scholarly journals Alternative Splicing Increases Sirtuin Gene Family Diversity and Modulates Their Subcellular Localization and Function

2021 ◽  
Vol 22 (2) ◽  
pp. 473
Author(s):  
Xiaomin Zhang ◽  
Fathima S. Ameer ◽  
Gohar Azhar ◽  
Jeanne Y. Wei
Keyword(s):  
Alternative Splicing ◽  
Subcellular Localization ◽  
Structural Changes ◽  
Catalytic Domain ◽  
Gene Diversity ◽  
Exon Skipping ◽  
Age Related ◽  
C Terminus ◽  
Domain Loss ◽  
And Function

Alternative splicing generates multiple distinct isoforms that increase transcriptome and proteome diversity. There are seven sirtuin genes in humans, each consists of multiple exons that are likely to undergo alternative splicing. Our aim was to characterize the effect of alternative splicing on the sirtuin genes. Here, we report the identification of 23 human sirtuin isoforms, most of which were not previously reported. Five of the sirtuin genes had more than one isoform, whereas sirtuin-6 had nine isoforms. Exon skipping was the main event. Most of the sirtuin isoforms were deficient in parts of the protein domains, including the catalytic domain, the N- or C-terminus, nuclear localization signal or mitochondrial targeting signal. The domain loss caused potential structural changes. Three SIRT1 isoforms had a differential effect on the mitochondrial oxygen consumption rate. Age-related changes in the expression of SIRT1 isoforms were observed in the human heart in fetus, adults, and very old individuals. We also identified 15 sirtuin isoforms in mice. Our data indicate that alternative splicing increases sirtuin gene diversity and may modulate subcellular localization and function, thereby adding complexity to the gene regulation of mitochondrial respiration, metabolism, and cardiac function during maturation and aging.

scholarly journals A survey of computational methods in transcriptome-wide alternative splicing analysis

2015 ◽  
Vol 6 (1) ◽  
pp. 59-66 ◽  
Author(s):  
Jianbo Wang ◽  
Zhenqing Ye ◽  
Tim H.-M. Huang ◽  
Huidong Shi ◽  
Victor Jin
Keyword(s):  
Alternative Splicing ◽  
Experimental Validation ◽  
Gene Diversity ◽  
Exon Skipping ◽  
Differential Splicing ◽  
Sequencing Data ◽  
Future Directions ◽  
Specific Analysis ◽  
Software Implementations ◽  
Expected Outcomes

AbstractAlternative splicing is widely recognized for its roles in regulating genes and creating gene diversity. Consequently the identification and quantification of differentially spliced transcripts is pivotal for transcriptome analysis. Here, we review the currently available computational approaches for the analysis of RNA-sequencing data with a focus on exon-skipping events of alternative splicing and discuss the novelties as well as challenges faced to perform differential splicing analyses. In accordance with operational needs we have classified the software tools, which may be instrumental for a specific analysis based on the experimental objectives and expected outcomes. In addition, we also propose a framework for future directions by pinpointing more extensive experimental validation to assess the accuracy of the software predictions and improvements that would facilitate visualizations, data processing, and downstream analyses along with their associated software implementations.

Structure and function changes in rat adrenal glands during aging

1988 ◽  
Vol 255 (6) ◽  
pp. E903-E911 ◽  
Author(s):  
E. Reaven ◽  
M. Kostrna ◽  
J. Ramachandran ◽  
S. Azhar
Keyword(s):  
Adrenal Gland ◽  
Plasma Volume ◽  
Endocrine Cells ◽  
Structural Changes ◽  
Adrenal Weight ◽  
Hormone Production ◽  
Age Related ◽  
Old Rats ◽  
And Function ◽  
Serum Acth

The current study examines corticosterone production in young and old rats with a view to understanding how hormone production is related to aging changes in the adrenal gland. For this purpose, we compared total (plasma volume-corrected) values for adrenocorticotropic hormone (ACTH)-induced maximal corticosterone production in young, mature (5-mo-old), and aging (18-mo-old) rats. These values were subsequently corrected for measured age-related differences in adrenal weight, adrenal cortex volume, specific adrenal zone volumes, and total number of corticosterone-producing cells in the adrenals of the differently aged rats. In addition, corticosterone disposal rates were measured in the two groups of rats, and adrenal cortical ACTH binding sites were identified by autoradiography after perfusion with 125I-labeled ACTH analogue. The results show that maximal serum ACTH-induced corticosterone concentrations (per ml serum) in the 18-mo-old rats are somewhat less than those seen in the younger animals. However, because the plasma volume is greater in the older animals (and corticosterone disposal rates do not vary), total circulating corticosterone production is, in fact, equivalent in the two groups of animals. When these total values for corticosterone are corrected for various structural changes in the adrenal gland with age, corticosterone production was found to be lower in the older group of rats: i.e., one sees an approximately 50% decline when corticosterone is expressed per adrenal weight or zonal volume and an approximately 20% decline when expressed per number of endocrine cells per adrenal.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Structural Adaptation of Cold-Active RTX Lipase fromPseudomonassp. Strain AMS8 Revealed via Homology and Molecular Dynamics Simulation Approaches

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Mohd. Shukuri Mohamad Ali ◽  
Siti Farhanie Mohd Fuzi ◽  
Menega Ganasen ◽  
Raja Noor Zaliha Raja Abdul Rahman ◽  
Mahiran Basri ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Industrial Applications ◽  
Structure And Function ◽  
Molecular Engineering ◽  
Dynamics Simulation ◽  
Structural Adaptation ◽  
C Terminus ◽  
Different Temperatures ◽  
And Function ◽  
3D Molecular Structure

The psychrophilic enzyme is an interesting subject to study due to its special ability to adapt to extreme temperatures, unlike typical enzymes. Utilizing computer-aided software, the predicted structure and function of the enzyme lipase AMS8 (LipAMS8) (isolated from the psychrophilicPseudomonassp., obtained from the Antarctic soil) are studied. The enzyme shows significant sequence similarities with lipases fromPseudomonassp. MIS38 andSerratia marcescens. These similarities aid in the prediction of the 3D molecular structure of the enzyme. In this study, 12 ns MD simulation is performed at different temperatures for structural flexibility and stability analysis. The results show that the enzyme is most stable at 0°C and 5°C. In terms of stability and flexibility, the catalytic domain (N-terminus) maintained its stability more than the noncatalytic domain (C-terminus), but the non-catalytic domain showed higher flexibility than the catalytic domain. The analysis of the structure and function of LipAMS8 provides new insights into the structural adaptation of this protein at low temperatures. The information obtained could be a useful tool for low temperature industrial applications and molecular engineering purposes, in the near future.

scholarly journals Thousands of exon skipping events differentiate among splicing patterns in sixteen human tissues

F1000Research ◽  
2013 ◽  
Vol 2 ◽  
pp. 188 ◽  
Author(s):  
Liliana Florea ◽  
Li Song ◽  
Steven L Salzberg
Keyword(s):  
Alternative Splicing ◽  
Gene Diversity ◽  
Exon Skipping ◽  
Human Tissues ◽  
Rna Seq ◽  
Gene Splicing ◽  
Link Type ◽  
Normal Human ◽  
Splicing Patterns

Alternative splicing is widely recognized for its roles in regulating genes and creating gene diversity. However, despite many efforts, the repertoire of gene splicing variation is still incompletely characterized, even in humans. Here we describe a new computational system, ASprofile, and its application to RNA-seq data from Illumina’s Human Body Map project (>2.5 billion reads).  Using the system, we identified putative alternative splicing events in 16 different human tissues, which provide a dynamic picture of splicing variation across the tissues. We detected 26,989 potential exon skipping events representing differences in splicing patterns among the tissues. A large proportion of the events (>60%) were novel, involving new exons (~3000), new introns (~16000), or both. When tracing these events across the sixteen tissues, only a small number (4-7%) appeared to be differentially expressed (‘switched’) between two tissues, while 30-45% showed little variation, and the remaining 50-65% were not present in one or both tissues compared.  Novel exon skipping events appeared to be slightly less variable than known events, but were more tissue-specific. Our study represents the first effort to build a comprehensive catalog of alternative splicing in normal human tissues from RNA-seq data, while providing insights into the role of alternative splicing in shaping tissue transcriptome differences. The catalog of events and the ASprofile software are freely available from the Zenodo repository(http://zenodo.org/record/7068; doi:10.5281/zenodo.7068) and from our web site http://ccb.jhu.edu/software/ASprofile.

scholarly journals Sirtuin-1 isoforms differentially regulate mitochondrial function

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 671-671
Author(s):  
Xiaomin Zhang ◽  
Fathima Ameer ◽  
Jasmine Crane ◽  
Gohar Azhar ◽  
Jeanne Wei
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Mitochondrial Gene ◽  
Intracellular Localization ◽  
Sirtuin 1 ◽  
Protein Domain ◽  
Mitochondrial Gene Expression ◽  
Age Related ◽  
And Function ◽  
Mitofusin 1

Abstract Alternative splicing generates multiple distinct isoforms that increase transcriptome and proteome diversity. Alternatively spliced isoforms may lose part of the protein domain and have different intracellular localization as well as distinct functions. The main form of the SIRT1 (SIRT1v1) protein contains 11 exons. We have identified two new isoforms, SIRT1v2 (lost 2 exons), and SIRT1v3 (lost 3 exons), but their effect on mitochondrial gene expression has not been reported. To study the effect of the three SIRT1 isoforms on mitochondrial gene expression and function, neuronal cells were transfected with SIRT1 isoforms v1, v2 or v3 plasmids, respectively. Gene expression was measured by quantitative reverse transcription PCR (RT-qPCR). Our data showed SIRT1 isoforms v1, v2 and v3 differentially regulated PCG-1alpha and PCG-1beta, which are the upstream regulators of mitochondrial structure and function. SIRT1v1 upregulated mitofusin-1 (MFN1), the mitochondrial dynamin-like GTPase (OPA1) gene, and the transcription factor A mitochondrial (TFAM) gene. In contrast, the SIRT1-v2 isoform repressed the MFN1, MFN2, and TFAM genes, while the SIRT1-v3 isoform repressed the MFN1 gene. In addition, the three SIRT1 isoforms differentially affected the mitochondrial respiratory complex I genes, including NDUFAB1, NDUFS1, NDUFV1, NDUFV2. The data indicates that SIRT1 regulates mitochondrial biogenesis and function through a signaling pathway involving PGC-1alpha, PCG-1beta, mitofusin 1 and 2, OPA1, and TFAM genes. Taken together, alternative splicing generated three SIRT1 isoform proteins with diverse functions. Age-related changes in the alternative splicing events are likely to impact sirtuin-regulated cellular functions and signaling pathways in aging and senescence.

scholarly journals Phylogenetic Profiling and Disordered Region Assessment of MECP2, CDKL5, and FOXG1 to Reveal Strategies for Rett Syndrome Treatment

2019 ◽  
Author(s):  
Muhamad Fahmi ◽  
Gen Yasui ◽  
Kaito Seki ◽  
Syouichi Katayama ◽  
Takako Kaneko-Kawano ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Catalytic Domain ◽  
Neurodevelopmental Disorder ◽  
Potential Candidate ◽  
Disordered Structure ◽  
Binding Partners ◽  
C Terminus ◽  
Phylogenetic Profiling ◽  
And Function ◽  
Insight Into

Rett syndrome (RTT), a neurodevelopmental disorder, is mainly caused by mutations in methyl CpG-binding protein 2 (MECP2), which alter the functions of domains to either bind to methylated DNA or interact with a transcriptional co-repressor complex. It has been established that alterations in cyclin-dependent kinase-like 5 (CDKL5) or forkhead box protein G1 (FOXG1) correspond to distinct neurodevelopmental disorders, given that a series of studies have indicated that RTT is also caused by alterations in either one of these genes. We tried to elucidate RTT through evolution and structure assessment of MeCP2, CDKL5, and FOXG1, by focusing on their binding partners and disordered structures. Here, we provide insight into the similarities of the FOXG1 and MECP2 binding partners evolution and function. On the other hand, we suggest that CDKL5 could be a potential candidate for a classical RTT treatment, particularly based on its disordered structure that spans after the catalytic domain to the C-terminus, which shows abundant linear motifs that can bind to molecules with divergent structures of similar affinity. Additionally, we provide insight into the relationship between disordered structure and disease.

Effect of chronic ANG I-converting enzyme inhibition on aging processes. I. Kidney structure and function

1994 ◽  
Vol 266 (3) ◽  
pp. R1038-R1051 ◽  
Author(s):  
D. Heudes ◽  
O. Michel ◽  
J. Chevalier ◽  
E. Scalbert ◽  
E. Ezan ◽  
...  
Keyword(s):  
Enzyme Inhibition ◽  
Structural Changes ◽  
Progressive Increase ◽  
Structure And Function ◽  
Point Of View ◽  
Converting Enzyme ◽  
Kidney Structure ◽  
Age Related ◽  
Converting Enzyme Inhibition ◽  
And Function

The effect of angiotensin I-converting enzyme inhibition (ACEI) on the age-related changes in the kidney structure and function was investigated in rodents. Normotensive male Wistar (WAG)/Rij rats were treated with perindopril from the age of 6 mo to the day of killing at 12, 24, or 30 mo. Mean blood pressure, constant from 6 to 30 mo, was reduced by 19 mmHg in treated animals. With age, the major functional modifications were a decrease in glomerular filtration rate and in renal blood flow, a rise in intrarenal vascular resistance (IVR), a reduced tubular reabsorption of salts, and a progressive increase in proteinuria. ACEI significantly reduced IVR and proteinuria. From a structural point of view, the glomeruli showed 1) an increase in size, 2) a decrease in capillary surface, 3) a diffuse thickening of the glomerular basement membrane, 4) an expansion of the mesangial matrix, and 5) an accumulation of albumin droplets in podocytes inducing 6) a dispersed focal and segmental glomerulosclerosis which, at 30 mo, affected < 2% of glomeruli. Of these six age-related structural changes, ACEI delayed the appearance of the three latter changes.

Collagen in the Developing Larynx

1992 ◽  
Vol 101 (4) ◽  
pp. 328-332 ◽  
Author(s):  
David T. Cheung ◽  
Grace Lian ◽  
Seymour R. Cohen ◽  
Marcel E. Nimni ◽  
Natasha Perelman ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Structural Changes ◽  
Clinical Findings ◽  
Newborn Period ◽  
Structural Framework ◽  
Age Related ◽  
Human Larynx ◽  
And Function

The primary purpose of this study was to determine the types of collagen in the developing human larynx that contribute to the structural framework and function of various components of this organ. The infant larynx is much more than a mere miniature of the adult “voice box.” There are many age-related differences that occur in the larynx from the newborn period to the adult period of life. While collagen has been studied in numerous tissues, both normal and diseased, there have been no studies of the whole organ content, types, and/or changes of collagen in the developing human larynx that may account for many of the clinical findings. This study may at least in part explain whether collagen differences may account for the structural changes and responses that are seen in clinical practice.

scholarly journals Thousands of exon skipping events differentiate among splicing patterns in sixteen human tissues

F1000Research ◽  
2013 ◽  
Vol 2 ◽  
pp. 188 ◽  
Author(s):  
Liliana Florea ◽  
Li Song ◽  
Steven L Salzberg
Keyword(s):  
Alternative Splicing ◽  
Gene Diversity ◽  
Exon Skipping ◽  
Human Tissues ◽  
Rna Seq ◽  
Gene Splicing ◽  
Link Type ◽  
Normal Human ◽  
Splicing Patterns

Alternative splicing is widely recognized for its roles in regulating genes and creating gene diversity. However, despite many efforts, the repertoire of gene splicing variation is still incompletely characterized, even in humans. Here we describe a new computational system, ASprofile, and its application to RNA-seq data from Illumina’s Human Body Map project (>2.5 billion reads).  Using the system, we identified putative alternative splicing events in 16 different human tissues, which provide a dynamic picture of splicing variation across the tissues. We detected 26,989 potential exon skipping events representing differences in splicing patterns among the tissues. A large proportion of the events (>60%) were novel, involving new exons (~3000), new introns (~16000), or both. When tracing these events across the sixteen tissues, only a small number (4-7%) appeared to be differentially expressed (‘switched’) between two tissues, while 30-45% showed little variation, and the remaining 50-65% were not present in one or both tissues compared.  Novel exon skipping events appeared to be slightly less variable than known events, but were more tissue-specific. Our study represents the first effort to build a comprehensive catalog of alternative splicing in normal human tissues from RNA-seq data, while providing insights into the role of alternative splicing in shaping tissue transcriptome differences. The catalog of events and the ASprofile software are freely available from the Zenodo repository(http://zenodo.org/record/7068; doi:10.5281/zenodo.7068) and from our web site http://ccb.jhu.edu/software/ASprofile.

scholarly journals Osteoblast connexin43 modulates skeletal architecture by regulating both arms of bone remodeling

2011 ◽  
Vol 22 (8) ◽  
pp. 1240-1251 ◽  
Author(s):  
Marcus Watkins ◽  
Susan K. Grimston ◽  
Jin Yi Norris ◽  
Bertrand Guillotin ◽  
Angela Shaw ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Remodeling ◽  
Structural Changes ◽  
Mechanical Load ◽  
Bone Apposition ◽  
Age Related ◽  
High Bone ◽  
Skeletal Phenotype ◽  
Skeletal Homeostasis ◽  
And Function

Connexin43 (Cx43) has an important role in skeletal homeostasis, and Cx43 gene (Gja1) mutations have been linked to oculodentodigital dysplasia (ODDD), a human disorder characterized by prominent skeletal abnormalities. To determine the function of Cx43 at early steps of osteogenesis and its role in the ODDD skeletal phenotype, we have used the Dermo1 promoter to drive Gja1 ablation or induce an ODDD mutation in the chondro-osteogenic linage. Both Gja1 null and ODDD mutant mice develop age-related osteopenia, primarily due to a progressive enlargement of the medullary cavity and cortical thinning. This phenotype is the consequence of a high bone turnover state, with increased endocortical osteoclast-mediated bone resorption and increased periosteal bone apposition. Increased bone resorption is a noncell autonomous defect, caused by exuberant stimulation of osteoclastogenesis by Cx43-deficient bone marrow stromal cells, via decreased Opg production. The latter is part of a broad defect in osteoblast differentiation and function, which also results in abnormal structural and material properties of bone leading to decreased resistance to mechanical load. Thus Cx43 in osteogenic cells is a critical regulator of both arms of the bone remodeling cycle, its absence causing structural changes remindful of aged or disused bone.

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