Somatic polyploidy promotes cell function under stress and energy depletion: evidence from tissue-specific mammal transcriptome

2010 ◽  
Vol 10 (4) ◽  
pp. 433-446 ◽  
Author(s):  
Olga V. Anatskaya ◽  
Alexander E. Vinogradov
Keyword(s):  
Cell Function ◽  
Energy Depletion ◽  
Tissue Specific ◽  
Somatic Polyploidy

scholarly journals Arginase 2 and Polyamines in Human Pancreatic Beta Cells: Possible Role in the Pathogenesis of Type 2 Diabetes

2021 ◽  
Vol 22 (22) ◽  
pp. 12099
Author(s):  
Lorella Marselli ◽  
Emanuele Bosi ◽  
Carmela De Luca ◽  
Silvia Del Guerra ◽  
Marta Tesi ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Beta Cells ◽  
Beta Cell Function ◽  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Pancreas Development ◽  
Tissue Specific

Arginase 2 (ARG2) is a manganese metalloenzyme involved in several tissue specific processes, from physiology to pathophysiology. It is variably expressed in extra-hepatic tissues and is located in the mitochondria. In human pancreatic beta cells, ARG2 is downregulated in type 2 diabetes. The enzyme regulates the synthesis of polyamines, that are involved in pancreas development and regulation of beta cell function. Here, we discuss several features of ARG2 and polyamines, which can be relevant to the pathophysiology of type 2 diabetes.

scholarly journals The mucolipin-2 (TRPML2) ion channel: a tissue-specific protein crucial to normal cell function

2015 ◽  
Vol 468 (2) ◽  
pp. 177-192 ◽  
Author(s):  
Math P. Cuajungco ◽  
Joshua Silva ◽  
Ania Habibi ◽  
Jessica A. Valadez
Keyword(s):  
Ion Channel ◽  
Normal Cell ◽  
Cell Function ◽  
Specific Protein ◽  
Tissue Specific

scholarly journals Detailed metabolic phenotyping of four tissue specific Cas9 transgenic mouse lines

2021 ◽  
Author(s):  
Simon T. Bond ◽  
Aowen Zhuang ◽  
Christine Yang ◽  
Eleanor A.M. Gould ◽  
Tim Sikora ◽  
...  
Keyword(s):  
Cell Function ◽  
Heart Function ◽  
Whole Body ◽  
Tissue Specific ◽  
Guide Rnas ◽  
Specific Effects ◽  
Liver Health ◽  
Foreign Proteins

CRISPR/Cas9 technology has revolutionized gene editing and fast tracked our capacity to manipulate genes of interest for the benefit of both research and therapeutic applications. Whilst many advances have, and continue to be made in this area, perhaps the most utilized technology to date has been the generation of knockout cells, tissues and animals by taking advantage of Cas9 function to promote indels in precise locations in the genome. Whilst the advantages of this technology are many fold, some questions still remain regarding the effects that long term expression of foreign proteins such as Cas9, have on mammalian cell function. Several studies have proposed that chronic overexpression of Cas9, with or without its accompanying guide RNAs, may have deleterious effects on cell function and health. This is of particular concern when applying this technology in vivo, where chronic expression of Cas9 in tissues of interest may promote disease-like phenotypes and thus confound the investigation of the effects of the gene of interest. Although these concerns remain valid, no study to our knowledge has yet to demonstrate this directly. Thus, in this study we used the lox-stop-lox (LSL) spCas9 ROSA26 transgenic (Tg) mouse line to generate four tissue-specific Cas9-Tg models with expression in the heart, liver, skeletal muscle and adipose tissue. We performed comprehensive phenotyping of these mice up to 20-weeks of age and subsequently performed molecular analysis of their organs. We demonstrated that Cas9 expression in these tissues had no detrimental effect on whole body health of the animals, nor did it induce any tissue-specific effects on energy metabolism, liver health, inflammation, fibrosis, heart function or muscle mass. Thus, our data suggests that these models are suitable for studying the tissue specific effects of gene deletion using the LSL-Cas9-Tg model, and that phenotypes observed utilizing these models can be confidently interpreted as being gene specific, and not confounded by the chronic overexpression of Cas9.

scholarly journals Epigenetics of Muscle- and Brain-Specific Expression of KLHL Family Genes

2020 ◽  
Author(s):  
Kenneth Ehrlich ◽  
Carl Baribault ◽  
Melanie Ehrlich
Keyword(s):  
Cell Function ◽  
Open Chromatin ◽  
Target Tissue ◽  
Dna Hypomethylation ◽  
Specific Expression ◽  
Tissue Specific ◽  
Factors Affecting ◽  
Super Enhancer ◽  
Ubiquitin Ligase Complex ◽  
Promoter Dna

KLHL genes and the related KBTBD genes encode components of the Cullin-E3 ubiquitin ligase complex and typically target tissue-specific proteins for degradation, thereby affecting differentiation, homeostasis, metabolism, cell signaling, and the oxidative stress response. Despite their importance in normal cell function and in disease (KLHL40, KLHL41, KBTBD13, KEAP1, and ENC1), previous studies that examined epigenetic factors affecting transcription were predominantly limited to promoter DNA methylation. Using diverse tissue and cell culture whole-genome profiles, we examined 17 KLHL or KBTBD genes preferentially expressed in skeletal muscle or brain to identify tissue-specific enhancer and promoter chromatin, open chromatin (DNaseI hypersensitivity), and DNA hypomethylation. Sixteen of the 17 genes displayed muscle- or brain-specific enhancer chromatin in their gene bodies, and most exhibited specific intergenic enhancer chromatin as well. Seven genes were embedded in a super-enhancer. The enhancer chromatin regions typically displayed foci of DNA hypomethylation at peaks of open chromatin. In addition, we found evidence that gene neighbors (HHATL and FBXO32) of KLHL40 and KLHL38 harbor enhancer chromatin that likely upregulates the adjacent KLHL gene. Many KLHL/KBTBD genes had tissue-specific promoter chromatin at their 5’ ends, but surprisingly, two (KBTBD11 and KLHL31) had constitutively unmethylated promoter chromatin in their 3’ exons that overlaps a retrotransposed KLHL gene. Our findings demonstrate the importance of expanding epigenetic analyses beyond the 5’ ends of genes in studies of normal and abnormal gene regulation.

Age-Related Changes in Tissue-Specific Stem Cells.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-3-sci-3
Author(s):  
Amy J. Wagers ◽  
Massimiliano Cerletti ◽  
Shane R. Mayack ◽  
Francis S. Kim ◽  
Jennifer L. Shadrach
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Function ◽  
Bone Marrow Failure ◽  
Cell Activity ◽  
Older Individuals ◽  
Extrinsic Factors ◽  
Tissue Specific ◽  
Age Related ◽  
Tissue Specific Stem Cells

Abstract Aging of multicellular organisms typically involves progressive decline in the body’s ability to maintain homeostatic cell replacement and to regenerate tissues and organs after injury. In both the blood and the skeletal muscle, aging significantly impairs regenerative activity and can dysregulate normal homeostatic production of mature cells. These age-acquired defects in tissue function profoundly impact the health of older individuals, as evidenced by the high incidence of age-related muscle deterioration (sarcopenia), bone marrow failure, immune dysfunction, and blood cancers in the elderly. How aging causes deterioration of tissue function is poorly understood, but several lines of evidence suggest that loss or functional impairment of tissue-specific stem cells directly contributes to age-dependent failures in tissue repair. Interestingly, the effects of aging on tissue stem cell function appear to arise at least in part from alterations in the aged tissue environment, which can inhibit stem cell activity in older animals and may be regulated by factors that circulate naturally in the bloodstream. By making use of sensitive in vivo and in vitro approaches, including direct cell isolation by FACS, we are investigating the extrinsic factors and interactions that control stem cell function in aged animals. Our current studies have pointed us toward a discrete set of metabolic regulators and inflammatory cytokines, which may alter the signals that stem cells receive from their environment in aged animals. The knowledge we gain from these ongoing studies will help to define novel strategies to delay or reverse the onset of age-related disease, extending the healthful life of aging individuals.

scholarly journals Epigenetics of Muscle- and Brain-Specific Expression of KLHL Family Genes

2020 ◽  
Vol 21 (21) ◽  
pp. 8394
Author(s):  
Kenneth C. Ehrlich ◽  
Carl Baribault ◽  
Melanie Ehrlich
Keyword(s):  
Cell Function ◽  
Open Chromatin ◽  
Target Tissue ◽  
Dna Hypomethylation ◽  
Neighboring Gene ◽  
Specific Expression ◽  
Tissue Specific ◽  
Ubiquitin Ligase Complex ◽  
Specific Proteins ◽  
Promoter Dna

KLHL and the related KBTBD genes encode components of the Cullin-E3 ubiquitin ligase complex and typically target tissue-specific proteins for degradation, thereby affecting differentiation, homeostasis, metabolism, cell signaling, and the oxidative stress response. Despite their importance in cell function and disease (especially, KLHL40, KLHL41, KBTBD13, KEAP1, and ENC1), previous studies of epigenetic factors that affect transcription were predominantly limited to promoter DNA methylation. Using diverse tissue and cell culture whole-genome profiles, we examined 17 KLHL or KBTBD genes preferentially expressed in skeletal muscle or brain to identify tissue-specific enhancer and promoter chromatin, open chromatin (DNaseI hypersensitivity), and DNA hypomethylation. Sixteen of the 17 genes displayed muscle- or brain-specific enhancer chromatin in their gene bodies, and most exhibited specific intergenic enhancer chromatin as well. Seven genes were embedded in super-enhancers (particularly strong, tissue-specific clusters of enhancers). The enhancer chromatin regions typically displayed foci of DNA hypomethylation at peaks of open chromatin. In addition, we found evidence for an intragenic enhancer in one gene upregulating expression of its neighboring gene, specifically for KLHL40/HHATL and KLHL38/FBXO32 gene pairs. Many KLHL/KBTBD genes had tissue-specific promoter chromatin at their 5′ ends, but surprisingly, two (KBTBD11 and KLHL31) had constitutively unmethylated promoter chromatin in their 3′ exons that overlaps a retrotransposed KLHL gene. Our findings demonstrate the importance of expanding epigenetic analyses beyond the 5′ ends of genes in studies of normal and abnormal gene regulation.

scholarly journals Abrogation of donor T-cell IL-21 signaling leads to tissue-specific modulation of immunity and separation of GVHD from GVL

Blood ◽  
2011 ◽  
Vol 118 (2) ◽  
pp. 446-455 ◽  
Author(s):  
Alan M. Hanash ◽  
Lucy W. Kappel ◽  
Nury L. Yim ◽  
Rebecca A. Nejat ◽  
Gabrielle L. Goldberg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytokine Production ◽  
Cell Function ◽  
Mesenteric Lymph Nodes ◽  
Inflammatory Cytokine Production ◽  
Tissue Specific ◽  
Th Cell ◽  
Donor T Cells ◽  
Cell Cytokine Production

Abstract IL-21 is a proinflammatory cytokine produced by Th17 cells. Abrogation of IL-21 signaling has recently been shown to reduce GVHD while retaining graft-versus-leukemia/lymphoma (GVL) responses. However, the mechanisms by which IL-21 may lead to a separation of GVHD and GVL remain incompletely understood. In a murine MHC-mismatched BM transplantation model, we observed that IL-21 receptor knockout (IL-21R KO) donor T cells mediate decreased systemic and gastrointestinal GVHD in recipients of a transplant. This reduction in GVHD was associated with expansion of transplanted donor regulatory T cells and with tissue-specific modulation of Th-cell function. IL-21R KO and wild-type donor T cells showed equivalent alloactivation, but IL-21R KO T cells showed decreased infiltration and inflammatory cytokine production within the mesenteric lymph nodes. However, Th-cell cytokine production was maintained peripherally, and IL-21R KO T cells mediated equivalent immunity against A20 and P815 hematopoietic tumors. In summary, abrogation of IL-21 signaling in donor T cells leads to tissue-specific modulation of immunity, such that gastrointestinal GVHD is reduced, but peripheral T-cell function and GVL capacity are retained. IL-21 is thus an exciting target for therapeutic intervention and improvement of clinical transplantation outcomes.

scholarly journals CHANGES IN THE DISTRIBUTION OF A HISTONE IN DORSAL ROOT GANGLION NEURONS DURING DEVELOPMENT

1968 ◽  
Vol 38 (3) ◽  
pp. 515-522 ◽  
Author(s):  
Steven E. Kornguth ◽  
Lawrence G. Tomasi
Keyword(s):  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Nervous Tissue ◽  
Cellular Localization ◽  
Basic Protein ◽  
Cell Function ◽  
Dorsal Root Ganglion Neurons ◽  
Adult Rats ◽  
Tissue Specific ◽  
Ganglion Neurons

The isolation and cellular localization of a basic protein (histone) from central nervous tissue have been previously reported. In the tissues previously studied (nervous tissue, testis, liver, spleen, kidney, ovary), the basic protein was restricted in distribution to the nuclei of neurons and spermatogonia. In the present study, the temporal appearance of the histone within neurons and the changes in its distribution during ontogenesis were examined. The reaction between a fluorescent immune γ-globulin prepared against this purified tissue-specific histone and the neurons from the dorsal root ganglia of the rat was investigated. The dorsal root ganglia examined were those from fetuses, 2-, 10-, and 40-day-old rats, and from adult rats. At the earliest stages, only the nucleoli reacted. Subsequently, threads of fluorescent material were seen to emerge from the nucleoli. The extent of this reaction between the immune globulin and the threads within the nuclei continued to increase with maturation. No changes in fluorescence localization during development could be seen in the nuclei of neurons in the cerebellum or brain stem. The role that this tissue-specific histone may play in cell function is discussed.

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