title: 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 existin vivofor 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 diminishEzh2andSuv4-20hresponsible 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.
authors.affiliation: Department of Biology, University of Texas at San Antonio, San Antonio, Texas 78249, USA.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Rhodes
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Sandstrom
authors.affiliation: Department of Biology, University of Texas at San Antonio, San Antonio, Texas 78249, USA.
authors.forename: Shu-Wei Angela
authors.initials: SA
authors.lastname: Huang
authors.affiliation: Department of Biology, University of Texas at San Antonio, San Antonio, Texas 78249, USA.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Ludwig Maximilians University and Munich Center for Integrated Protein Science (CiPSM), Biomedical Center, Planegg-Martinsried, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Schotta
authors.affiliation: Department of Neurological Surgery, University of California at San Francisco, San Francisco, California 94143, USA.
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.affiliation: Department of Biology, University of Texas at San Antonio, San Antonio, Texas 78249, USA; Neuroscience Institute, University of Texas at San Antonio, San Antonio, Texas 78249, USA.
authors.forename: Chin-Hsing Annie
authors.initials: CA
authors.lastname: Lin
keywords: Chromatin Immunoprecipitation (ChIP); Cre recombinant protein; Enhancer of zeste (Human- Gene: EZH2, Protein: EZH2) (Mouse- Gene: Ezh2, Protein: Histone-lysine N-methyltransferase EZH2); Epigenetic Repression; Glioblastoma Multiforme (GBM); Neural Stem Progenitor Cells (NSPCs); Stereotaxic injection; Suppressor of variegation homolog 1 (Human- Gene: KMT5B or SUV420H1, Protein: lysine methyltransferase 5B, synonym Suv4-20h1) (Mouse- Gene: Suv4-20h1, synonym Kmt5b, Protein: Histone-lysine N-methyltransferase KMT5B, synonym Suv4-20h1); Suppressor of variegation homolog 2 (Human- Gene: KMT5C or SUV420H2, Protein: lysine methyltransferase 5C, synonym Suv4-20h2) (Mouse- Gene: Suv4-20h2, synonym Kmt5c, Protein: Histone-lysine N-methyltransferase KMT5C, synonym Suv4-20h2); tri-methylation at histone 3 lysine 27 (H3K27me3) and histone 4 lysine 20 (H4K20me3).