scholarly journals The UTX Tumor Suppressor Directly Senses Oxygen to Control Chromatin and Cell Fate

2019 ◽  
Author(s):  
Abhishek A. Chakraborty ◽  
Tuomas Laukka ◽  
Matti Myllykoski ◽  
Alison E. Ringel ◽  
Matthew A. Booker ◽  
...  
Keyword(s):  
Cell Fate ◽  
Indirect Effects ◽  
Mammalian Cells ◽  
Control Cell ◽  
Histone Demethylase ◽  
Hypoxic Induction ◽  
Hypoxic Conditions ◽  
Chromatin Regulators ◽  
Oxygen Sensitive ◽  
Demethylase Activity

AbstractMammalian cells express multiple 2-oxoglutarate (OG)-dependent dioxygenases, including many chromatin regulators. The oxygen affinities, and hence oxygen sensing capabilities, of the 2-oxoglutarate (OG)-dependent dioxygenases reported to date vary widely. Hypoxia can affect chromatin, but whether this reflects a direct effect on chromatin-modifying dioxygenases, or indirect effects caused by the hypoxic-induction of the HIF transcription factor or the endogenous 2-OG competitor 2-hydroxyglutarate (2-HG), is unclear. Here we report that hypoxia induces a HIF- and 2-HG-independent histone modification signature consistent with KDM inactivation. We also show that the H3K27 histone demethylase KDM6A (also called UTX), but not its paralog KDM6B, is oxygen-sensitive. KDM6A loss, like hypoxia, prevented H3K27me3 erasure and blocked differentiation. Conversely, restoring H3K27me3 homeostasis in hypoxic cells reversed these effects. Therefore, oxygen directly affects chromatin regulators to control cell fate.One Sentence SummaryKDM6A demethylase activity is diminished under hypoxic conditions and causes changes in gene expression programs that govern cell fate.

scholarly journals Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate

Science ◽  
2019 ◽  
Vol 363 (6432) ◽  
pp. 1217-1222 ◽  
Author(s):  
Abhishek A. Chakraborty ◽  
Tuomas Laukka ◽  
Matti Myllykoski ◽  
Alison E. Ringel ◽  
Matthew A. Booker ◽  
...  
Keyword(s):  
Cell Fate ◽  
Histone Methylation ◽  
Mammalian Cells ◽  
Control Cell ◽  
Hypoxia Inducible Factor ◽  
Histone Demethylase ◽  
Histone Demethylases ◽  
Independent Manner ◽  
H3k27 Methylation ◽  
Oxygen Sensitive

Oxygen sensing is central to metazoan biology and has implications for human disease. Mammalian cells express multiple oxygen-dependent enzymes called 2-oxoglutarate (OG)-dependent dioxygenases (2-OGDDs), but they vary in their oxygen affinities and hence their ability to sense oxygen. The 2-OGDD histone demethylases control histone methylation. Hypoxia increases histone methylation, but whether this reflects direct effects on histone demethylases or indirect effects caused by the hypoxic induction of the HIF (hypoxia-inducible factor) transcription factor or the 2-OG antagonist 2-hydroxyglutarate (2-HG) is unclear. Here, we report that hypoxia promotes histone methylation in a HIF- and 2-HG–independent manner. We found that the H3K27 histone demethylase KDM6A/UTX, but not its paralog KDM6B, is oxygen sensitive. KDM6A loss, like hypoxia, prevented H3K27 demethylation and blocked cellular differentiation. Restoring H3K27 methylation homeostasis in hypoxic cells reversed these effects. Thus, oxygen directly affects chromatin regulators to control cell fate.

scholarly journals The histone demethylase KDM5 is essential for larval growth in Drosophila

2018 ◽  
Author(s):  
Coralie Drelon ◽  
Helen M. Belalcazar ◽  
Julie Secombe
Keyword(s):  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Biological Activities ◽  
Larval Growth ◽  
Imaginal Discs ◽  
Complete Loss ◽  
Histone Demethylase ◽  
Ideal System ◽  
Demethylase Activity ◽  
Regulated Gene Expression

AbstractRegulated gene expression is necessary for developmental and homeostatic processes. The KDM5 family of proteins are histone H3 lysine 4 demethylases that can regulate transcription through both demethylase-dependent and independent mechanisms. While loss and overexpression of KDM5 proteins are linked to intellectual disability and cancer, respectively, their normal developmental functions remain less characterized. Drosophila melanogaster provides an ideal system to investigate KDM5 function, as it encodes a single ortholog in contrast to the four paralogs found in mammalian cells. To examine the consequences of complete loss of KDM5, we generated a null allele of Drosophila kdm5, also known as little imaginal discs (lid), and show that it is essential for development. Animals lacking KDM5 die during late pupal development but show a dramatically delayed larval development that coincides with decreased proliferation and increased cell death in imaginal discs. Interestingly, this developmental delay is independent of the well-characterized Jumonji C (JmjC) domain-encoded histone demethylase activity and plant homedomain (PHD) motif-mediated chromatin binding activities of KDM5, suggesting key functions for less characterized domains. Consistent with the phenotypes observed, transcriptome analyses of kdm5 null mutant wing imaginal discs revealed the dysregulation of genes involved in several cellular processes, including cell cycle progression and DNA repair. Together, our data provide the first description of complete loss of KDM5 function in a metazoan and offer an invaluable tool for defining the biological activities of KDM5 family proteins.

scholarly journals Glutathione in Cerebral Microvascular Endothelial Biology and Pathobiology: Implications for Brain Homeostasis

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Wei Li ◽  
Carmina Busu ◽  
Magdalena L. Circu ◽  
Tak Yee Aw
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cell ◽  
Cell Fate ◽  
Mammalian Cells ◽  
Redox Regulation ◽  
Cell Injury ◽  
Control Cell ◽  
Endothelial Cell Proliferation ◽  
Special Focus ◽  
Vascular Integrity

The integrity of the vascular endothelium of the blood-brain barrier (BBB) is central to cerebrovascular homeostasis. Given the function of the BBB as a physical and metabolic barrier that buffers the systemic environment, oxidative damage to the endothelial monolayer will have significant deleterious impact on the metabolic, immunological, and neurological functions of the brain. Glutathione (GSH) is a ubiquitous major thiol within mammalian cells that plays important roles in antioxidant defense, oxidation-reduction reactions in metabolic pathways, and redox signaling. The existence of distinct GSH pools within the subcellular organelles supports an elegant mode for independent redox regulation of metabolic processes, including those that control cell fate. GSH-dependent homeostatic control of neurovascular function is relatively unexplored. Significantly, GSH regulation of two aspects of endothelial function is paramount to barrier preservation, namely, GSH protection against oxidative endothelial cell injury and GSH control of postdamage cell proliferation in endothelial repair and/or wound healing. This paper highlights our current insights and hypotheses into the role of GSH in cerebral microvascular biology and pathobiology with special focus on endothelial GSH and vascular integrity, oxidative disruption of endothelial barrier function, GSH regulation of endothelial cell proliferation, and the pathological implications of GSH disruption in oxidative stress-associated neurovascular disorders, such as diabetes and stroke.

scholarly journals Hypoxic induction of an HIF-1α–dependent bFGF autocrine loop drives angiogenesis in human endothelial cells

Blood ◽  
2006 ◽  
Vol 107 (7) ◽  
pp. 2705-2712 ◽  
Author(s):  
Maura Calvani ◽  
Annamaria Rapisarda ◽  
Badarch Uranchimeg ◽  
Robert H. Shoemaker ◽  
Giovanni Melillo
Keyword(s):  
Endothelial Cells ◽  
Mammalian Cells ◽  
Neutralizing Antibodies ◽  
Umbilical Vein ◽  
Hypoxia Inducible Factor ◽  
Transcriptional Response ◽  
Low Oxygen ◽  
Autocrine Loop ◽  
Hypoxic Induction ◽  
Hypoxic Conditions

AbstractHypoxia is a major pathophysiological condition for the induction of angiogenesis, which is a crucial aspect of growth in solid tumors. In mammalian cells, the transcriptional response to oxygen deprivation is largely mediated by hypoxia-inducible factor 1 (HIF-1), a heterodimer composed of HIF-1α and HIF-1β subunits. However, the response of endothelial cells to hypoxia and the specific involvement of HIF-α subunits in this process are still poorly understood. We show that human umbilical vein endothelial cells (HUVECs) cultured in the absence of growth factors survive and form tubelike structures when cultured under hypoxic, but not normoxic, conditions. HUVECs expressed both HIF-1α and HIF-2α when cultured under hypoxic conditions. Transfection of HIF-1α, but not HIF-2α, siRNA to HUVECs completely abrogated hypoxic induction of cords. Neutralizing antibodies to bFGF, but not IGF-1, VEGF, or PDGF-BB, blocked survival and sprouting of HUVECs under hypoxic conditions, suggesting the existence of an autocrine loop induced by low oxygen levels. Notably, bFGF-dependent induction of cord formation under normoxic conditions required HIF-1α activity, which was also essential for hypoxic induction of bFGF mRNA and protein expression. These results uncover the existence of an HIF-1α–bFGF amplification pathway that mediates survival and sprouting of endothelial cells under hypoxic conditions.

scholarly journals Noncatalytic Function of a JmjC Domain Protein Disrupts Heterochromatin

2019 ◽  
Vol 12 ◽  
pp. 251686571986224
Author(s):  
Kehan Bao ◽  
Songtao Jia
Keyword(s):  
Transcriptional Regulation ◽  
Cancer Cells ◽  
Histone Acetyltransferase ◽  
Histone Demethylase ◽  
Epigenetic Landscape ◽  
Disease Etiology ◽  
Chromatin Regulators ◽  
Demethylase Activity ◽  
Jmjc Domain ◽  
Domain Protein

Chromatin-modifying enzymes are frequently overexpressed in cancer cells, and their enzymatic activities play important roles in changing the epigenetic landscape responsible for tumorigenesis. However, many of these proteins also execute noncatalytic functions, which are poorly understood. In fission yeast, overexpression of Epe1, a histone demethylase homolog, causes heterochromatin defects. Interestingly, in our recent work, we discovered that overexpressed Epe1 recruits SAGA, a histone acetyltransferase complex important for transcriptional regulation, to disrupt heterochromatin, independent of its demethylase activity. Our findings suggest that overexpressed chromatin-modifying enzymes can alter the epigenetic landscape through changing their proteomic environments, an area that needs to be further explored in dissecting disease etiology associated with overexpression of chromatin regulators.

Use of Flexible Materials with a Novel Pressure Driven Equibiaxial Cell Stretching Device for Mechanical Stimulation of Single Mammalian Cells

2003 ◽  
Vol 773 ◽  
Author(s):  
James D. Kubicek ◽  
Stephanie Brelsford ◽  
Philip R. LeDuc
Keyword(s):  
Cell Fate ◽  
Mechanical Stimulation ◽  
Mammalian Cells ◽  
Cellular Response ◽  
Single Cells ◽  
Complex Nature ◽  
Cellular Behavior ◽  
Cell Stretching ◽  
Stimulation Of ◽  
Pressure Driven

AbstractMechanical stimulation of single cells has been shown to affect cellular behavior from the molecular scale to ultimate cell fate including apoptosis and proliferation. In this, the ability to control the spatiotemporal application of force on cells through their extracellular matrix connections is critical to understand the cellular response of mechanotransduction. Here, we develop and utilize a novel pressure-driven equibiaxial cell stretching device (PECS) combined with an elastomeric material to control specifically the mechanical stimulation on single cells. Cells were cultured on silicone membranes coated with molecular matrices and then a uniform pressure was introduced to the opposite surface of the membrane to stretch single cells equibiaxially. This allowed us to apply mechanical deformation to investigate the complex nature of cell shape and structure. These results will enhance our knowledge of cellular and molecular function as well as provide insights into fields including biomechanics, tissue engineering, and drug discovery.

scholarly journals Notch signaling coordinates ommatidial rotation in the Drosophila eye via transcriptional regulation of the EGF-Receptor ligand Argos

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yildiz Koca ◽  
Benjamin E. Housden ◽  
William J. Gault ◽  
Sarah J. Bray ◽  
Marek Mlodzik
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Planar Cell Polarity ◽  
Egf Receptor ◽  
Control Cell ◽  
Loss Of Function ◽  
Egfr Signaling ◽  
Specific Expression ◽  
Egfr Signaling Pathway ◽  
Ommatidial Rotation

AbstractIn all metazoans, a small number of evolutionarily conserved signaling pathways are reiteratively used during development to orchestrate critical patterning and morphogenetic processes. Among these, Notch (N) signaling is essential for most aspects of tissue patterning where it mediates the communication between adjacent cells to control cell fate specification. In Drosophila, Notch signaling is required for several features of eye development, including the R3/R4 cell fate choice and R7 specification. Here we show that hypomorphic alleles of Notch, belonging to the Nfacet class, reveal a novel phenotype: while photoreceptor specification in the mutant ommatidia is largely normal, defects are observed in ommatidial rotation (OR), a planar cell polarity (PCP)-mediated cell motility process. We demonstrate that during OR Notch signaling is specifically required in the R4 photoreceptor to upregulate the transcription of argos (aos), an inhibitory ligand to the epidermal growth factor receptor (EGFR), to fine-tune the activity of EGFR signaling. Consistently, the loss-of-function defects of Nfacet alleles and EGFR-signaling pathway mutants are largely indistinguishable. A Notch-regulated aos enhancer confers R4 specific expression arguing that aos is directly regulated by Notch signaling in this context via Su(H)-Mam-dependent transcription.

scholarly journals Positive Feedback Between PU.1 and the Cell Cycle Controls Myeloid Differentiation

Science ◽  
2013 ◽  
Vol 341 (6146) ◽  
pp. 670-673 ◽  
Author(s):  
Hao Yuan Kueh ◽  
Ameya Champhekar ◽  
Stephen L. Nutt ◽  
Michael B. Elowitz ◽  
Ellen V. Rothenberg
Keyword(s):  
Cell Cycle ◽  
Cell Fate ◽  
Positive Feedback ◽  
Regulatory Gene ◽  
Control Cell ◽  
Stem Cell Differentiation ◽  
Myeloid Differentiation ◽  
Cycle Duration ◽  
Gene Circuits ◽  
Cell Cycles

Regulatory gene circuits with positive-feedback loops control stem cell differentiation, but several mechanisms can contribute to positive feedback. Here, we dissect feedback mechanisms through which the transcription factor PU.1 controls lymphoid and myeloid differentiation. Quantitative live-cell imaging revealed that developing B cells decrease PU.1 levels by reducing PU.1 transcription, whereas developing macrophages increase PU.1 levels by lengthening their cell cycles, which causes stable PU.1 accumulation. Exogenous PU.1 expression in progenitors increases endogenous PU.1 levels by inducing cell cycle lengthening, implying positive feedback between a regulatory factor and the cell cycle. Mathematical modeling showed that this cell cycle–coupled feedback architecture effectively stabilizes a slow-dividing differentiated state. These results show that cell cycle duration functions as an integral part of a positive autoregulatory circuit to control cell fate.

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