scholarly journals Temporal and Spatial Transcriptomic Dynamics across Brain Development in Xenopus laevis tadpoles

2021 ◽  
Author(s):  
Aaron C Ta ◽  
Lin-Chien Huang ◽  
Caroline R McKeown ◽  
Jennifer E Bestman ◽  
Kendall Van Keuren-Jensen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Progenitor Cell ◽  
Neural Progenitor ◽  
Biological Processes ◽  
Cell Type ◽  
Mouse Development ◽  
Embryonic Mouse ◽  
Temporal And Spatial ◽  
The Brain

Abstract Amphibian metamorphosis is a transitional period that involves significant changes in the cell type populations and biological processes occurring in the brain. Analysis of gene expression dynamics during this process may provide insight into the molecular events underlying these changes. We conducted differential gene expression analyses of the developing X. laevis tadpole brain during this period in two ways: first, over stages of development in the midbrain, and second, across regions of the brain at a single developmental stage. We found that genes pertaining to positive regulation of neural progenitor cell proliferation as well as known progenitor cell markers were upregulated in the midbrain prior to metamorphic climax; concurrently, expression of cell cycle timing regulators decreased across this period, supporting the notion that cell cycle lengthening contributes to a decrease in proliferation by the end of metamorphosis. We also found that at the start of metamorphosis, neural progenitor populations appeared to be similar across the fore-, mid-, and hindbrain regions. Genes pertaining to negative regulation of differentiation were upregulated in the spinal cord compared to the rest of the brain, however, suggesting that a different program may regulate neurogenesis there. Finally, we found that regulation of biological processes like cell fate commitment and synaptic signaling follow similar trajectories in the brain across early tadpole metamorphosis and mid- to late-embryonic mouse development. By comparing expression across both temporal and spatial conditions, we have been able to illuminate cell type and biological pathway dynamics in the brain during metamorphosis.

scholarly journals Histone modifications form a cell-type-specific chromosomal bar code that persists through the cell cycle

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
John A. Halsall ◽  
Simon Andrews ◽  
Felix Krueger ◽  
Charlotte E. Rutledge ◽  
Gabriella Ficz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Histone Modifications ◽  
Expression Patterns ◽  
Cell Types ◽  
Cell Type ◽  
Bar Code ◽  
Genes Encoding ◽  
Cell Type Specific ◽  
Rolling Windows

AbstractChromatin configuration influences gene expression in eukaryotes at multiple levels, from individual nucleosomes to chromatin domains several Mb long. Post-translational modifications (PTM) of core histones seem to be involved in chromatin structural transitions, but how remains unclear. To explore this, we used ChIP-seq and two cell types, HeLa and lymphoblastoid (LCL), to define how changes in chromatin packaging through the cell cycle influence the distributions of three transcription-associated histone modifications, H3K9ac, H3K4me3 and H3K27me3. We show that chromosome regions (bands) of 10–50 Mb, detectable by immunofluorescence microscopy of metaphase (M) chromosomes, are also present in G1 and G2. They comprise 1–5 Mb sub-bands that differ between HeLa and LCL but remain consistent through the cell cycle. The same sub-bands are defined by H3K9ac and H3K4me3, while H3K27me3 spreads more widely. We found little change between cell cycle phases, whether compared by 5 Kb rolling windows or when analysis was restricted to functional elements such as transcription start sites and topologically associating domains. Only a small number of genes showed cell-cycle related changes: at genes encoding proteins involved in mitosis, H3K9 became highly acetylated in G2M, possibly because of ongoing transcription. In conclusion, modified histone isoforms H3K9ac, H3K4me3 and H3K27me3 exhibit a characteristic genomic distribution at resolutions of 1 Mb and below that differs between HeLa and lymphoblastoid cells but remains remarkably consistent through the cell cycle. We suggest that this cell-type-specific chromosomal bar-code is part of a homeostatic mechanism by which cells retain their characteristic gene expression patterns, and hence their identity, through multiple mitoses.

scholarly journals Histone chaperone HIRA regulates neural progenitor cell proliferation and neurogenesis via β-catenin

2017 ◽  
Vol 216 (7) ◽  
pp. 1975-1992 ◽  
Author(s):  
Yanxin Li ◽  
Jianwei Jiao
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Progenitor Cell ◽  
Neural Progenitor Cells ◽  
Neural Progenitor Cell ◽  
Neural Progenitor ◽  
Histone Chaperone ◽  
Epigenetic Mechanism ◽  
Progenitor Cell Proliferation ◽  
Early Neurogenesis

Histone cell cycle regulator (HIRA) is a histone chaperone and has been identified as an epigenetic regulator. Subsequent studies have provided evidence that HIRA plays key roles in embryonic development, but its function during early neurogenesis remains unknown. Here, we demonstrate that HIRA is enriched in neural progenitor cells, and HIRA knockdown reduces neural progenitor cell proliferation, increases terminal mitosis and cell cycle exit, and ultimately results in premature neuronal differentiation. Additionally, we demonstrate that HIRA enhances β-catenin expression by recruiting H3K4 trimethyltransferase Setd1A, which increases H3K4me3 levels and heightens the promoter activity of β-catenin. Significantly, overexpression of HIRA, HIRA N-terminal domain, or β-catenin can override neurogenesis abnormities caused by HIRA defects. Collectively, these data implicate that HIRA, cooperating with Setd1A, modulates β-catenin expression and then regulates neurogenesis. This finding represents a novel epigenetic mechanism underlying the histone code and has profound and lasting implications for diseases and neurobiology.

scholarly journals Overlapping and Unique Roles for C-Terminal Binding Protein 1 (CtBP1) and CtBP2 during Mouse Development

2002 ◽  
Vol 22 (15) ◽  
pp. 5296-5307 ◽  
Author(s):  
Jeffrey D. Hildebrand ◽  
Philippe Soriano
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Genetic Interaction ◽  
Binding Protein ◽  
Biological Processes ◽  
Vertebrate Development ◽  
Mouse Development ◽  
Axial Patterning ◽  
Wide Range

ABSTRACT The C-terminal binding protein (CtBP) family of proteins has been linked to multiple biological processes through their association with numerous transcription factors. We generated mice harboring mutations in both Ctbp1 and Ctbp2 to address the in vivo function of CtBPs during vertebrate development. Ctbp1 mutant mice are small but viable and fertile, whereas Ctbp2-null mice show defects in axial patterning and die by E10.5 due to aberrant extraembryonic development. Mice harboring various combinations of Ctbp1 and Ctbp2 mutant alleles exhibit dosage-sensitive defects in a wide range of developmental processes. The strong genetic interaction, as well as transcription assays with CtBP-deficient cells, indicates that CtBPs have overlapping roles in regulating gene expression. We suggest that the observed phenotypes reflect the large number of transcription factors whose activities are compromised in the absence of CtBP.

scholarly journals Progesterone Increases Rat Neural Progenitor Cell Cycle Gene Expression and Proliferation Via Extracellularly Regulated Kinase and Progesterone Receptor Membrane Components 1 and 2

Endocrinology ◽  
2009 ◽  
Vol 150 (7) ◽  
pp. 3186-3196 ◽  
Author(s):  
Lifei Liu ◽  
Junming Wang ◽  
Liqin Zhao ◽  
Jon Nilsen ◽  
Kelsey McClure ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Progesterone Receptor ◽  
Progenitor Cell ◽  
Neural Progenitor Cell ◽  
Neural Progenitor ◽  
Mammalian Brain ◽  
Cell Cycle Gene ◽  
Cell Cycle Genes ◽  
Expression Of Genes ◽  
Membrane Components

Progesterone receptor (PR) expression and regulation of neural progenitor cell (NPC) proliferation was investigated using NPC derived from adult rat brain. RT-PCR revealed that PRA mRNA was not detected in rat NPCs, whereas membrane-associated PRs, PR membrane components (PGRMCs) 1 and 2, mRNA were expressed. Progesterone-induced increase in 5-bromo-2-deoxyuridine incorporation was confirmed by fluorescent-activated cell sorting analysis, which indicated that progesterone promoted rat NPC exit of G0/G1 phase at 5 h, followed by an increase in S-phase at 6 h and M-phase at 8 h, respectively. Microarray analysis of cell-cycle genes, real-time PCR, and Western blot validation revealed that progesterone increased expression of genes that promote mitosis and decreased expression of genes that repress cell proliferation. Progesterone-induced proliferation was not dependent on conversion to metabolites and was antagonized by the ERK1/2 inhibitor UO126. Progesterone-induced proliferation was isomer and steroid specific. PGRMC1 small interfering RNA treatment, together with computational structural analysis of progesterone and its isomers, indicated that the proliferative effect of progesterone is mediated by PGRMC1/2. Progesterone mediated NPC proliferation and concomitant regulation of mitotic cell cycle genes via a PGRMC/ERK pathway mechanism is a potential novel therapeutic target for promoting neurogenesis in the mammalian brain.

scholarly journals E2f3a and E2f3b Contribute to the Control of Cell Proliferation and Mouse Development

2008 ◽  
Vol 29 (2) ◽  
pp. 414-424 ◽  
Author(s):  
Jean-Leon Chong ◽  
Shih-Yin Tsai ◽  
Nidhi Sharma ◽  
Rene Opavsky ◽  
Richard Price ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Specific Gene ◽  
Mouse Development ◽  
Double Knockout ◽  
Proliferation And Apoptosis ◽  
The Individual ◽  
Redundant Functions

ABSTRACT The E2f3 locus encodes two Rb-binding gene products, E2F3a and E2F3b, which are differentially regulated during the cell cycle and are thought to be critical for cell cycle progression. We targeted the individual inactivation of E2f3a or E2f3b in mice and examined their contributions to cell proliferation and development. Chromatin immunoprecipitation and gene expression experiments using mouse embryo fibroblasts deficient in each isoform showed that E2F3a and E2F3b contribute to G1/S-specific gene expression and cell proliferation. Expression of E2f3a or E2f3b was sufficient to support E2F target gene expression and cell proliferation in the absence of other E2F activators, E2f1 and E2f2, suggesting that these isoforms have redundant functions. Consistent with this notion, E2f3a −/− and E2f3b −/− embryos developed normally, whereas embryos lacking both isoforms (E2f3 −/−) died in utero. We also find that E2f3a and E2f3b have redundant and nonredundant roles in the context of Rb mutation. Analysis of double-knockout embryos suggests that the ectopic proliferation and apoptosis in Rb −/− embryos is mainly mediated by E2f3a in the placenta and nervous system and by both E2f3a and E2f3b in lens fiber cells. Together, we conclude that the contributions of E2F3a and E2F3b in cell proliferation and development are context dependent.

scholarly journals Identification of a neuronal gene expression signature: role of cell cycle arrest in murine neuronal differentiation in vitro

2011 ◽  
Vol 301 (3) ◽  
pp. R727-R745 ◽  
Author(s):  
Hady Felfly ◽  
Jin Xue ◽  
Alexander C. Zambon ◽  
Alysson Muotri ◽  
Dan Zhou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Stem Cells ◽  
Neuronal Differentiation ◽  
Gene Expression Signature ◽  
Neuronal Morphology ◽  
Primary Neurons ◽  
Embryonic Mouse ◽  
Expression Signature ◽  
Neuronal Gene

Stem cells are a potential key strategy for treating neurodegenerative diseases in which the generation of new neurons is critical. A better understanding of the characteristics and molecular properties of neural stem cells (NSCs) and differentiated neurons can help with assessing neuronal maturity and, possibly, in devising better therapeutic strategies. We have performed an in-depth gene expression profiling study of murine NSCs and primary neurons derived from embryonic mouse brains. Microarray analysis revealed a neuron-specific gene expression signature that distinguishes primary neurons from NSCs, with elevated levels of transcripts involved in neuronal functions, such as neurite development and axon guidance in primary neurons and decreased levels of multiple cytokine transcripts. Among the differentially expressed genes, we found a statistically significant enrichment of genes in the ephrin, neurotrophin, CDK5, and actin pathways, which control multiple neuronal-specific functions. We then artificially blocked the cell cycle of NSCs with mitomycin C (MMC) and examined cellular morphology and gene expression signatures. Although these MMC-treated NSCs displayed a neuronal morphology and expressed some neuronal differentiation marker genes, their gene expression patterns were very different from primary neurons. We conclude that 1) fully differentiated mouse primary neurons display a specific neuronal gene expression signature; 2) cell cycle block at the S phase in NSCs with MMC does not induce the formation of fully differentiated neurons; 3) cytokines change their expression pattern during differentiation of NSCs into neurons; and 4) signaling pathways of ephrin, neurotrophin, CDK5, and actin, related to major neuronal features, are dynamically enriched in genes showing changes in expression level.

scholarly journals The MAP4K4-STRIPAK complex promotes growth and tissue invasion in medulloblastoma

2021 ◽  
Author(s):  
Jessica Migliavacca ◽  
Buket Zuellig ◽  
Charles Capdeville ◽  
Michael Andreas Grotzer ◽  
Martin Baumgartner
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Target Gene ◽  
Biological Processes ◽  
Precise Control ◽  
Target Gene Expression ◽  
Tissue Invasion ◽  
Proliferative Effect ◽  
Pathway Regulation ◽  
The Brain

Proliferation and motility are mutually exclusive biological processes associated with cancer that depend on precise control of upstream signaling pathways with overlapping functionalities. We find that STRN3 and STRN4 scaffold subunits of the STRIPAK complex interact with MAP4K4 for pathway regulation in medulloblastoma. Disruption of the MAP4K4-STRIPAK complex impairs growth factor-induced migration and tissue invasion and stalls YAP/TAZ target gene expression and oncogenic growth. The migration promoting functions of the MAP4K4-STRIPAK complex involve the activation of novel PKCs and the phosphorylation of the membrane targeting S157 residue of VASP through MAP4K4. The anti-proliferative effect of complex disruption is associated with reduced YAP/TAZ target gene expression and results in repressed tumor growth in the brain tissue. This dichotomous functionality of the STRIPAK complex in migration and proliferation control acts through MAP4K4 regulation in tumor cells and provides relevant mechanistic insights into novel tumorigenic functions of the STRIPAK complex in medulloblastoma.

scholarly journals The lncRNA EPB41L4A-AS1 regulates gene expression in the nucleus and exerts cell type-dependent effects on cell cycle progression

2021 ◽  
Author(s):  
Helle Samdal ◽  
Siv Anita Hegre ◽  
Konika Chawla ◽  
Nina-Beate Liabakk ◽  
Per Arne Aas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Phase Distribution ◽  
Cell Types ◽  
Metabolic Reprogramming ◽  
Cycle Phase ◽  
Cell Type ◽  
Chip Sequencing ◽  
Cell Cycle Phase Distribution

AbstractThe long non-coding RNA (lncRNA) EPB41L4A-AS1 is aberrantly expressed in various cancers and has been reported to be involved in metabolic reprogramming and as a repressor of the Warburg effect. Although the biological relevance of EPB41L4A-AS1 is evident, its functional role seems to vary depending on cell type and state of disease. By combining RNA sequencing and ChIP sequencing of cell cycle synchronized HaCaT cells we previously identified EPB41L4A-AS1 to be one of 59 lncRNAs with potential cell cycle functions. Here, we demonstrate that EPB41L4A-AS1 exists as bright foci and regulates gene expression in the nucleus in both cis and trans. Specifically, we find that EPB41L4A-AS1 positively regulates its sense overlapping gene EPB41L4A and influences expression of hundreds of other genes, including genes involved in cell proliferation. Finally, we show that EPB41L4A-AS1 affects cell cycle phase distribution, though these effects vary between cell types.

scholarly journals Ush regulates hemocyte-specific gene expression, fatty acid metabolism and cell cycle progression and cooperates with dNuRD to orchestrate hematopoiesis

2020 ◽  
Author(s):  
Jonathan Lenz ◽  
Robert Liefke ◽  
Julianne Funk ◽  
Samuel Shoup ◽  
Andrea Nist ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Stem Cell ◽  
Specific Gene ◽  
Cell Cycle Regulators ◽  
Cell Type ◽  
Nurd Complex ◽  
Nucleosome Remodeling ◽  
Specific Gene Expression ◽  
Cell Type Specific

AbstractThe generation of lineage-specific gene expression programmes that alter proliferation capacity, metabolic profile and cell type-specific functions during differentiation from multipotent stem cells to specialised cell types is crucial for development. During differentiation gene expression programmes are dynamically modulated by a complex interplay between sequence-specific transcription factors, associated cofactors and epigenetic regulators. Here, we study U-shaped (Ush), a multi-zinc finger protein that maintains the multipotency of stem cell-like hemocyte progenitors during Drosophila hematopoiesis. Using genomewide approaches we reveal that Ush binds to promoters and enhancers and that it controls the expression of three gene classes that encode proteins relevant to stem cell-like functions and differentiation: cell cycle regulators, key metabolic enzymes and proteins conferring specific functions of differentiated hemocytes. We employ complementary biochemical approaches to characterise the molecular mechanisms of Ush-mediated gene regulation. We uncover distinct Ush isoforms one of which binds the Nucleosome Remodeling and Deacetylation (NuRD) complex using an evolutionary conserved peptide motif. Remarkably, the Ush/NuRD complex specifically contributes to the repression of lineage-specific genes but does not impact the expression of cell cycle regulators or metabolic genes. This reveals a mechanism that enables specific and concerted modulation of functionally related portions of a wider gene expression programme. Finally, we use genetic assays to demonstrate that Ush and NuRD regulate enhancer activity during hemocyte differentiation in vivo and that both cooperate to suppress the differentiation of lamellocytes, a highly specialised blood cell type. Our findings reveal that Ush coordinates proliferation, metabolism and cell type-specific activities by isoform-specific cooperation with an epigenetic regulator.

Sign in / Sign up

Export Citation Format

Share Document