Tracing the Origins of Glioblastoma by Investigating the Role of Gliogenic and Related Neurogenic Genes/Signaling Pathways in GBM Development: A Systematic Review

Background: Glioblastoma is one of the most aggressive tumors. The etiology and the factors determining its onset are not yet entirely known. This study investigates the origins of GBM and for this purpose it focuses primarily on developmental gliogenic processes. It also focuses on impact of the related neurogenic developmental processes in glioblastoma oncogenesis. It also addresses why glial cells are at more risk of tumor development compared to neurons.Methods:Databases including PubMed, MEDLINE and Google Scholar were searched for published articles without any date restrictions, involving glioblastoma, gliogenesis, neurogenesis, stemness, neural stem cells, gliogenic signaling and pathways, neurogenic signaling and pathways, astrocytogenic genes.Results:The origin of GBM is dependent on dysregulation in multiple genes and pathways that accumulatively converge the cells towards oncogenesis. There are multiple layers of steps in glioblastoma oncogenesis including the failure of cell fate specific genes to keep the cells differentiated in their specific cell type such as p300, BMP, HOPX, NRSF/REST and others. There are genes and signaling pathways that are involved in differentiation and also contribute to GBM such as FGFR3, JAK-STAT, hey1 and others. The genes that contribute to differentiation processes but also contribute to stemness in GBM include notch, Sox9, Sox4, c-myc gene overrides p300 and then GFAP, leading to upregulation of nestin, SHH, NF-κB and others. GBM mutations pathologically impact the cell circuitry such as the interaction between Sox2 and JAK-STAT pathway, resulting in GBM development and progression. Conclusion: Glioblastoma originates when the gene expression of key gliogenic genes and signaling pathways become dysregulated. This study identifies key gliogenic genes having the ability to control oncogenesis in glioblastoma cells, including p300, BMP, PAX6, HOPX, NRSF/REST, LIF, TGF beta. It also identifies key neurogenic genes having the ability to control oncogenesis including PAX6, neurogenins including Ngn1, NeuroD1, NeuroD4, Numb, NKX6-1 Ebf, Myt1, ASCL1 and others. This study also postulates how aging contributes to the onset of glioblastoma by dysregulating the gene expression of NF-κB, REST/NRSF, ERK, AKT, EGFR and others.

Abstract MP142: Genome-wide Studies Reveal the Essential and Opposite Roles of Arid1a in Controlling Human Cardiogenesis and Neurogenesis From Pluripotent Stem Cells

Background: Early human heart and brain development simultaneously occur during embryogenesis. Notably, in human newborns, congenital heart defects strongly associate with neurodevelopmental abnormalities, suggesting a common gene/complex underlying both cardiogenesis and neurogenesis. However, due to lack of in vivo studies, the molecular mechanisms that govern both early human heart and brain development remain elusive. The evolutionarily conserved ATP-dependent SWI/SNF complex is one of the largest chromatin remodeling complexes, consisting of ~15 subunits, including SMARCA2 (also known as BRM) or SMARCA4 (also known as BRG1) as the ATPase catalytic subunit. Several BRG1-associated factors (BAFs), such as ARID1A (Baf250a), have DNA binding capacity and assemble with either BRM or BRG1 to form a functional chromatin-remodeling complex. A single amino acid mutation (Arid1aV 1068G/V1068G ), impaired Arid1a-DNA interactions and resulted in both cardiac neural defects. Mutations in 4 different SWI/SNF subunits including ARID1A/B were identified in human congenital syndromes that include both neural and cardiac defects. Results: Here, we report ARID1A, which is a DNA-binding-subunit of the SWI/SNF epigenetic complex, controls both neurogenesis and cardiogenesis from human embryonic stem cells (hESCs) via employing distinct mechanisms. CRISPR/Cas-9 knockout of ARID1A (ARID1A -/- ) led to spontaneous differentiation of neural cells together with globally enhanced expression of neurogenic genes in undifferentiated hESCs. Additionally, when compared with WT hESCs, cardiac differentiation from ARID1A -/- hESCs was prominently suppressed, whereas neural differentiation was significantly promoted. Whole genome-wide ChIP-seq and ATAC-seq analyses revealed that ARID1A was required to open chromatin accessibility on promoters of essential cardiogenic genes, and temporally associated with key cardiogenic transcriptional factors T and MEF2C during early cardiac development. However, during neural development, transcription of most essential neurogenic genes was dependent on ARID1A and ARID1A could interact with REST, which is a known transcriptional repressor. Conclusions: We uncovered the key and opposite roles by ARID1A to govern both early human cardiac and neural development and characterized the mechanisms. We found global chromatin accessibility on cardiogenic genes was dependent on ARID1A, whereas transcriptional activity of neurogenic genes was regulated by ARID1A, possibly through ARID1A-REST interaction.

Genome-wide Studies Reveal the Essential and Opposite Roles of ARID1A in Controlling Human Cardiogenesis and Neurogenesis from Pluripotent Stem Cells

BackgroundEarly human heart and brain development simultaneously occur during embryogenesis. Notably, in human newborns, congenital heart defects strongly associate with neurodevelopmental abnormalities, suggesting a common gene/complex underlying both cardiogenesis and neurogenesis. However, due to lack of in vivo studies, the molecular mechanisms that govern both early human heart and brain development remain elusive.ResultsHere, we report ARID1A, which is a DNA-binding-subunit of the SWI/SNF epigenetic complex, controls both neurogenesis and cardiogenesis from human embryonic stem cells (hESCs) via employing distinct mechanisms. Knockout of ARID1A (ARID1A-/-) led to spontaneous differentiation of neural cells together with globally enhanced expression of neurogenic genes in undifferentiated hESCs. Additionally, when compared with WT hESCs, cardiac differentiation from ARID1A-/- hESCs was prominently suppressed, whereas neural differentiation was significantly promoted. Whole genome-wide scRNA-seq, ATAC-seq, and ChIP-seq analyses revealed that ARID1A was required to open chromatin accessibility on promoters of essential cardiogenic genes, and temporally associated with key cardiogenic transcriptional factors T and MEF2C during early cardiac development. However, during early neural development, transcription of most essential neurogenic genes was dependent on ARID1A, which could interact with a known neural restrictive silencer factor REST/NRSF.ConclusionsWe uncovered the opposite roles by ARID1A to govern both early cardiac and neural development from pluripotent stem cells. Global chromatin accessibility on cardiogenic genes is dependent on ARID1A, whereas transcriptional activity of neurogenic genes is under control by ARID1A, possibly through ARID1A-REST/NRSF interaction.

Assessment and site-specific manipulation of DNA (hydroxy-)methylation during mouse corticogenesis

Dynamic changes in DNA (hydroxy-)methylation are fundamental for stem cell differentiation. However, the signature of these epigenetic marks in specific cell types during corticogenesis is unknown. Moreover, site-specific manipulation of cytosine modifications is needed to reveal the significance and function of these changes. Here, we report the first assessment of (hydroxy-)methylation in neural stem cells, neurogenic progenitors, and newborn neurons during mammalian corticogenesis. We found that gain in hydroxymethylation and loss in methylation occur sequentially at specific cellular transitions during neurogenic commitment. We also found that these changes predominantly occur within enhancers of neurogenic genes up-regulated during neurogenesis and target of pioneer transcription factors. We further optimized the use of dCas9-Tet1 manipulation of (hydroxy-)methylation, locus-specifically, in vivo, showing the biological relevance of our observations for Dchs1, a regulator of corticogenesis involved in developmental malformations and cognitive impairment. Together, our data reveal the dynamics of cytosine modifications in lineage-related cell types, whereby methylation is reduced and hydroxymethylation gained during the neurogenic lineage concurrently with up-regulation of pioneer transcription factors and activation of enhancers for neurogenic genes.

Loss of neurogenesis in Hydra leads to compensatory regulation of neurogenic and neurotransmission genes in epithelial cells

Hydra continuously differentiates a sophisticated nervous system made of mechanosensory cells (nematocytes) and sensory–motor and ganglionic neurons from interstitial stem cells. However, this dynamic adult neurogenesis is dispensable for morphogenesis. Indeed animals depleted of their interstitial stem cells and interstitial progenitors lose their active behaviours but maintain their developmental fitness, and regenerate and bud when force-fed. To characterize the impact of the loss of neurogenesis in Hydra , we first performed transcriptomic profiling at five positions along the body axis. We found neurogenic genes predominantly expressed along the central body column, which contains stem cells and progenitors, and neurotransmission genes predominantly expressed at the extremities, where the nervous system is dense. Next, we performed transcriptomics on animals depleted of their interstitial cells by hydroxyurea, colchicine or heat-shock treatment. By crossing these results with cell-type-specific transcriptomics, we identified epithelial genes up-regulated upon loss of neurogenesis: transcription factors ( Dlx , Dlx1 , DMBX1/Manacle , Ets1 , Gli3 , KLF11 , LMX1A , ZNF436 , Shox1 ), epitheliopeptides ( Arminins , PW peptide ), neurosignalling components ( CAMK1D , DDCl2 , Inx1 ), ligand-ion channel receptors ( CHRNA1 , NaC7 ), G-Protein Coupled Receptors and FMRFRL. Hence epitheliomuscular cells seemingly enhance their sensing ability when neurogenesis is compromised. This unsuspected plasticity might reflect the extended multifunctionality of epithelial-like cells in early eumetazoan evolution.

SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis

Newborn granule neurons generated from neural progenitor cells (NPCs) in the adult hippocampus play a key role in spatial learning and pattern separation. However, the molecular mechanisms that control activation of their neurogenic program remain poorly understood. Here, we report a novel function for the pluripotency factor sex-determining region Y (SRY)-related HMG box 2 (SOX2) in regulating the epigenetic landscape of poised genes activated at the onset of neuronal differentiation. We found that SOX2 binds to bivalently marked promoters of poised proneural genes [neurogenin 2 (Ngn2) and neurogenic differentiation 1 (NeuroD1)] and a subset of neurogenic genes [e.g., SRY-box 21 (Sox21), brain-derived neurotrophic factor (Bdnf), and growth arrest and DNA-damage–inducible, beta (Gadd45b)] where it functions to maintain the bivalent chromatin state by preventing excessive polycomb repressive complex 2 activity. Conditional ablation of SOX2 in adult hippocampal NPCs impaired the activation of proneural and neurogenic genes, resulting in increased neuroblast death and functionally aberrant newborn neurons. We propose that SOX2 sets a permissive epigenetic state in NPCs, thus enabling proper activation of the neuronal differentiation program under neurogenic cue.