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RP58 Represses Transcriptional Programs Linked to Nonneuronal Cell Identity and Glioblastoma Subtypes in Developing Neurons.

TitleRP58 Represses Transcriptional Programs Linked to Nonneuronal Cell Identity and Glioblastoma Subtypes in Developing Neurons.
Publication TypeJournal Article
Year of Publication2021
AuthorsXiang C, Frietze KK, Bi Y, Li Y, Dal Pozzo V, Pal S, Alexander N, Baubet V, D'Acunto V, Mason CE, Davuluri RV, Dahmane N
JournalMol Cell Biol
Volume41
Issue7
Paginatione0052620
Date Published2021 06 23
ISSN1098-5549
KeywordsAnimals, Cell Differentiation, Cell Movement, Gene Expression Regulation, Developmental, Glioblastoma, Mice, Neurogenesis, Neuroglia, Neurons, Repressor Proteins
Abstract

How mammalian neuronal identity is progressively acquired and reinforced during development is not understood. We have previously shown that loss of RP58 (ZNF238 or ZBTB18), a BTB/POZ-zinc finger-containing transcription factor, in the mouse brain leads to microcephaly, corpus callosum agenesis, and cerebellum hypoplasia and that it is required for normal neuronal differentiation. The transcriptional programs regulated by RP58 during this process are not known. Here, we report for the first time that in embryonic mouse neocortical neurons a complex set of genes normally expressed in other cell types, such as those from mesoderm derivatives, must be actively repressed in vivo and that RP58 is a critical regulator of these repressed transcriptional programs. Importantly, gene set enrichment analysis (GSEA) analyses of these transcriptional programs indicate that repressed genes include distinct sets of genes significantly associated with glioma progression and/or pluripotency. We also demonstrate that reintroducing RP58 in glioma stem cells leads not only to aspects of neuronal differentiation but also to loss of stem cell characteristics, including loss of stem cell markers and decrease in stem cell self-renewal capacities. Thus, RP58 acts as an in vivo master guardian of the neuronal identity transcriptome, and its function may be required to prevent brain disease development, including glioma progression.

DOI10.1128/MCB.00526-20
Alternate JournalMol Cell Biol
PubMed ID33903225
Grant ListR01 NS093120 / NS / NINDS NIH HHS / United States