Mutual antagonism between Sox10 and NFIA regulates diversification of glial lineages and glioma subtypes

Abstract

Lineage progression and diversification is regulated by the coordinated action of unique sets of transcription factors. Oligodendrocytes (OL) and astrocytes (AS) comprise the glial sub-lineages in the central nervous system (CNS) and how their associated regulatory factors orchestrate lineage diversification during development and disease remains an open question. Sox10 and NFIA are key transcriptional regulators of gliogenesis associated with OL and AS. We found that NFIA inhibits Sox10 induction of OL differentiation through direct association and antagonism of its function. Conversely, we found that Sox10 antagonizes NFIA function and suppresses AS differentiation. Using this developmental paradigm as a model for glioma, we found that this relationship similarly regulates the generation of glioma sub-types. These studies describe the antagonistic relationship between Sox10/NFIA that regulates the balance of OL and AS fate during development and demonstrate for the first time that the transcriptional processes governing glial sub-lineage diversification oversee the generation of glioma sub-types.

Glia-specific enhancers and chromatin structure regulate NFIA expression and glioma tumorigenesis

“…Strikingly, CRISPR-mediated deletion of both the e123 and e161 enhancers resulted in decreased tumor growth and NFIA expression, and disrupted chromatin conformation. That tumor growth is attenuated when NFIA expression is reduced in the absence of both e123/e161 is consistent with other studies demonstrating that it plays a multiple key role in glioma proliferation and tumorigenesis 27,28,49 . In mouse glioma stem cell and human cell line xenograft models, NFIA regulates cell proliferation via repression of p21, whereas in an IUE-based model of oligodendroglioma, NFIA influences the generation of glioma “fates” or sub-types 29,30,52 .…”

“…Given that developmental processes are often reutilized during tumorigenesis, we sought to determine whether similar regulatory mechanisms are associated with NFIA expression in glioma 27,28 . Taking a bioinformatics approach, we assessed the co-expression of NFIA with its associated transcriptional regulators across a cohort of >400 high-grade human glioma expression datasets 29 .…”

“…To test this hypothesis, we used two different mouse models of glioma that harness in utero electroporation (IUE) of the embryonic cortex to facilitate gene manipulation. One model utilizes CRISPR/Cas9 (herein CRISPR/IUE) 31 gene editing of NF1 , PTEN , and p53, tumor suppressors that are commonly mutated in human glioma 32–34 , while the other utilizes PiggyBac (PB) targeting of glial lineages with oncogenic Ras to produce malignant glioma (herein PB-Ras/IUE) (Supplemental Figure S7; 28,35 ). Mutations in Ras are rare in glioma, however EGFR , PDGFR , and NF1 are frequently mutated and all of these pathways signal through Ras.…”

Long non-coding RNA RP5-833A20.1 inhibits proliferation, metastasis and cell cycle progression by suppressing the expression of NFIA in U251 cells

“…Furthermore, the overexpression of RP5-833A20.1 inhibited proliferation and cell cycle progression, and induced apoptosis in U251 cells. Studies have indicated that NFIA is involved in and may be central to a variety of biological processes through complicated mechanisms in glioma (22,23). In the present study, it was found that the expression of NFIA was downregulated in glioma tissues, compared with corresponding adjacent nontumor tissues.…”

“…Previous evidence indicates that lncRNAs are important in the pathogenesis of glioma, including HOTAIR (20), H19 (21) and Linc-POU3F3 (8 been annotated, only a few lncRNAs have been functionally characterized in glioma. Nuclear factor IA (NFIA), a member of the NFI family, is essential in glial development in the central nervous system; it specifies glial identity, maintains glial progenitors and regulates astrocyte differentiation (22,23). Increasing evidence has shown that NFIA is involved in and may be central in a variety of biological processes through complicated mechanisms in glioma (24,25).…”