Histone demethylase JMJD1C is phosphorylated by mTOR to activate de novo lipogenesis

Viscarra, José A.; Wang, Yuhui; Nguyen, Hai P.; Choi, Yoon Gi; Sul, Hei Sook

doi:10.1038/s41467-020-14617-1

Cited by 56 publications

(40 citation statements)

References 51 publications

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“…Recently, mTORC1 also was found to phosphorylate the histone H3 lysine 9 (H3K9) demethylase JMJD1C in a nutrient-dependent manner. Phosphorylated JMJD1C then interacts with the transcription factor USF-1 to demethylate H3K9me2 at genes promoting lipogenesis in the liver, and this pathway plays a critical role in diet-induced lipogenesis [133]. Therefore, both mTORC1-dependent histone methylation and demethylation at distinct histone residues contribute to mTORC1-regulated metabolism.…”

Section: Histone Methylationmentioning

confidence: 99%

Nuclear Functions of TOR: Impact on Transcription and the Epigenome

Laribee

Weisman

2020

Genes

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The target of rapamycin (TOR) protein kinase is at the core of growth factor- and nutrient-dependent signaling pathways that are well-known for their regulation of metabolism, growth, and proliferation. However, TOR is also involved in the regulation of gene expression, genomic and epigenomic stability. TOR affects nuclear functions indirectly through its activity in the cytoplasm, but also directly through active nuclear TOR pools. The mechanisms by which TOR regulates its nuclear functions are less well-understood compared with its cytoplasmic activities. TOR is an important pharmacological target for several diseases, including cancer, metabolic and neurological disorders. Thus, studies of the nuclear functions of TOR are important for our understanding of basic biological processes, as well as for clinical implications.

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Section: Histone Methylationmentioning

confidence: 99%

Nuclear Functions of TOR: Impact on Transcription and the Epigenome

Laribee

Weisman

2020

Genes

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“…JMJD1C protein, also known as probable JmjC domain‐containing histone demethylation protein 1C (JHDM2C/KDM3C), is a probable histone demethylase that specifically demethylates Lys‐9 mono or dimethyl of histone H3 (H3K9me1/2). The functions of JMJD1C protein are studied in vitro on mouse and human cells in many studies and it was found that this protein performs diverse critical functions such as lipogenesis control, 82 the emergence of myeloprolative neoplasms, 83–86 anti‐inflammatory effects, 87 controlling of spermatogenesis 88,89 and, especially, the important self‐renewal and maintenance of the stem cells 90–93 . However, to our knowledge, regarding ASD, the only functional genetic study on the JMJD1C has been performed by Sáez et al 57 .…”

Section: Discussionmentioning

confidence: 99%

Finding underlying genetic mechanisms of two patients with autism spectrum disorder carrying familial apparently balanced chromosomal translocations

Toraman

Bilginer

Hesapçıoğlu

et al. 2021

The Journal of Gene Medicine

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Background Genetic etiologies of autism spectrum disorders (ASD) are complex, and the genetic factors identified so far are very diverse. In complex genetic diseases such as ASD, de novo or inherited chromosomal abnormalities are valuable findings for researchers with respect to identifying the underlying genetic risk factors. With gene mapping studies on these chromosomal abnormalities, dozens of genes have been associated with ASD and other neurodevelopmental genetic diseases. In the present study, we aimed to idenitfy the causative genetic factors in patients with ASD who have an apparently balanced chromosomal translocation in their karyotypes. Methods For mapping the broken genes as a result of chromosomal translocations, we performed whole genome DNA sequencing. Chromosomal breakpoints and large DNA copy number variations (CNV) were determined after genome alignment. Identified CNVs and single nucleotide variations (SNV) were evaluated with VCF‐BED intersect and Gemini tools, respectively. A targeted resequencing approach was performed on the JMJD1C gene in all of the ASD cohorts (220 patients). For molecular modeling, we used a homology modeling approach via the SWISS‐MODEL. Results We found that there was no contribution of the broken genes or regulator DNA sequences to ASD, whereas the SNVs on the JMJD1C, CNKSR2 and DDX11 genes were the most convincing genetic risk factors for underlying ASD phenotypes. Conclusions Genetic etiologies of ASD should be analyzed comprehensively by taking into account of the all chromosomal structural abnormalities and de novo or inherited CNV/SNVs with all possible inheritance patterns.

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“…In addition to increased fatty acid uptake into hepatocytes, DNL also contributes significantly to TG accumulation in the pathogenesis of NAFLD [2]. Recently, it has been reported that the H3K9me2 demethylase, JMJD1C, is recruited to lipogenic promoter regions by USF-1 and demethylates H3K9me2, thus stimulating lipogenic gene expression [19]. This suggests that JMJD1C plays an important epigenetic regulatory role in the activation of lipogenesis.…”

Section: Discussionmentioning

confidence: 99%

Histone H3K9 Demethylase JMJD2B Plays a Role in LXRα-Dependent Lipogenesis

Kim

Jung

Kim

et al. 2020

IJMS

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Ligand-activated liver X receptor α (LXRα) upregulates the expression of hepatic lipogenic genes, which leads to triglyceride (TG) accumulation, resulting in nonalcoholic fatty liver disease (NAFLD). Thus, LXRα regulation may provide a novel therapeutic target against NAFLD. However, histone methylation-mediated epigenetic regulation involved in LXRα-dependent lipogenesis is poorly understood. In this study, we investigated the functional role of the histone demethylase Jumonji domain-containing protein 2B (JMJD2B) in LXRα-dependent lipogenesis. JMJD2B expression level was upregulated in HepG2 cells treated with LXRα agonist T0901317 or palmitate and the liver of mice administered with T0901317 or fed a high-fat diet. Knockdown of JMJD2B using siRNA abrogated T0901317-induced LXRα-dependent lipogenic gene expression and lowered intracellular TG accumulation. Conversely, overexpression of JMJD2B in HepG2 cells upregulated the expression of LXRα-dependent lipogenic genes, in line with increased intracellular TG levels. JMJD2B overexpression or T0901317 treatment induced the recruitment of JMJD2B and LXRα to LXR response elements (LXRE) in the promoter region of LXRα-target gene and reduced the enrichment of H3K9me2 and H3K9me3 in the vicinity of the LXRE. Furthermore, JMJD2B enhanced T0901317 or LXRα-induced transcriptional activities of reporters containing LXRE. A co-immunoprecipitation assay revealed that JMJD2B interacted with activated LXRα. Moreover, overexpression of JMJD2B in mice resulted in upregulation of hepatic LXRα-dependent lipogenic genes, consistent with development of hepatic steatosis. Taken together, these results indicate that JMJD2B plays a role in LXRα-mediated lipogenesis via removing the repressive histone marks, H3K9me2 and H3K9me3, at LXRE, which might contribute to hepatic steatosis.

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Histone demethylase JMJD1C is phosphorylated by mTOR to activate de novo lipogenesis

Cited by 56 publications

References 51 publications

Nuclear Functions of TOR: Impact on Transcription and the Epigenome

Nuclear Functions of TOR: Impact on Transcription and the Epigenome

Finding underlying genetic mechanisms of two patients with autism spectrum disorder carrying familial apparently balanced chromosomal translocations

Histone H3K9 Demethylase JMJD2B Plays a Role in LXRα-Dependent Lipogenesis

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