Cross-species analyses unravel the complexity of H3K27me3 and H4K20me3 in the context of neural stem progenitor cells

Abstract

Neural stem progenitor cells (NSPCs) in the human subventricular zone (SVZ) potentially contribute to life-long neurogenesis, yet subtypes of glioblastoma multiforme (GBM) contain NSPC signatures that highlight the importance of cell fate regulation. Among numerous regulatory mechanisms, the post-translational methylations onto histone tails are crucial regulator of cell fate. The work presented here focuses on the role of two repressive chromatin marks tri-methylations on histone H3 lysine 27 (H3K27me3) and histone H4 lysine 20 (H4K20me3) in the adult NSPC within the SVZ. To best model healthy human NSPCs as they exist in vivo for epigenetic profiling of H3K27me3 and H4K20me3, we utilized NSPCs isolated from the adult SVZ of baboon brain (Papio anubis) with brain structure and genomic level similar to human. The putative role of H3K27me3 in normal NSPCs predominantly falls into the regulation of gene expression, cell cycle, and differentiation, whereas H4K20me3 is involved in DNA replication/repair, metabolism, and cell cycle. Using conditional knock-out mouse models to diminish Ezh2 and Suv4-20h responsible for H3K27me3 and H4K20me3, respectively, we found that both repressive marks have irrefutable function for cell cycle regulation in the NSPC population. While both EZH2/H3K27me3 and Suv4-20h/H4K20me3 have implication in cancers, our comparative genomics approach between healthy NSPCs and human GBM specimens revealed that substantial sets of genes enriched with H3K27me3 and H4K20me3 in the NSPCs are altered in the human GBM. In sum, our integrated analyses across species highlight important roles of H3K27me3 and H4K20me3 in normal and disease conditions in the context of NSPC.

The Mitochondrial Protein VDAC1 at the Crossroads of Cancer Cell Metabolism: The Epigenetic Link

“…In addition, the repressive chromatin marks H3K27me3 and H4K20me3 were shown to play important roles in normal and disease conditions in the context of neural stem progenitor cells where H3K27me3 is found primarily at promoters in gene-rich regions, and is closely associated with developmental regulators in embryonic stem cells, including Hox and Sox genes. Moreover, their levels were altered in the human GBM [119]. In this context, our results indicated that the modified histones H3K4me, 3H3K9me, H3K27me, H3K27me3, and H4K20me3 were strongly reduced in the si-hVDAC1-TTs (Figure 4).…”

Comparative analyses identify molecular signature of MRI-classified SVZ-associated glioblastoma

“…Additionally, we sought to interrogate the gene expression signature common across various GBM subclasses (http://tcgadata.nci.nih.gov/), 2,9 glioma stem cell profile, 14 and the SVZassociated GBMs. 10,16,17 Our analysis across these large data sets identified that 9 genes (PBK, CENPA, KIF15, DEPDC1, CDC6, DLG7, KIF18A, EZH2, HMMR) crucial for cell cycle, centromere assembly, and chromosome segregation were commonly upregulated that highlights a unique mechanism to distinguish GBM from non-neoplastic tissues. Further, the notion that region-specific neural stem and progenitor cells (NSPCs) may give rise to molecularly distinct subtypes of brain tumor upon dysregulation.…”

“…To ascertain characteristics of NSPCs as they exist in vivo for gene expression analysis, we purified NSPCs from the non-human primate baboon brain for deep RNA-Seq analysis to reveal gene expression pattern specific in NSPCs. 16,17 Using deep RNA-Seq, we had analyzed differential gene expression in MRI-classified group I and group II GBM compared with control specimens. Subsequently, we attempted the comparison of expression profiles between endogenous NSPCs and MRI-classified SVZ-associated GBM (Fig.…”

“…In addition, our previous comparative analysis between healthy NSPCs and MRI-characterized group I/II GBM specimens revealed that substantial sets of genes enriched with H3K27me3, catalyzed by EZH2, are altered in the human GBM. 17 Furthermore, the deposition of centromeric protein CENPA (a histone H3 variant) are known to be critical for centromere assembly during chromosome segregation at the stage of mitosis and the accurate distribution of genetic materials through cell division depends on the centromere marked by CENPA, 27 which is upregulated across GBM cases.…”

“…The biologic and clinical relevance of epigenetic dysregulation and intratumoral heterogeneity are becoming more apparent for diagnosis and prediction of patient outcome, in which tumor cells with reversible epigenetic states may drive drug resistance. Therefore, our previous exploration at the forefront of epigenetic heterogeneity in GBM using large-scale and computational approaches presents a high degree of aberrant histone methylation associated with altered gene expression in MRI-classified group I/II GBM 16,17 It is worth mentioning that these SVZ-associated The level of H3K36me3 is increased in histone fractions of GBM patients. The unmodified H4 was used for loading control.…”