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Written | Point mutations in Qi histone H3.
3 are very common in aggressive brain tumors in children, namely pediatric high-grade gliomas (pHGGs).
Interestingly, the current data show that different mutations are often distributed in relatively discrete areas, showing specific temporal and spatial positioning: H3.
3G34R is mainly limited to the forebrain, while H3.
3K27M preferentially occurs in the hindbrain.
In addition, the vast majority of H3.
3G34R mutant tumors contain both TP53 and ATRX loss-of-function mutations.
These evidences suggest that the occurrence of tumors depends on specific cellular and genetic backgrounds.
However, neither the cell type of origin nor the molecular mechanism of oncogenic transformation is unclear.
Recently, Cell magazine published a back-to-back report from the Viviane Tabar team at the Memorial Sloan Kettering Cancer Center in the United States entitled Dissecting the impact of regional identity and the oncogenic role of human-specific NOTCH2NL in an hESC model of H3.
3G34R-mutant glioma , And two articles entitled Regional identity of human neural stem cells determines oncogenic responses to histone H3.
3 mutants from Steven M.
Pollard's team at the University of Edinburgh in the United Kingdom.Both studies established an H3.
3G34R mutant glioma model derived from human embryonic neural stem cells (hESC).
Through this model, the ventral forebrain interneuron progenitor cells were identified as the putative cell of origin and explained The molecular mechanism of the specific temporal and spatial characteristics of H3.
3G34R glioma.
The platform provided by the two studies will help to further analyze the mechanism of action of other types of histone mutations, including the H3.
3G34R mutation, and also provide help for the future treatment plan design for this fatal cerebral hemisphere tumor.
Based on previous research, the researchers of the Viviane Tabar team (hereinafter referred to as Tabar, etc.
) will use CRISPR-Cas9 to edit the representative six genotypes (mock, p53-KO or H3.
3WT or H3 in the context of TP53/ATRX-KO).
3G34R) human embryonic stem cell-derived lines differentiate into vFNPCs (ventral forebrain interneuron progenitor cells) or vHNPCs (ventral hindbrain neuron progenitor cells).
After the cells gradually formed 3D spheres, it was found that the H3.
3G34R mutation and ATRX and When combined with TP53 mutations, it can strongly impair neuronal differentiation, and can still promote cell proliferation even under the stimulation of differentiation signals.
Compared with the hindbrain, these phenotypes are more prominent in the forebrain model.
Consistent with this, the cells were labeled with luciferase and transplanted into the brain of immunodeficient mice.
It was found that mice in the vFNPC-H3.
3G34R group developed highly aggressive tumors, accompanied by the presence of markers of forebrain and interneurons.
The expression remained in the tumor, but the hindbrain did not form a tumor.
These results further support the key role of neurodevelopmental background in the formation of H3.
3G34R mutant glioma.
In order to reveal the molecular mechanism behind the observed carcinogenic phenotype, Tabar et al.
isolated cells from neurospheres of different genetic backgrounds and analyzed gene expression profiles by RNA sequencing, and found that H3.
3G34R mutant tumors are highly expressed (top 10%).
Genes have mRNA differential splicing, mainly in the form of intron retention (IR).
Among them, the splicing change of NOTCH2NL is the largest and the expression level is significantly higher in H3.
3G34 mutant tumors. Based on this, Tabar et al.
through the "gain-of-function" and "loss-of-function" experiments found that overexpression of NOTCH2NL can promote the double proliferation of forebrain cells, but the opposite effect is obtained in the hindbrain; shRNA knocks down NOTCH2NL Later, the total number of cells in the H3.
3G34R mutant cell line and the ability to form spheroids were reduced, and intracranial injections of immunodeficient mice also showed a lower tumor burden.
Similar to the previous article, the researchers of Steven M.
Pollard's team (hereinafter referred to as Pollard, etc.
) constructed embryonic neural stem cell cultures derived from different brain regions, according to the phenotypic response to different H3.
3 mutations (supporting the proliferation of forebrain cells).
At the same time, it induces the inhibition of brain cell growth) confirms the anatomical selectivity of pHGG, and requires cooperative mutation to enhance its carcinogenic effect.
In terms of mechanism, consistent with the findings of Tabar et al.
, Pollard et al.
believe that H3.
3G34R does not cause extensive transcription or epigenetic changes, but affects the recruitment of the transcription repressor ZMYND11 of highly expressed genes.
Specifically, ZMYND11 is a specific reader of H3.
3K36me3, which acts as an unconventional transcriptional co-repressor by regulating the extension and splicing of highly expressed genes, while H3.
3G34R can reduce the binding to ZMYND11 and enhance the forebrain The expression of key transcriptional regulatory genes locks the cell into a proliferation state.
Interestingly, Pollard et al.
also observed that the cytostatic effect induced by H3.
3G34R in brain stem neural stem cells was accompanied by the activation of the senescence effector CDKN1A/p21, suggesting that cellular senescence may be a target for controlling the proliferation of forebrain cells.
To this end, Pollard et al.
used CRISPR-Cas9 gene editing to remove the transcription factor FOXG1 (a known inhibitor of the CDKN1A/p21 locus) and found that in vitro proliferation was reduced and the tumor-forming ability of H3.
3G34R patient-derived cells in vivo was lost.
On the contrary, knocking out FOXG1 in H3.
3-WT HGG patient-derived cell lines did not cause damage to proliferation, indicating that H3.
3-G34R mutant cells are more dependent on FOXG1 expression. In general, these two studies provide new insights into the mechanism of glioma mediated by the H3.
3G34R mutation, highlighting the synergistic effects of TP53 and ATRX mutations in the carcinogenic process.
In addition, they also reveal the selection Sexual mRNA splicing, NOTCH2NL locus amplification, and H3.
3G34R can enhance the role of pre-existing forebrain-related transcription circuits in tumorigenesis by disrupting the binding of the transcription repressor ZMYND11.
In the future, further work is needed to fully analyze why the states of progenitor cells in different brain regions have differential sensitivity to different H3.
3 mutations, and whether the mechanisms that maintain the characteristics of the forebrain and hindbrain can be used as clinical treatment targets.
Original link: https://doi.
org/10.
1016/j.
stem.
2021.
02.
003https://doi.
org/10.
1016/j.
stem.
2021.
01.
016 Reprinting instructions [Original article] BioArt original article, personal sharing is welcome , Reprinting is prohibited without permission, and the copyright of all published works is owned by BioArt.
BioArt reserves all statutory rights and offenders must be investigated.
Plate maker: Eleven
3 are very common in aggressive brain tumors in children, namely pediatric high-grade gliomas (pHGGs).
Interestingly, the current data show that different mutations are often distributed in relatively discrete areas, showing specific temporal and spatial positioning: H3.
3G34R is mainly limited to the forebrain, while H3.
3K27M preferentially occurs in the hindbrain.
In addition, the vast majority of H3.
3G34R mutant tumors contain both TP53 and ATRX loss-of-function mutations.
These evidences suggest that the occurrence of tumors depends on specific cellular and genetic backgrounds.
However, neither the cell type of origin nor the molecular mechanism of oncogenic transformation is unclear.
Recently, Cell magazine published a back-to-back report from the Viviane Tabar team at the Memorial Sloan Kettering Cancer Center in the United States entitled Dissecting the impact of regional identity and the oncogenic role of human-specific NOTCH2NL in an hESC model of H3.
3G34R-mutant glioma , And two articles entitled Regional identity of human neural stem cells determines oncogenic responses to histone H3.
3 mutants from Steven M.
Pollard's team at the University of Edinburgh in the United Kingdom.Both studies established an H3.
3G34R mutant glioma model derived from human embryonic neural stem cells (hESC).
Through this model, the ventral forebrain interneuron progenitor cells were identified as the putative cell of origin and explained The molecular mechanism of the specific temporal and spatial characteristics of H3.
3G34R glioma.
The platform provided by the two studies will help to further analyze the mechanism of action of other types of histone mutations, including the H3.
3G34R mutation, and also provide help for the future treatment plan design for this fatal cerebral hemisphere tumor.
Based on previous research, the researchers of the Viviane Tabar team (hereinafter referred to as Tabar, etc.
) will use CRISPR-Cas9 to edit the representative six genotypes (mock, p53-KO or H3.
3WT or H3 in the context of TP53/ATRX-KO).
3G34R) human embryonic stem cell-derived lines differentiate into vFNPCs (ventral forebrain interneuron progenitor cells) or vHNPCs (ventral hindbrain neuron progenitor cells).
After the cells gradually formed 3D spheres, it was found that the H3.
3G34R mutation and ATRX and When combined with TP53 mutations, it can strongly impair neuronal differentiation, and can still promote cell proliferation even under the stimulation of differentiation signals.
Compared with the hindbrain, these phenotypes are more prominent in the forebrain model.
Consistent with this, the cells were labeled with luciferase and transplanted into the brain of immunodeficient mice.
It was found that mice in the vFNPC-H3.
3G34R group developed highly aggressive tumors, accompanied by the presence of markers of forebrain and interneurons.
The expression remained in the tumor, but the hindbrain did not form a tumor.
These results further support the key role of neurodevelopmental background in the formation of H3.
3G34R mutant glioma.
In order to reveal the molecular mechanism behind the observed carcinogenic phenotype, Tabar et al.
isolated cells from neurospheres of different genetic backgrounds and analyzed gene expression profiles by RNA sequencing, and found that H3.
3G34R mutant tumors are highly expressed (top 10%).
Genes have mRNA differential splicing, mainly in the form of intron retention (IR).
Among them, the splicing change of NOTCH2NL is the largest and the expression level is significantly higher in H3.
3G34 mutant tumors. Based on this, Tabar et al.
through the "gain-of-function" and "loss-of-function" experiments found that overexpression of NOTCH2NL can promote the double proliferation of forebrain cells, but the opposite effect is obtained in the hindbrain; shRNA knocks down NOTCH2NL Later, the total number of cells in the H3.
3G34R mutant cell line and the ability to form spheroids were reduced, and intracranial injections of immunodeficient mice also showed a lower tumor burden.
Similar to the previous article, the researchers of Steven M.
Pollard's team (hereinafter referred to as Pollard, etc.
) constructed embryonic neural stem cell cultures derived from different brain regions, according to the phenotypic response to different H3.
3 mutations (supporting the proliferation of forebrain cells).
At the same time, it induces the inhibition of brain cell growth) confirms the anatomical selectivity of pHGG, and requires cooperative mutation to enhance its carcinogenic effect.
In terms of mechanism, consistent with the findings of Tabar et al.
, Pollard et al.
believe that H3.
3G34R does not cause extensive transcription or epigenetic changes, but affects the recruitment of the transcription repressor ZMYND11 of highly expressed genes.
Specifically, ZMYND11 is a specific reader of H3.
3K36me3, which acts as an unconventional transcriptional co-repressor by regulating the extension and splicing of highly expressed genes, while H3.
3G34R can reduce the binding to ZMYND11 and enhance the forebrain The expression of key transcriptional regulatory genes locks the cell into a proliferation state.
Interestingly, Pollard et al.
also observed that the cytostatic effect induced by H3.
3G34R in brain stem neural stem cells was accompanied by the activation of the senescence effector CDKN1A/p21, suggesting that cellular senescence may be a target for controlling the proliferation of forebrain cells.
To this end, Pollard et al.
used CRISPR-Cas9 gene editing to remove the transcription factor FOXG1 (a known inhibitor of the CDKN1A/p21 locus) and found that in vitro proliferation was reduced and the tumor-forming ability of H3.
3G34R patient-derived cells in vivo was lost.
On the contrary, knocking out FOXG1 in H3.
3-WT HGG patient-derived cell lines did not cause damage to proliferation, indicating that H3.
3-G34R mutant cells are more dependent on FOXG1 expression. In general, these two studies provide new insights into the mechanism of glioma mediated by the H3.
3G34R mutation, highlighting the synergistic effects of TP53 and ATRX mutations in the carcinogenic process.
In addition, they also reveal the selection Sexual mRNA splicing, NOTCH2NL locus amplification, and H3.
3G34R can enhance the role of pre-existing forebrain-related transcription circuits in tumorigenesis by disrupting the binding of the transcription repressor ZMYND11.
In the future, further work is needed to fully analyze why the states of progenitor cells in different brain regions have differential sensitivity to different H3.
3 mutations, and whether the mechanisms that maintain the characteristics of the forebrain and hindbrain can be used as clinical treatment targets.
Original link: https://doi.
org/10.
1016/j.
stem.
2021.
02.
003https://doi.
org/10.
1016/j.
stem.
2021.
01.
016 Reprinting instructions [Original article] BioArt original article, personal sharing is welcome , Reprinting is prohibited without permission, and the copyright of all published works is owned by BioArt.
BioArt reserves all statutory rights and offenders must be investigated.
Plate maker: Eleven
