Methylation-dependent regulation of hypoxia inducible factor-1 alpha gene expression by the transcription factor Kaiso

Pierre, Christina C.; Longo, Joseph; Bassey-Archibong, Blessing; Hallett, Robin; Milosavljevic, Snezana; Beatty, Laura; Hassell, John A.; Daniel, Juliet M.

doi:10.1016/j.bbagrm.2015.10.018

Cited by 23 publications

(23 citation statements)

References 65 publications

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“…Given that hypoxia regulates lysine methylation of HIF1A/HIF-1a which mediates hypoxic responses and regulates gene expression involved in autophagy, 13 we wondered whether hypoxia could change lysine methylation of ATG16L1 in cardiomyocytes and whether lysine methylation of ATG16L1 might be an important regulatory mechanism underlying ATG16L1mediated autophagy. To test these ideas, we first carried out LC3B conversion and GFP-LC3 puncta formation experiments to investigate the autophagic activity in H9c2 cells and primary neonatal rat ventricular cardiomyocytes (NRVCs) that were subjected to 4 h hypoxia and then followed by reoxygenation (H/R) for 3 h. The conversion of LC3B-I to LC3B-II indicates the formation of autophagosomes, and the ratio of LC3B-II to TUBA or LC3B-I acts as the primary indicator of autophagy induction.…”

Section: H/r Induces Autophagic Activity But Decreases Atg16l1 Methylmentioning

confidence: 99%

Crosstalk between lysine methylation and phosphorylation of ATG16L1 dictates the apoptosis of hypoxia/reoxygenation-induced cardiomyocytes

et al. 2018

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Post-translational modifications of autophagy-related (ATG) genes are necessary to modulate their functions. However, ATG protein methylation and its physiological role have not yet been elucidated. The methylation of non-histone proteins by SETD7, a SET domain-containing lysine methyltransferase, is a novel regulatory mechanism to control cell protein function in response to various cellular stresses. Here we present evidence that the precise activity of ATG16L1 protein in hypoxia/reoxygenation (H/R)-treated cardiomyocytes is regulated by a balanced methylation and phosphorylation switch. We first show that H/R promotes autophagy and decreases SETD7 expression, whereas autophagy inhibition by 3-MA increases SETD7 level in cardiomyocytes, implying a tight correlation between autophagy and SETD7. Then we demonstrate that SETD7 methylates ATG16L1 at lysine 151 while KDM1A/LSD1 (lysine demethylase 1A) removes this methyl mark. Furthermore, we validate that this methylation at lysine 151 impairs the binding of ATG16L1 to the ATG12-ATG5 conjugate, leading to inhibition of autophagy and increased apoptosis in H/R-treated cardiomyocytes. However, the cardiomyocytes with shRNA-knocked down SETD7 or inhibition of SETD7 activity by a small molecule chemical, display increased autophagy and decreased apoptosis following H/R treatment. Additionally, methylation at lysine 151 inhibits phosphorylation of ATG16L1 at S139 by CSNK2 which was previously shown to be critical for autophagy maintenance, and vice versa. Together, our findings define a novel modification of ATG16L1 and highlight the importance of an ATG16L1 phosphorylation-methylation switch in determining the fate of H/R-treated cardiomyocytes.

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Section: H/r Induces Autophagic Activity But Decreases Atg16l1 Methylmentioning

confidence: 99%

Crosstalk between lysine methylation and phosphorylation of ATG16L1 dictates the apoptosis of hypoxia/reoxygenation-induced cardiomyocytes

et al. 2018

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“…3) rendering an involvement of these factors in AREG regulation rather unlikely. In addition, we tested expression of ZBTB33 ( Zinc Finger and BTB Domain Containing 33) and ZBTB4 ( Zinc Finger and BTB Domain Containing 4), zinc finger transcriptional regulatory factors known to bind CpG‐methylated DNA . Both genes showed an expression pattern similar to the AREG expression pattern (Supporting Information Fig.…”

Section: Resultsmentioning

confidence: 99%

Epigenetic regulation of Amphiregulin and Epiregulin in colorectal cancer

Bormann

Stinzing

Tierling

et al. 2018

Intl Journal of Cancer

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Expression of the epidermal growth factor ligands amphiregulin (AREG) and epiregulin (EREG) is positively correlated with a response to EGFR‐targeted therapies in colorectal cancer. Gene‐body methylation sites, which show a strong inverse correlation with AREG and EREG gene expression, were identified in cell lines using targeted 454 FLX‐bisulfite sequencing and SIRPH analyses for AREG/EREG promoters and intragenic CpGs. Upon treatment of colorectal cancer cells with 5‐aza‐2′‐desoxycytidine, methylation decreases at specific intragenic CpGs accompanied by upregulation of AREG and EREG gene expression. The same AREG gene‐body methylation was also found in human colorectal cancer samples and is independent of KRAS and NRAS mutations. Methylation is specifically decreased in the tumor epithelial compartment as compared to stromal tissue and normal epithelium. Investigation of a promoter/enhancer function of the AREG exon 2 region revealed a potential promoter function in reverse orientation. Retrospective comparison of the predictive power of AREG gene‐body methylation versus AREG gene expression using samples from colorectal cancer patients treated with anti‐EGFR inhibitors with complete clinical follow‐up revealed that AREG expression is superior to AREG gene methylation. AREG and EREG genes undergo a complex regulation involving both intragenic methylation and promoter‐dependent control.

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“…Treatment of the DNA methylation inhibitor 5-Aza-2′-deoxycytidine blocks CpG methylation at the HIF1A promoter, leading to increased autoregulation by HIF-1 and subsequent its downstream target gene expression [52]. The transcription factor Kaiso binds methylated HIF1A promoter and suppresses HIF-1α mRNA expression under hypoxia to impair HIF-1 transcriptional activity [53]. Recently, it was shown that DNMT3a methylates the CpG at the promoter of the EPAS1 gene and decreases expression of HIF-2α in normal human epithelial cells.…”

Section: Regulation Of Hif Transcriptional Activity By Epigenetic Wrimentioning

confidence: 99%

Epigenetic regulators: multifunctional proteins modulating hypoxia-inducible factor-α protein stability and activity

Luo

Wang

2017

Cell. Mol. Life Sci.

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The hypoxia-inducible factor (HIF) is a heterodimeric transcription factor governing a transcriptional program in response to reduced O2 availability in metazoans. It contributes to physiology and pathogenesis of many human diseases through its downstream target genes. Emerging studies have shown that the transcriptional activity of HIF is highly regulated at multiple levels and the epigenetic regulators are essential for HIF-mediated transactivation. In this review, we will discuss the comprehensive regulation of HIF transcriptional activity by different types of epigenetic regulators.

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Methylation-dependent regulation of hypoxia inducible factor-1 alpha gene expression by the transcription factor Kaiso

Cited by 23 publications

References 65 publications

Crosstalk between lysine methylation and phosphorylation of ATG16L1 dictates the apoptosis of hypoxia/reoxygenation-induced cardiomyocytes

Crosstalk between lysine methylation and phosphorylation of ATG16L1 dictates the apoptosis of hypoxia/reoxygenation-induced cardiomyocytes

Epigenetic regulation of Amphiregulin and Epiregulin in colorectal cancer

Epigenetic regulators: multifunctional proteins modulating hypoxia-inducible factor-α protein stability and activity

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