scholarly journals Differential chromatin accessibility in developing projection neurons is correlated with transcriptional regulation of cell fate

2019 ◽  
Author(s):  
Whitney E. Heavner ◽  
Shaoyi Ji ◽  
James H. Notwell ◽  
Ethan S. Dyer ◽  
Alex M. Tseng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Progenitor Cells ◽  
Cell Fate ◽  
Expression Profiles ◽  
Chromatin Accessibility ◽  
Transcriptional Networks ◽  
Projection Neurons ◽  
Cortical Projection ◽  
Functional Features

AbstractWe are only just beginning to catalog the vast diversity of cell types in the cerebral cortex. Such categorization is a first step toward understanding how diversification relates to function. All cortical projection neurons arise from a uniform pool of progenitor cells that lines the ventricles of the forebrain. It is still unclear how these progenitor cells generate the more than fifty unique types of mature cortical projection neurons defined by their distinct gene expression profiles. Here we compare gene expression and chromatin accessibility of two subclasses of projection neurons with divergent morphological and functional features as they develop in the mouse brain between embryonic day 13 and postnatal day 5 in order to identify transcriptional networks that diversity neuron cell fate. We find groups of transcription factors whose expression is correlated with chromatin accessibility, transcription factor binding motifs, and lncRNAs that define each subclass and validate the function of a family of novel candidate genes in vitro. Our multidimensional approach reveals that subclass-specific chromatin accessibility is significantly correlated with gene expression, providing a resource for generating new specific genetic drivers and revealing regions of the genome that are particularly susceptible to harmful genetic mutations by virtue of their correlation with important developmental genes.

scholarly journals Transcription factor expression defines subclasses of developing projection neurons highly similar to single-cell RNA-seq subtypes

2020 ◽  
Vol 117 (40) ◽  
pp. 25074-25084 ◽  
Author(s):  
Whitney E. Heavner ◽  
Shaoyi Ji ◽  
James H. Notwell ◽  
Ethan S. Dyer ◽  
Alex M. Tseng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Single Cell ◽  
Progenitor Cells ◽  
Cell Fate ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Projection Neurons ◽  
Cortical Projection ◽  
Functional Features

We are only just beginning to catalog the vast diversity of cell types in the cerebral cortex. Such categorization is a first step toward understanding how diversification relates to function. All cortical projection neurons arise from a uniform pool of progenitor cells that lines the ventricles of the forebrain. It is still unclear how these progenitor cells generate the more than 50 unique types of mature cortical projection neurons defined by their distinct gene-expression profiles. Moreover, exactly how and when neurons diversify their function during development is unknown. Here we relate gene expression and chromatin accessibility of two subclasses of projection neurons with divergent morphological and functional features as they develop in the mouse brain between embryonic day 13 and postnatal day 5 in order to identify transcriptional networks that diversify neuron cell fate. We compare these gene-expression profiles with published profiles of single cells isolated from similar populations and establish that layer-defined cell classes encompass cell subtypes and developmental trajectories identified using single-cell sequencing. Given the depth of our sequencing, we identify groups of transcription factors with particularly dense subclass-specific regulation and subclass-enriched transcription factor binding motifs. We also describe transcription factor-adjacent long noncoding RNAs that define each subclass and validate the function of Myt1l in balancing the ratio of the two subclasses in vitro. Our multidimensional approach supports an evolving model of progressive restriction of cell fate competence through inherited transcriptional identities.

Gene expression profiles of RAW264.7 macrophages stimulated with preparations of LPS differing in isolation and purity

2011 ◽  
Vol 18 (1) ◽  
pp. 80-88 ◽  
Author(s):  
Holly R Rutledge ◽  
Weiwen Jiang ◽  
Jun Yang ◽  
Laura A Warg ◽  
David A Schwartz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Differentially Expressed ◽  
Transcriptional Networks ◽  
Molecular Pathways ◽  
Raw264.7 Macrophages ◽  
Lps Treatment

Lipopolysaccharide is a major component of the cell wall of Gram-negative bacteria and a potent stimulator of innate immune response via TLR4. Studies on the LPS action both in vivo and in vitro have used different preparations of LPS, including ultra-pure LPS (LIST) and a less pure but less expensive form (Sigma) isolated from Escherichia coli serotype O111:B4. The difference between the effects of these compounds has not been well studied although this information is important in understanding TLR stimulation. In this study, we compared response of RAW264.7 macrophage cells treated LIST or Sigma LPS for 6 h and 24 h. Gene expression data were analyzed to identify specific genes and pathways that are in common and unique to the two LPS preparations. Seven hundred fifty-five genes were differentially expressed at 6 h in response to Sigma LPS and 973 were differentially expressed following LIST LPS treatment, with 503 in common. At 24 h, Sigma LPS induced or repressed 901 genes while 1646 genes were differentially regulated by LIST LPS treatment; 701 genes were shared by two forms of LPS. Although considerably more genes were differentially expressed in response to LIST LPS, similar molecular pathways and transcriptional networks were activated by the two LPS preparations. We also treated bone marrow-derived macrophages (BMMs) from three strains of mice with different concentrations of LIST and Sigma LPS and showed that BMMs produced more IL-6 and TNF-α in response to LIST LPS at low LPS concentrations but, at higher LPS concentrations, more cytokines were produced in response to stimulation by Sigma LPS. Together, these findings suggest that, despite activation of similar molecular pathways by LIST and Sigma LPS preparations, residual protein impurities in the Sigma LPS preparation may nevertheless influence the transcriptional profile attributed to TLR4 stimulation.

scholarly journals Mapping Astrocyte Transcriptional Signatures in Response to Neuroactive Compounds

2021 ◽  
Vol 22 (8) ◽  
pp. 3975
Author(s):  
Debosmita Sardar ◽  
Brittney Lozzi ◽  
Junsung Woo ◽  
Teng-Wei Huang ◽  
Caroline Cvetkovic ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Chromatin Accessibility ◽  
Normal Brain ◽  
Gamma Aminobutyric Acid ◽  
Neuroactive Compounds ◽  
Critical Components

Astrocytes play central roles in normal brain function and are critical components of synaptic networks that oversee behavioral outputs. Despite their close affiliation with neurons, how neuronal-derived signals influence astrocyte function at the gene expression level remains poorly characterized, largely due to difficulties associated with dissecting neuron- versus astrocyte-specific effects. Here, we use an in vitro system of stem cell-derived astrocytes to identify gene expression profiles in astrocytes that are influenced by neurons and regulate astrocyte development. Furthermore, we show that neurotransmitters and neuromodulators induce distinct transcriptomic and chromatin accessibility changes in astrocytes that are unique to each of these neuroactive compounds. These findings are highlighted by the observation that noradrenaline has a more profound effect on transcriptional profiles of astrocytes compared to glutamate, gamma-aminobutyric acid (GABA), acetylcholine, and serotonin. This is demonstrated through enhanced noradrenaline-induced transcriptomic and chromatin accessibility changes in vitro and through enhanced calcium signaling in vivo. Taken together, our study reveals distinct transcriptomic and chromatin architecture signatures in astrocytes in response to neuronal-derived neuroactive compounds. Since astrocyte function is affected in all neurological disorders, this study provides a new entry point for exploring genetic mechanisms of astrocyte–neuron communication that may be dysregulated in disease.

CCAAT Enhancer Binding Protein-α (C/EBPα) Determines Myeloid Versus Erythroid Cell Fate in Multipotential Progenitors.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1603-1603
Author(s):  
Hyung-Chan Suh ◽  
John Gooya ◽  
Katie Renn ◽  
Alan Friedman ◽  
Peter Johnson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Progenitor Cells ◽  
Cell Fate ◽  
Myeloid Cell ◽  
Retroviral Vectors ◽  
Erythroid Cell ◽  
Erythroid Cells ◽  
Cell Fate Decisions

Abstract C/EBPα is a bZip transcription factor, which is required for granulocyte development, and loss of C/EBPα function is associated with the development of acute myelogenous leukemia and myelodysplastic syndrome. While the precise mechanisms that regulate cell fate decisions during hematopoietic development are largely unknown, expression of transcription factors (PU.1 and GATA-1) can induce lineage conversion. In this regard, C/EBPα can drive the differentiation of B cells into macrophages, and bi-potential cell lines into granulocytes at the expense of macrophages. C/EBPα can also promote the transdifferentiation of myoblasts into adipocytes. We have recently found that there are increased numbers of erythroid cells in the fetal liver of C/EBPα −/ − mice. Also, C/EBPα is expressed in more primitive progenitor cells than granulocyte/macrophage progenitors (GMP) including hematopoietic stem cells. Therefore, we initiated experiments to evaluate whether C/EBPα has a functional role in regulating cell fate decisions in progenitors more primitive than GMP where it may promote a myeloid versus erythroid cell fate decision. To test this hypothesis, we over-expressed C/EBPα using retroviral vectors in 1) bone marrow cells (BMC) and evaluated their growth and differentiation in vitro, and in vivo when transplanted into mice; 2) purified multipotential progenitors with erythroid and myeloid potential, and erythroid restricted progenitors; and 3) murine erythroid leukemia (MEL) cells. We found that there was a marked decrease in erythroid lineage cells and an increase in myeloid cells in mice transplanted with BMC that over-expressed C/EBPα. We also observed a decrease in erythroid cell growth in vitro with BMC that expressed C/EBPα. Furthermore, when infected with retroviral vectors that express C/EBPα, erythroid restricted progenitors acquired myeloid cell morphology and myeloid specific cell surface markers. In addition, MEL cells that over-express C/EBPα showed increased myeloid gene expression including GM-CSFR, PR3 and myeloid specific esterase, while they showed decreased expression of β-globin and Epo receptor (EpoR) which is required for erythroid cell differentiation and survival. We detected high levels of EpoR in C/EBPα −/ − suggesting an inverse relationship between C/EBPα and EpoR expression. Thus, C/EBPα is a dual function transcription factor that can repress erythroid specific genes while enhancing myeloid lineage gene expression. Consequently, C/EBPα acts as a switch to drive hematopoietic progenitor cells toward myeloid cell development at the expense of erythroid maturation, and can reprogram erythroid cells into myeloid cells. # Funded in part by DHHS #NO1-CO-12400

scholarly journals Global gene expression profiles of hematopoietic stem and progenitor cells from patients with chronic myeloid leukemia: the effect of in vitro culture with or without imatinib

2017 ◽  
Vol 6 (12) ◽  
pp. 2942-2956 ◽  
Author(s):  
Sócrates Avilés-Vázquez ◽  
Antonieta Chávez-González ◽  
Alfredo Hidalgo-Miranda ◽  
Dafne Moreno-Lorenzana ◽  
Lourdes Arriaga-Pizano ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Myeloid Leukemia ◽  
Progenitor Cells ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Global Gene Expression ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells

scholarly journals Molecular Signatures of Self-Renewal, Differentiation, and Lineage Choice in Multipotential Hemopoietic Progenitor Cells In Vitro

2004 ◽  
Vol 24 (2) ◽  
pp. 741-756 ◽  
Author(s):  
Ludovica Bruno ◽  
Reinhard Hoffmann ◽  
Fraser McBlane ◽  
John Brown ◽  
Rajeev Gupta ◽  
...  
Keyword(s):  
Gene Expression ◽  
Progenitor Cells ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Morphological Changes ◽  
Self Renewal ◽  
Cell Fate Decisions ◽  
Hemopoietic Progenitor ◽  
Hemopoietic Progenitor Cells

ABSTRACT The molecular mechanisms governing self-renewal, differentiation, and lineage specification remain unknown. Transcriptional profiling is likely to provide insight into these processes but, as yet, has been confined to “static” molecular profiles of stem and progenitors cells. We now provide a comprehensive, statistically robust, and “dynamic” analysis of multipotent hemopoietic progenitor cells undergoing self-renewal in response to interleukin-3 (IL-3) and multilineage differentiation in response to lineage-affiliated cytokines. Cells undergoing IL-3-dependent proliferative self-renewal displayed striking complexity, including expression of genes associated with different lineage programs, suggesting a highly responsive compartment poised to rapidly execute intrinsically or extrinsically initiated cell fate decisions. A remarkable general feature of early differentiation was a resolution of complexity through the downregulation of gene expression. Although effector genes characteristic of mature cells were upregulated late, coincident with morphological changes, lineage-specific changes in gene expression were observed prior to this, identifying genes which may provide early harbingers of unilineage commitment. Of particular interest were genes that displayed differential behavior irrespective of the lineage elaborated, many of which were rapidly downregulated within 4 to 8 h after exposure to a differentiation cue. These are likely to include genes important in self-renewal, the maintenance of multipotentiality, or the negative regulation of differentiation per se.

scholarly journals Functional Integrity and Gene Expression Profiles of Human Cord Blood-Derived Hematopoietic Stem and Progenitor Cells Generated In Vitro

2018 ◽  
Vol 7 (8) ◽  
pp. 602-614 ◽  
Author(s):  
Roberto Dircio-Maldonado ◽  
Patricia Flores-Guzman ◽  
Julieta Corral-Navarro ◽  
Ileana Mondragón-García ◽  
Alfredo Hidalgo-Miranda ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cord Blood ◽  
Progenitor Cells ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Human Cord Blood ◽  
Hematopoietic Stem ◽  
Functional Integrity ◽  
Stem And Progenitor Cells

scholarly journals COMPASS Family Histone Methyltransferase ASH2L Mediates Corticogenesis via Transcriptional Regulation of Wnt Signalling

2018 ◽  
Author(s):  
Liang Li ◽  
Xiangbin Ruan ◽  
Chang Wen ◽  
Pan Chen ◽  
Wei Liu ◽  
...  
Keyword(s):  
Cell Fate ◽  
Neural Progenitor Cells ◽  
Histone Methyltransferase ◽  
Projection Neurons ◽  
Cell Fate Specification ◽  
Cortical Projection ◽  
Proliferation Ability ◽  
Late Stages

AbstractCell fate specification in neural progenitor cells (NPCs) is orchestrated via extrinsic and intrinsic molecular programs, and histone methylation in these decisions has been ascribed to a crucial function regulating gene expression. Here, we show that the COMPASS family histone methyltransferase co-factor ASH2L is required in NPCs proliferation and upper layer cortical projection neurons production and position. Deletion of Ash2l impairs trimethylation of H3K4 and transcriptional machinery specifically for subsets of Wnt-β-catenin signalling, disrupting their transcription and consequently inhibiting the proliferation ability of NPCs in late stages of neurogenesis. Consistently, Ash2l conditional mutants exhibit thinning neocortex with reduced upper layer neurons and altered neuronal position. Moreover, overexpressing β-catenin after Ash2l elimination or knockdown can rescue the proliferation deficiency of NPCs both in vivo and in vitro. These results demonstrate an essential and highly specific role for Ash2l in controlling NPCs proliferation and late-born neurons lamination in corticogenesis via transcriptionally regulating Wnt-β-catenin signalling, and provide clues to how the COMPASS family epigenetic factors coordinate cell fate determination during cortex development.

scholarly journals Transcriptome analysis of gravitational effects on mouse skeletal muscles under microgravity and artificial 1 g onboard environment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Risa Okada ◽  
Shin-ichiro Fujita ◽  
Riku Suzuki ◽  
Takuto Hayashi ◽  
Hirona Tsubouchi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Transcriptome Analysis ◽  
Fiber Type ◽  
Expression Profiles ◽  
Space Station ◽  
Gene Expression Profiles

AbstractSpaceflight causes a decrease in skeletal muscle mass and strength. We set two murine experimental groups in orbit for 35 days aboard the International Space Station, under artificial earth-gravity (artificial 1 g; AG) and microgravity (μg; MG), to investigate whether artificial 1 g exposure prevents muscle atrophy at the molecular level. Our main findings indicated that AG onboard environment prevented changes under microgravity in soleus muscle not only in muscle mass and fiber type composition but also in the alteration of gene expression profiles. In particular, transcriptome analysis suggested that AG condition could prevent the alterations of some atrophy-related genes. We further screened novel candidate genes to reveal the muscle atrophy mechanism from these gene expression profiles. We suggest the potential role of Cacng1 in the atrophy of myotubes using in vitro and in vivo gene transductions. This critical project may accelerate the elucidation of muscle atrophy mechanisms.

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