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Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis.

ABSTRACT: Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.

SUBMITTER: Chen CCL

PROVIDER: S-EPMC7791404 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Histone H3.3G34-mutant interneuron progenitors co-opt PDGFRA for gliomagenesis

Project description:Histone H3.3 glycine 34 to arginine/valine (H3.3G34R/V) mutations occur in deadly hemispheric high-grade gliomas. These tumors show exquisite regional and temporal specificity, suggesting a developmental context permissive to the effects of G34R/V mutations. Here we present the molecular landscape of G34R/V gliomas (n = 83) and show that ~50% bear activating mutations in PDGFRA, with strong selection pressure for PDGFRAMUT clones at recurrence. We show that G34R/V tumors arise in interneuron progenitors of the foetal ventral forebrain, expressing GSX2 and the DLX family of homeobox transcription factors, where terminal neuronal differentiation is impaired through aberrant G34R/V-mediated H3K27me3. Frequent co-occurrence of G34R/V & PDGFRAMUT is facilitated in this interneuron lineage-of-origin as PDGFRA forms an aberrant chromatin loop with the adjacent GSX2, hijacking its active chromatin conformation. At the single-cell level, G34R/V tumors entirely lack oligodendroglial transcriptional programs prominent in other glioma entities, and instead harbour dual neuronal and astroglial compartments. CRISPR-removal of H3.3G34R/V does not impact tumorigenicity suggesting this mutation becomes dispensable, while PDGFRAMUT are potently oncogenic regardless of G34 mutation. Collectively, our results suggest that G34R/V gliomas arise in foetal interneuron progenitors unable to terminally differentiate, enabling co-option of PDGFRA through inappropriate expression and activating mutations to promote gliogenesis and oncogenicity. Reliance on PDGFRA for oncogenesis may be of therapeutic opportunity in G34R/V glioma.

2020-11-30 | GSE146731 | GEO

Histone H3.3G34-mutant interneuron progenitors co-opt PDGFRA for gliomagenesis

Project description:Histone H3.3G34-mutant interneuron progenitors co-opt PDGFRA for gliomagenesis

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H3.3G34R/V-transformed interneuron progenitors co-opt PDGFRA for gliomagenesis

Project description:Histone H3.3 glycine 34 to arginine/valine (H3.3G34R/V) mutations occur in deadly hemispheric high-grade gliomas. These tumors show exquisite regional and temporal specificity, suggesting a developmental context permissive to the effects of G34R/V mutations. Here we present the molecular landscape of G34R/V gliomas (n=85) and show that 50% bear activating mutations in PDGFRA, with strong selection pressure for PDGFRAMUT clones at recurrence. We show that G34R/V tumors arise in interneuron progenitors of the foetal ventral forebrain expressing GSX2 and the DLX family of homeobox transcription factors, where terminal neuronal differentiation is impaired through aberrant G34R/V-mediated H3K27me3. Frequent co-occurrence of G34R/V & PDGFRAMUT is facilitated in this interneuron lineage-of-origin as PDGFRA forms an aberrant chromatin loop with the adjacent GSX2, hijacking its active chromatin conformation. At the single-cell level, G34R/V tumours entirely lack oligodendroglial transcriptional programs prominent in other glioma entities, and instead harbour dual neuronal and astroglial compartments. CRISPR-removal of H3.3G34R/V does not impact tumorigenicity suggesting this mutation becomes dispensable, while PDGFRAMUT are potently oncogenic regardless of G34 mutation. Collectively, our results suggest that G34R/V gliomas arise in foetal interneuron progenitors unable to undergo terminal differentiation, enabling co-option of PDGFRA through inappropriate expression and activating mutations to promote gliogenesis and oncogenicity. Reliance on PDGFRA for oncogenesis may be of therapeutic opportunity in G34R/V glioma.

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Altered patterning of trisomy 21 interneuron progenitors.

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SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans.

Project description:Recent collaborative efforts have subclassified malignant glioblastomas into 4 clinical relevant subtypes based on their signature genetic lesions. Platelet-derived growth factor receptor ? (PDGFRA) overexpression is concomitant with a loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) locus (encoding P16INK4A and P14ARF) in a large number of tumors within one subtype of glioblastomas. Here we report that activation of PDGFR? conferred tumorigenicity to Ink4a/Arf-deficient mouse astrocytes and human glioma cells in the brain. Restoration of p16INK4a but not p19ARF suppressed PDGFR?-promoted glioma formation. Mechanistically, abrogation of signaling modules in PDGFR? that lost capacity to bind to SHP-2 or PI3K significantly diminished PDGFR?-promoted tumorigenesis. Furthermore, inhibition of SHP-2 by shRNAs or pharmacological inhibitors disrupted the interaction of PI3K with PDGFR?, suppressed downstream AKT/mTOR activation, and impaired tumorigenesis of Ink4a/Arf-null cells, whereas expression of an activated PI3K mutant rescued the effect of SHP-2 inhibition on tumorigenicity. PDGFR? and PDGF-A are coexpressed in clinical glioblastoma specimens, and such co-expression is linked with activation of SHP-2/AKT/mTOR signaling. Together, our data suggest that in glioblastomas with Ink4a/Arf deficiency, overexpressed PDGFR? promotes tumorigenesis through the PI3K/AKT/mTOR-mediated pathway regulated by SHP-2 activity. These findings functionally validate the genomic analysis of glioblastomas and identify SHP-2 as a potential target for treatment of glioblastomas.

| S-EPMC3049395 | biostudies-literature

Cadherin 8 regulates proliferation of cortical interneuron progenitors.

Project description:Cortical interneurons are born in the ventral forebrain and migrate tangentially in two streams at the levels of the intermediate zone (IZ) and the pre-plate/marginal zone to the developing cortex where they switch to radial migration before settling in their final positions in the cortical plate. In a previous attempt to identify the molecules that regulate stream specification, we performed transcriptomic analysis of GFP-labelled interneurons taken from the two migratory streams during corticogenesis. A number of cadherins were found to be expressed differentially, with Cadherin-8 (Cdh8) selectively present in the IZ stream. We verified this expression pattern at the mRNA and protein levels on tissue sections and found approximately half of the interneurons of the IZ expressed Cdh8. Furthermore, this cadherin was also detected in the germinal zones of the subpallium, suggesting that it might be involved not only in the migration of interneurons but also in their generation. Quantitative analysis of cortical interneurons in animals lacking the cadherin at E18.5 revealed a significant increase in their numbers. Subsequent functional in vitro experiments showed that blocking Cdh8 function led to increased cell proliferation, with the opposite results observed with over-expression, supporting its role in interneuron generation.

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Project description:In the cerebellum, all GABAergic neurons are generated from the Ptf1a-expressing ventricular zone (Ptf1a domain). However, the machinery to produce different types of GABAergic neurons remains elusive. Here we show temporal regulation of distinct GABAergic neuron progenitors in the cerebellum. Within the Ptf1a domain at early stages, we find two subpopulations; dorsally and ventrally located progenitors that express Olig2 and Gsx1, respectively. Lineage tracing reveals the former are exclusively Purkinje cell progenitors (PCPs) and the latter Pax2-positive interneuron progenitors (PIPs). As development proceeds, PCPs gradually become PIPs starting from ventral to dorsal. In gain- and loss-of-function mutants for Gsx1 and Olig1/2, we observe abnormal transitioning from PCPs to PIPs at inappropriate developmental stages. Our findings suggest that the temporal identity transition of cerebellar GABAergic neuron progenitors from PCPs to PIPs is negatively regulated by Olig2 and positively by Gsx1, and contributes to understanding temporal control of neuronal progenitor identities.

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