Involvement of REST corepressor 3 in prognosis of human hepatitis B

Xue, Jihua; Zheng, Ming‐Hua; Xu, Xiaowei; Wu, Shanshan; Chen, Zhi; Chen, Feng

doi:10.1038/aps.2011.49

Cited by 6 publications

(6 citation statements)

References 38 publications

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“…While the incomplete expression profile of Rcor2 makes it difficult to predict the extent and severity of its genetic deletion phenotype, the Rcor1 and Rcor2 combined deletions should largely phenocopy that of LSD1 in the absence of other positively acting Rcor factors. Since very little is known about Rcor3 expression or function other than its expression in adult hepatic cells (28), predicting its deletion phenotype is practically impossible. However, our results predict antagonistic phenotypes for Rcor 1/2 versus Rcor3 in their respective regions of expression.…”

Section: Discussionmentioning

confidence: 99%

Antagonistic actions of Rcor proteins regulate LSD1 activity and cellular differentiation

Upadhyay

Chowdhury

Vaidyanathan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Lysine-specific demethylase 1 (LSD1) demethylates nucleosomal histone H3 lysine 4 (H3K4) residues in collaboration with the corepressor CoREST/REST corepressor 1 (Rcor1) and regulates cell fates by epigenetically repressing gene targets. The balanced regulation of this demethylase, if any, is however unknown. We now demonstrate the actions of two other Rcor paralogs, Rcor2 and Rcor3, in regulating LSD1 enzymatic activity and biological function in hematopoietic cells. All three Rcor proteins interact with LSD1 and with the erythro-megakaryocytic transcription factor growth factor independence (Gfi)1b; however, whereas Rcor2, like Rcor1, facilitates LSD1-mediated nucleosomal demethylation, Rcor3 competitively inhibits this process. Appending the SANT2 domain of Rcor1 to Rcor3 confers the ability to facilitate LSD1-mediated demethylation on the chimeric Rcor protein. Consistent with their biochemical activities, endogenous Rcor1, Rcor2, and LSD1 promote differentiation, whereas Rcor3 opposes these processes. Recruitment of Rcor3 to cognate gene targets by Gfi1b and LSD1 leads to inhibition of H3K4 demethylation of chromatin and transcriptional derepression of these loci. Remarkably, profound alterations in Rcor1/3 levels during erythroid versus megakaryocytic differentiation potentiate antagonistic outcomes. In mature erythroid cells, a strong upsurge in Rcor3 and a sharp decline in Rcor1 levels counteract LSD1/Rcor1/2-mediated differentiation. In contrast, the opposite changes in Rcor1/3 levels in megakaryocytes favor differentiation and likely maintain homeostasis between these lineages. Overall, our results identify Rcor3 as a natural inhibitor of LSD1 and highlight a dual mechanism of regulating the enzymatic activity and restraining the epigenetic impact of this robust demethylase during hematopoietic differentiation.

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Section: Discussionmentioning

confidence: 99%

Antagonistic actions of Rcor proteins regulate LSD1 activity and cellular differentiation

Upadhyay

Chowdhury

Vaidyanathan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…To avoid bias, we mined expression data for all four genes. We found that RCOR3, CYTL1 and E2F8 are not expressed appreciably in neuronal tissues, while subsequent literature searches intimate an involvement of these transcripts in hepatitis, chondrogenesis and hepatocellular carcinoma (3,23,24). In contrast, TENM4 is expressed primarily in the brain and has been detected in several transcriptomes derived from neuronal tissues (see Materials and Methods).…”

Section: Exome Sequencingmentioning

confidence: 91%

Missense mutations inTENM4, a regulator of axon guidance and central myelination, cause essential tremor

et al. 2015

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Essential tremor (ET) is a common movement disorder with an estimated prevalence of 5% of the population aged over 65 years. In spite of intensive efforts, the genetic architecture of ET remains unknown. We used a combination of whole-exome sequencing and targeted resequencing in three ET families. In vitro and in vivo experiments in oligodendrocyte precursor cells and zebrafish were performed to test our findings. Whole-exome sequencing revealed a missense mutation in TENM4 segregating in an autosomal-dominant fashion in an ET family. Subsequent targeted resequencing of TENM4 led to the discovery of two novel missense mutations. Not only did these two mutations segregate with ET in two additional families, but we also observed significant over transmission of pathogenic TENM4 alleles across the three families. Consistent with a dominant mode of inheritance, in vitro analysis in oligodendrocyte precursor cells showed that mutant proteins mislocalize. Finally, expression of human mRNA harboring any of three patient mutations in zebrafish embryos induced defects in axon guidance, confirming a dominant-negative mode of action for these mutations. Our genetic and functional data, which is corroborated by the existence of a Tenm4 knockout mouse displaying an ET phenotype, implicates TENM4 in ET. Together with previous studies of TENM4 in model organisms, our studies intimate that processes regulating myelination in the central nervous system and axon guidance might be significant contributors to the genetic burden of this disorder.

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“…[327] Xu et al found that verapamil increased β-AR density and inhibited norepinephrine-induced β-AR downregulation of cardiomyocytes. [328] Staneva-Stoytcheva et al studied the influence of long-term treatment with verapamil, on β-adrenoceptors in rat cerebral cortex. They found that 13-day treatment of rats with verapamil significantly reduced (by about 30%) the number (B max ) of β-adrenoceptors.…”

Section: Verapamil Potassium Channels Blockingmentioning

confidence: 99%

Multitargeting in cardioprotection: An example of biaromatic compounds

Mokrov

2023

Archiv der Pharmazie

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A multitarget drug design approach is actively developing in modern medicinal chemistry and pharmacology, especially with regard to multifactorial diseases such as cardiovascular diseases, cancer, and neurodegenerative diseases. A detailed study of many well‐known drugs developed within the single‐target approach also often reveals additional mechanisms of their real pharmacological action. One of the multitarget drug design approaches can be the identification of the basic pharmacophore models corresponding to a wide range of the required target ligands. Among such models in the group of cardioprotectors is the linked biaromatic system. This review develops the concept of a “basic pharmacophore” using the biaromatic pharmacophore of cardioprotectors as an example. It presents an analysis of possible biological targets for compounds corresponding to the biaromatic pharmacophore and an analysis of the spectrum of biological targets for the five most known and most studied cardioprotective drugs corresponding to this model, and their involvement in the biological effects of these drugs.

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Involvement of REST corepressor 3 in prognosis of human hepatitis B

Cited by 6 publications

References 38 publications

Antagonistic actions of Rcor proteins regulate LSD1 activity and cellular differentiation

Antagonistic actions of Rcor proteins regulate LSD1 activity and cellular differentiation

Missense mutations inTENM4, a regulator of axon guidance and central myelination, cause essential tremor

Multitargeting in cardioprotection: An example of biaromatic compounds

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