Effect of BIX-01294 on H3K9me2 levels and the imprinted gene <i>Snrpn</i> in mouse embryonic fibroblast cells

Chen, Peng; Huang, Rongfu; Zheng, Fangfang; Jiang, Xiaohong; Chen, Xuan; Chen, Juan; Li, Ming; Huang, Hongfeng; Jiang, Yijing; Huang, Yanfang; Yang, Xiaoyu

doi:10.1042/bsr20150064

Cited by 17 publications

(11 citation statements)

References 37 publications

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“…In contrast to the H3K9me3 pattern, the immunofluorescence signal for both marks was detected in smaller and blurrier clusters, referred to as puncta. In agreement with previous studies using the same commercial H3K9me2 antibody [45,46], we found that these puncta did not co-localize with chromocenters in control or C9BAC astrocytes ( Fig. 2a, b).…”

Section: Reduced Levels Of Nuclear H3k9me3 In Primary Spinal Cord Astsupporting

confidence: 93%

Widespread loss of the silencing epigenetic mark H3K9me3 in astrocytes and neurons along with hippocampal-dependent cognitive impairment in C9orf72 BAC transgenic mice

et al. 2020

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Background: Hexanucleotide repeat expansions of the G 4 C 2 motif in a non-coding region of the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Tissues from C9ALS/FTD patients and from mouse models of ALS show RNA foci, dipeptide-repeat proteins, and notably, widespread alterations in the transcriptome. Epigenetic processes regulate gene expression without changing DNA sequences and therefore could account for the altered transcriptome profiles in C9ALS/FTD; here, we explore whether the critical repressive marks H3K9me2 and H3K9me3 are altered in a recently developed C9ALS/FTD BAC mouse model (C9BAC). Results: Chromocenters that constitute pericentric constitutive heterochromatin were visualized as DAPI-or Nucblue-dense foci in nuclei. Cultured C9BAC astrocytes exhibited a reduced staining signal for H3K9me3 (but not for H3K9me2) at chromocenters that was accompanied by a marked decline in the global nuclear level of this mark. Similar depletion of H3K9me3 at chromocenters was detected in astrocytes and neurons of the spinal cord, motor cortex, and hippocampus of C9BAC mice. The alterations of H3K9me3 in the hippocampus of C9BAC mice led us to identify previously undetected neuronal loss in CA1, CA3, and dentate gyrus, as well as hippocampal-dependent cognitive deficits. Conclusions: Our data indicate that a loss of the repressive mark H3K9me3 in astrocytes and neurons in the central nervous system of C9BAC mice represents a signature during neurodegeneration and memory deficit of C9ALS/FTD.

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Section: Reduced Levels Of Nuclear H3k9me3 In Primary Spinal Cord Astsupporting

confidence: 93%

Widespread loss of the silencing epigenetic mark H3K9me3 in astrocytes and neurons along with hippocampal-dependent cognitive impairment in C9orf72 BAC transgenic mice

et al. 2020

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“…The results showed a significant increase in microspore embryogenesis induction with short-term BIX-01294 in vitro treatments, together with a decrease in H3K9 methylation levels. In mammals, H3K9 methylation by G9a HKMT has been reported to lead to heterochromatinization, a mechanism of epigenetic silencing of embryonic genes ( Feldman et al, 2006 ; Chen et al, 2015 ). Interestingly, the pharmacological inhibition of G9a HKMT-mediated H3K9me2 by BIX-01294 was reported to improve cell reprogramming and to enhance the generation of iPSCs from neuronal progenitor cells and mouse embryonic fibroblasts transduced with Oct/Klf4 ( Shi et al, 2008a ).…”

Section: Discussionmentioning

confidence: 99%

“…The small molecule BIX-01294 is a diazepin-quinazolin-amine derivative which has been identified as a very specific inhibitor of G9a histone lysine methyltransferase and reduces bulk H3K9me2 levels in several mammalian cell lines; it can impair the closely related GLP HKMT only at very high concentrations ( Kubicek et al, 2007 ). BIX-01294 has also been shown to improve the reprogramming efficiency of neural progenitor cells toward induced pluripotent stem cells (iPSCs) ( Shi et al, 2008a , b ) as well as to improve reprogramming in other somatic cell systems of mammals ( Chen et al, 2015 ; Lin and Wu, 2015 ; Huang et al, 2016 ). However, BIX-01294 has not yet been tested in plant systems.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Histone H3K9 Methylation by BIX-01294 Promotes Stress-Induced Microspore Totipotency and Enhances Embryogenesis Initiation

et al. 2017

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Microspore embryogenesis is a process of cell reprogramming, totipotency acquisition and embryogenesis initiation, induced in vitro by stress treatments and widely used in plant breeding for rapid production of doubled-haploids, but its regulating mechanisms are still largely unknown. Increasing evidence has revealed epigenetic reprogramming during microspore embryogenesis, through DNA methylation, but less is known about the involvement of histone modifications. In this study, we have analyzed the dynamics and possible role of histone H3K9 methylation, a major repressive modification, as well as the effects on microspore embryogenesis initiation of BIX-01294, an inhibitor of histone methylation, tested for the first time in plants, in Brassica napus and Hordeum vulgare. Results revealed that microspore reprogramming and initiation of embryogenesis involved a low level of H3K9 methylation. With the progression of embryogenesis, methylation of H3K9 increased, correlating with gene expression profiles of BnHKMT SUVR4-like and BnLSD1-like (writer and eraser enzymes of H3K9me2). At early stages, BIX-01294 promoted cell reprogramming, totipotency and embryogenesis induction, while diminishing bulk H3K9 methylation. DNA methylation was also reduced by short-term BIX-01294 treatment. By contrast, long BIX-01294 treatments hindered embryogenesis progression, indicating that H3K9 methylation is required for embryo differentiation. These findings open up new possibilities to enhance microspore embryogenesis efficiency in recalcitrant species through pharmacological modulation of histone methylation by using BIX-01294.

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“…Other small molecule KMT inhibitors that have been developed as potential anticancer therapeutics include compounds targeting H3K9 KMTs (Table 3). Increased expression of the H3K9-specific KMT G9a was reported in lung cancer cell lines and treatment with inhibitor BIX-01294 reduces H3K9 methylation (83; 84). Similarly, SETDB1 is frequently amplified in melanoma and lung cancers and treatment with mithramycin down-regulates SETDB1 to inhibit proliferation (85; 86).…”

Section: Targeting Histone Methyltransferasesmentioning

confidence: 98%

Targeting Epigenetics in Cancer

Bennett

Licht

2018

Annu. Rev. Pharmacol. Toxicol.

194

138

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Alterations of genes regulating epigenetic processes are frequently found as cancer drivers and may cause widespread alterations of DNA methylation, histone modification patterns, or chromatin structure that disrupt normal patterns of gene expression. Because of the inherent reversibility of epigenetic changes, inhibitors targeting these processes are promising anticancer strategies. Small molecules targeting epigenetic regulators have been developed recently, and clinical trials of these agents are under way for hematologic malignancies and solid tumors. In this review, we describe how the writers, readers, and erasers of epigenetic marks are dysregulated in cancer and summarize the development of therapies targeting these mechanisms.

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Effect of BIX-01294 on H3K9me2 levels and the imprinted gene Snrpn in mouse embryonic fibroblast cells

Cited by 17 publications

References 37 publications

Widespread loss of the silencing epigenetic mark H3K9me3 in astrocytes and neurons along with hippocampal-dependent cognitive impairment in C9orf72 BAC transgenic mice

Widespread loss of the silencing epigenetic mark H3K9me3 in astrocytes and neurons along with hippocampal-dependent cognitive impairment in C9orf72 BAC transgenic mice

Inhibition of Histone H3K9 Methylation by BIX-01294 Promotes Stress-Induced Microspore Totipotency and Enhances Embryogenesis Initiation

Targeting Epigenetics in Cancer

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