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METTL7B is an essential epigenetic regulator of lineage specification in glioblastoma [DNAme]

ABSTRACT: Glioblastomas are the most common malignant brain tumours in adults; they are highly aggressive, heterogeneous and plastic. We have identified METTL7B as an essential regulator of lineage specification in glioblastoma, with impact on both tumour size and invasiveness in in vivo models. Single cell transcriptomic analysis of these tumours and of cerebral organoids derived from expanded potential stem cells overexpressing METTL7B identified a regulatory role for the gene in the neural stem cells to astrocyte differentiation trajectory. Mechanistically, METTL7B downregulates the expression of key neuronal differentiation players, including SALL2, via DNA methylation and post-translational modifications of histone marks.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243130 | GEO | 2024/07/01

REPOSITORIES: GEO

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Project description:The SALL2 transcription factor (TF), an evolutionarily conserved gene through vertebrates, is involved in normal development and neuronal differentiation and considered as a tumor suppressor in certain human cancers. Several transcriptional targets of SALL2 are identified, these include the p21CDKN1A and p16INK4A cyclin-dependent kinase inhibitors, and the PMAIP1 and Bax pro-apoptotic genes, among others in various cell types. The human and mouse SALL2 gene loci contain two promoters, each one controlling the expression of a different protein isoform (namely E1 and E1A). However, several improvements on the human genome assembly and gene annotation through next-generation sequencing technologies over time reveal correction and annotation of additional isoforms, obscuring dissection of SALL2 isoform-specific transcriptional targets. We here integrated current data of normal/tumor gene expression databases along with ChIP-seq binding profiles to analyze SALL2 isoforms expression distribution and infer isoform-specific SALL2 targets. We found that the canonical SALL2 isoform (E1) is one of the lowest expressed, while isoform E1A is highly predominant across cell types. To dissect SALL2 isoform-specific targets, we analyzed publicly available ChIP-seq data from glioblastoma multiforme (GBM) and in-house ChIP-seq datasets performed in SALL2 wild-type and isoform E1A knockout HEK293 cells. Another available ChIP-seq data in HEK293 cells (ENCODE Consortium Phase III) overexpressing a non-canonical SALL2 isoform (herein named short_E1A) was analyzed but not included in the final analysis because we demonstrated that short_E1A is mostly localized in the cytoplasm, making impractical to dissect its direct transcriptional targets in this cell model. Regardless of cell type, our analysis reveals a highly conserved network of brain-specific TFs (i.e., SALL3, POU3F2, and NPAS3) and PODXL as a gene that is likely regulated by SALL2 across cell types. Our data integration identified a conserved molecular network in which SALL2 regulates target genes and encourages validation of publicly available ChIP-seq datasets for assessing transcriptional targets of a specific gene/isoform. Financial support: This work was supported by Fondecyt Regular Grants #1151031, #1191172 to Roxana Pincheira Fondecyt Regular Grant #120 to Ariel Castro, Postdoctorate Fondecyt Grant #3160129 and Fondecyt de Iniciacion # 1119028 to Matias I.Hepp.

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METTL7B is an essential epigenetic regulator of lineage specification in glioblastoma [DNAme]

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