE ◽

10.1371/journal.pone.0034348 ◽

2012 ◽

Vol 7 (4) ◽

pp. e34348 ◽

Cited By ~ 10

Author(s):

Mei-Yi Wu ◽

Ming Jiang ◽

Xiaodong Zhai ◽

Arthur L. Beaudet ◽

Ray-Chang Wu

Keyword(s):

Prader Willi Syndrome ◽

Imprinting Center ◽

Maternal Imprinting

Download Full-text

Development of a Young Man with Prader-Willi Syndrome and Secondary Functional Encopresis

The Canadian Journal of Psychiatry ◽

10.1177/070674378903400210 ◽

1989 ◽

Vol 34 (2) ◽

pp. 123-127 ◽

Cited By ~ 15

Author(s):

Susan P.C. Carpenter

Keyword(s):

Personality Development ◽

Life Stage ◽

Behavioural Therapy ◽

Complex Problem ◽

Prader Willi Syndrome ◽

Case Review ◽

Therapeutic Modalities ◽

Eclectic Approach ◽

Physical Abilities

A case review of a twenty-two year old man suffering from Prader-Willi Syndrome, Secondary Functional Encopresis, mental retardation and aggressive behaviour is presented. Emphasis is made in assessing this man from various developmental perspectives. This includes: personality development, cognitive development, physical abilities, sexual development and family life stage. The role of a psychiatrist in treating this complex problem is established. An eclectic approach to treatment is reviewed using many therapeutic modalities found effective with the mentally handicapped. These modalities include: group therapy, play therapy, individual psychotherapy, behavioural therapy, family therapy, and use of medication. A literature review of Prader-Willi Syndrome is included.

Download Full-text

Intergenerational epigenetic inheritance in reef-building corals

10.1101/269076 ◽

2018 ◽

Cited By ~ 6

Author(s):

Yi Jin Liew ◽

Emily J. Howells ◽

Xin Wang ◽

Craig T. Michell ◽

John A. Burt ◽

...

Keyword(s):

Dna Methylation ◽

Intergenerational Transmission ◽

Epigenetic Inheritance ◽

Cpg Methylation ◽

Epigenetic Mechanisms ◽

Transgenerational Inheritance ◽

Genome Wide ◽

Methylation Patterns ◽

Hypermethylated Genes

MainThe notion that intergenerational or transgenerational inheritance operates solely through genetic means is slowly being eroded: epigenetic mechanisms have been shown to induce heritable changes in gene activity in plants1,2and metazoans1,3. Inheritance of DNA methylation provides a potential pathway for environmentally induced phenotypes to contribute to evolution of species and populations1–4. However, in basal metazoans, it is unknown whether inheritance of CpG methylation patterns occurs across the genome (as in plants) or as rare exceptions (as in mammals)4. Here, we demonstrate genome-wide intergenerational transmission of CpG methylation patterns from parents to sperm and larvae in a reef-building coral. We also show variation in hypermethylated genes in corals from distinct environments, indicative of responses to variations in temperature and salinity. These findings support a role of DNA methylation in the transgenerational inheritance of traits in corals, which may extend to enhancing their capacity to adapt to climate change.

Download Full-text

The role of promoter CpG methylation in the epigenetic control of stem cell related genes during differentiation

Cell Cycle ◽

10.4161/cc.8.6.7934 ◽

2009 ◽

Vol 8 (6) ◽

pp. 916-924 ◽

Cited By ~ 33

Author(s):

Temuujin Dansranjavin ◽

Susanne Krehl ◽

Thomas Mueller ◽

Lutz P. Mueller ◽

Hans-Joachim Schmoll ◽

...

Keyword(s):

Stem Cell ◽

Cpg Methylation ◽

Epigenetic Control

Download Full-text