scholarly journals Accurate prediction of functional states of cis-regulatory modules reveals the universal epigenetic code in mammals

2021 ◽  
Author(s):  
Pengyu Ni ◽  
Zhengchang Su
Keyword(s):  
Mouse Cell ◽  
Tissue Type ◽  
False Discovery Rates ◽  
Regulatory Modules ◽  
Cell Tissue ◽  
Machine Learning Model ◽  
A Genome ◽  
Epigenetic Code ◽  
A Cell ◽  
Functional States

Predicting cis-regulatory modules(CRMs) in a genome and predicting their functional states in various cell/tissue types of the organism are two related challenging computational tasks. Most current methods attempt to achieve both simultaneously using epigenetic data. Though conceptually attractive, they suffer high false discovery rates and limited applications. To fill the gaps, we proposed a two-step strategy to first predict a map of CRMs in the genome, and then predict functional states of the CRMs in various cell/tissue types of the organism. We have recently developed an algorithm for accurately predicting CRMs in a genome by integrating numerous transcription factor ChIP-seq datasets. Here, we showed that only three or four epigenetic marks data in a cell/tissue type were sufficient for a machine-learning model to accurately predict functional states of all CRMs. Our predictions are substantially more accurate than the best achieved so far. Interestingly, a model trained on different cell/tissue types in a mammal can accurately predict functional states of CRMs in different cell/tissue types of the mammal as well as in various cell/tissue types of a different mammal. Therefore, epigenetic code that defines functional states of CRMs in various cell/tissue types is universal at least in mammals. Moreover, we found that from tens to hundreds of thousands of CRMs were active in a human and mouse cell/tissue type, and up to 99.98% of them were reutilized in different cell/tissue types, while as small as 0.02% of them were unique to a cell/tissue type that might define the cell/tissue type.

scholarly journals Cell and tissue type independent age-associated DNA methylation changes are not rare but common

2018 ◽  
Author(s):  
Tianyu Zhu ◽  
Shijie C Zheng ◽  
Dirk S. Paul ◽  
S. Horvath ◽  
Andrew E. Teschendorff
Keyword(s):  
Dna Methylation ◽  
Cell Types ◽  
Tissue Type ◽  
Tissue Cell ◽  
Cell Type ◽  
Tissue Specific ◽  
Cell Tissue ◽  
A Cell ◽  
High Degree ◽  
Do So

AbstractAge-associated DNA methylation changes have been widely reported across many different tissue and cell types. Epigenetic ‘clocks’ that can predict chronological age with a surprisingly high degree of accuracy appear to do so independently of tissue and cell-type, suggesting that a component of epigenetic drift is cell-type independent. However, the relative amount of age-associated DNAm changes that are specific to a cell or tissue type versus the amount that occurs independently of cell or tissue type is unclear and a matter of debate, with a recent study concluding that most epigenetic drift is tissue-specific. Here, we perform a novel comprehensive statistical analysis, including matched multi cell-type and multi-tissue DNA methylation profiles from the same individuals and adjusting for cell-type heterogeneity, demonstrating that a substantial amount of epigenetic drift, possibly over 70%, is shared between significant numbers of different tissue/cell types. We further show that ELOVL2 is not unique and that many other CpG sites, some mapping to genes in the Wnt and glutamate receptor signaling pathways, are altered with age across at least 10 different cell/tissue types. We propose that while most age-associated DNAm changes are shared between cell-types that the putative functional effect is likely to be tissue-specific.

scholarly journals Novel Insights into the Role of Caveolin-2 in Cell- and Tissue-Specific Signaling and Function

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Grzegorz Sowa
Keyword(s):  
Tissue Type ◽  
Major Protein ◽  
Direct Role ◽  
Tissue Specific ◽  
Caveolin 1 ◽  
Cell Tissue ◽  
A Cell ◽  
Protein Components ◽  
And Function

Caveolin-2 is one of the major protein components of cholesterol- and glycosphingolipid-rich flask-shaped invaginations of plasma membrane caveolae. A new body of evidence suggests that caveolin-2 plays an important, and often more direct, role than caveolin-1 in regulating signaling and function in a cell- and tissue type-specific manner. The purpose of this paper is to primarily focus on discussing how these recent discoveries may help better understand the specific contribution of caveolin-2 to lipid raft- and caveolae-regulated cell/tissue-specific signaling and functions.

Proteomics: Opportunities and Challenges

2011 ◽  
Vol 3 (4) ◽  
pp. 1165-1172 ◽  
Author(s):  
Parag A Pathade ◽  
Vinod A Bairagi ◽  
Yogesh S. Ahire ◽  
Neela M Bhatia
Keyword(s):  
Biomedical Research ◽  
Therapy Monitoring ◽  
Dynamic State ◽  
Data Sets ◽  
Protein Markers ◽  
Drug Target Discovery ◽  
Proteomic Data ◽  
Cell Tissue ◽  
A Cell ◽  
Analytical Tools

‘‘Proteomics’’, is the emerging technology leading to high-throughput identification and understanding of proteins. Proteomics is the protein equivalent of genomics and has captured the imagination of biomolecular scientists, worldwide. Because proteome reveals more accurately the dynamic state of a cell, tissue, or organism, much is expected from proteomics to indicate better disease markers for diagnosis and therapy monitoring. Proteomics is expected to play a major role in biomedical research, and it will have a significant impact on the development of diagnostics and therapeutics for cancer, heart ailments and infectious diseases, in future. Proteomics research leads to the identification of new protein markers for diagnostic purposes and novel molecular targets for drug discovery.  Though the potential is great, many challenges and issues remain to be solved, such as gene expression, peptides, generation of low abundant proteins, analytical tools, drug target discovery and cost. A systematic and efficient analysis of vast genomic and proteomic data sets is a major challenge for researchers, today. Nevertheless, proteomics is the groundwork for constructing and extracting useful comprehension to biomedical research. This review article covers some opportunities and challenges offered by proteomics.   

scholarly journals Syntaxin 1A Gene Is Negatively Regulated in a Cell/Tissue Specific Manner by YY1 Transcription Factor, Which Binds to the −183 to −137 Promoter Region Together with Gene Silencing Factors Including Histone Deacetylase

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 146
Author(s):  
Takahiro Nakayama ◽  
Toshiyuki Fukutomi ◽  
Yasuo Terao ◽  
Kimio Akagawa
Keyword(s):  
Transcription Factor ◽  
Gene Silencing ◽  
Protein Complex ◽  
Promoter Region ◽  
Neuronal Cell ◽  
Syntaxin 1A ◽  
Tissue Specific ◽  
Cell Tissue ◽  
Specific Manner ◽  
A Cell

The HPC-1/syntaxin 1A (Stx1a) gene, which is involved in synaptic transmission and neurodevelopmental disorders, is a TATA-less gene with several transcription start sites. It is activated by the binding of Sp1 and acetylated histone H3 to the −204 to +2 core promoter region (CPR) in neuronal cell/tissue. Furthermore, it is depressed by the association of class 1 histone deacetylases (HDACs) to Stx1a–CPR in non-neuronal cell/tissue. To further clarify the factors characterizing Stx1a gene silencing in non-neuronal cell/tissue not expressing Stx1a, we attempted to identify the promoter region forming DNA–protein complex only in non-neuronal cells. Electrophoresis mobility shift assays (EMSA) demonstrated that the −183 to −137 OL2 promoter region forms DNA–protein complex only in non-neuronal fetal rat skin keratinocyte (FRSK) cells which do not express Stx1a. Furthermore, the Yin-Yang 1 (YY1) transcription factor binds to the −183 to −137 promoter region of Stx1a in FRSK cells, as shown by competitive EMSA and supershift assay. Chromatin immunoprecipitation assay revealed that YY1 in vivo associates to Stx1a–CPR in cell/tissue not expressing Stx1a and that trichostatin A treatment in FRSK cells decreases the high-level association of YY1 to Stx1a-CPR in default. Reporter assay indicated that YY1 negatively regulates Stx1a transcription. Finally, mass spectrometry analysis showed that gene silencing factors, including HDAC1, associate onto the −183 to −137 promoter region together with YY1. The current study is the first to report that Stx1a transcription is negatively regulated in a cell/tissue-specific manner by YY1 transcription factor, which binds to the −183 to −137 promoter region together with gene silencing factors, including HDAC.

scholarly journals Functional CRISPR screening identifies the ufmylation pathway as a regulator of SQSTM1/p62

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Rowena DeJesus ◽  
Francesca Moretti ◽  
Gregory McAllister ◽  
Zuncai Wang ◽  
Phil Bergman ◽  
...  
Keyword(s):  
Adaptor Protein ◽  
Er Stress Response ◽  
Genome Wide ◽  
A Genome ◽  
Crispr Screen ◽  
Selection Step ◽  
A Cell ◽  
Cell Type Specific ◽  
Cellular Pathways ◽  
Mtor Signalling

SQSTM1 is an adaptor protein that integrates multiple cellular signaling pathways and whose expression is tightly regulated at the transcriptional and post-translational level. Here, we describe a forward genetic screening paradigm exploiting CRISPR-mediated genome editing coupled to a cell selection step by FACS to identify regulators of SQSTM1. Through systematic comparison of pooled libraries, we show that CRISPR is superior to RNAi in identifying known SQSTM1 modulators. A genome-wide CRISPR screen exposed MTOR signalling and the entire macroautophagy machinery as key regulators of SQSTM1 and identified several novel modulators including HNRNPM, SLC39A14, SRRD, PGK1 and the ufmylation cascade. We show that ufmylation regulates SQSTM1 by eliciting a cell type-specific ER stress response which induces SQSTM1 expression and results in its accumulation in the cytosol. This study validates pooled CRISPR screening as a powerful method to map the repertoire of cellular pathways that regulate the fate of an individual target protein.

scholarly journals Molecular interactions of autophagy with the immune system and cancer

2017 ◽  
Author(s):  
Yonggeun Hong ◽  
Yunho Jin ◽  
Yunkyung Hong ◽  
Chanyoung Park
Keyword(s):  
Cell Death ◽  
Cancer Cell ◽  
Human Cancer ◽  
Therapeutic Option ◽  
Cancer Cell Line ◽  
Tissue Type ◽  
Alternative Source ◽  
Cancer Cell Death ◽  
Cell Tissue ◽  
Cellular Components

Autophagy is a highly conserved catabolic mechanism that mediates the degradation of damaged cellular components by inducing their fusion with lysosomes. This process provides cells with an alternative source of energy for the synthesis of new proteins and the maintenance of metabolic homeostasis in stressful environments. Numerous studies have demonstrated beneficial roles for the induction as well as the suppression of autophagy in cancer cells. Autophagy may induce either survival or death depending on the cell/tissue type. Radiation therapy is widely used therapeutic option to treat cancer, and it induces autophagy in human cancer cell line. Also, melatonin seems to affect cancer cell death via regulation of programmed cell death. In this review, we summarize the current understanding of autophagy and its regulation in cancer.

scholarly journals MMP-14-targeted Nanoprobe for in vivo Fluorescence Imaging of Rupture-prone Carotid Plaques

2021 ◽  
Author(s):  
Mengtao Han ◽  
Kaining Liu ◽  
Hongqiu Xiao ◽  
Tao Sun ◽  
Fei Wang ◽  
...  
Keyword(s):  
Fluorescence Imaging ◽  
Fluorescence Signal ◽  
Plaque Progression ◽  
Carotid Plaques ◽  
In Vivo Fluorescence ◽  
Cell Tissue ◽  
A Cell ◽  
In Vivo Fluorescence Imaging ◽  
Membrane Anchoring

Abstract Background: The identification of rupture-prone carotid plaques for preventing stroke remains a clinical challenge. Macrophage matrix metalloproteinase (MMP)-14, which contributes to plaque progression and destabilisation, could be a promising biomarker for plaque imaging. This study aimed to design and synthesise an MMP-14-targeted nanoprobe to noninvasively visualise the behaviour of M1 macrophages in atherosclerotic plaques.Methods: A fluorescence molecular imaging probe ([email protected]) was constructed by covalently attaching the fluorescent dye cyanine (Cy) 5.5, an MMP-14 substrate, and polyethylene glycol (PEG) 5000-wrapped gold nanoparticles (AuNPs), and then administered via tail vein injection to carotid atherosclerosis models for in vivo fluorescence imaging. Additionally, carotid tissues and cultured macrophages were analysed for nanoprobe binding, and MMP-14 and inflammation-related marker expression was evaluated by polymerase chain reaction, western blotting, and immunohistochemistry.Results: MMP-14 expression significantly increased with plaque progression, along with the upregulation of MMP-2 and inflammatory M1 markers, CD68 and F4/80, and significant downregulation of the M2 marker CD206. All of cell, tissue and in vivo fluorescence imaging exhibited a favourable targeting efficacy of [email protected] for MMP-14.Conclusions: MMP-14, a cell membrane-anchoring enzyme, can serve as a biomarker of vulnerable plaques, and MMP-14 substrate-based [email protected], with an intense fluorescence signal after activation and good biocompatibility, can be applied to screen for and monitor plaque progression in vivo.

scholarly journals Physiological function of Flo11p domains and the particular role of amyloid core sequences of this adhesin in Saccharomyces cerevisiae

2021 ◽  
Author(s):  
Clara Bouyx ◽  
Marion Schiavone ◽  
Marie-Ange Teste ◽  
Etienne Dague ◽  
Nathalie Sieczkowski ◽  
...  
Keyword(s):  
Cell Wall ◽  
Amyloid Β ◽  
Surface Hydrophobicity ◽  
Yeast Cells ◽  
Invasive Growth ◽  
Specific Domain ◽  
A Genome ◽  
A Cell ◽  
Cellular Aggregates

Flocculins are a family of glycosylated proteins that provide yeast cells with several properties such as biofilm formation, flocculation, invasive growth or formation of velum. These proteins are similarly organised with a N-terminal (adhesion) domain, a stalk-like central B-domain with several repeats and a C-terminal sequence carrying a cell wall anchor site. They also contain amyloid β-aggregation-prone sequences whose functional role is still unclear. In this work, we show that Flo11p differs from other flocculins by the presence of unique amyloid-forming sequences, whose the number is critical in the formation of adhesion nanodomains under a physical shear force. Using a genome editing approach to identify the function of domains in Flo11p phenotypes, we show that the formation of cellular aggregates whose density increases with the number of amyloid sequences cannot be attributed to a specific domain of Flo11p. The same is true for plastic adhesion and surface hydrophobicity the intensity of which depends mainly on the abundance of Flo11p on the cell surface. In contrast, the N and C domains of Flo11p are essential for invasive growth in agar, whereas a reduction in the number of repeats of the B domain weakens this phenotype. However, expression of FLO11 alone is not sufficient to trigger this invasion phenotype. Finally, we show that this flocculin contributes to the integrity of the cell wall.

scholarly journals Gene Therapy: The Molecular Bandage for Treating Genetic Disorders

1970 ◽  
Vol 3 (1) ◽  
pp. 24-27
Author(s):  
Md Manjurul Karim
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
Genetic Disorders ◽  
Clinical Status ◽  
Genetic Material ◽  
Review Article ◽  
Cell Tissue ◽  
Efficient Gene ◽  
Effective Delivery ◽  
A Cell

The concept of gene therapy involves the transfer of genetic material into a cell, tissue, or whole organ, with a view to curing a disease or at least improving the clinical status of a patient. Much of its success relies heavily on the development of an effective delivery system that is capable of efficient gene transfer in a variety of tissues, without causing any associated pathogenic effects. Viral vectors currently offer the best choice for efficient gene delivery, what has been discussed in this review article. Their performance and pathogenecity has been evaluated in animal models, and encouraging results form the basis for clinical trials to treat genetic disorders and acquired diseases. Despite some initial success in these trials, vector development remains a seminal concern for improved gene therapy technologies. DOI: http://dx.doi.org/10.3329/akmmcj.v3i1.10110 AKMMCJ 2012; 3(1): 24-27

scholarly journals The road to rack and ruin: selecting deleterious mitochondrial DNA variants

2014 ◽  
Vol 369 (1646) ◽  
pp. 20130451 ◽  
Author(s):  
Ian J. Holt ◽  
Dave Speijer ◽  
Thomas B. L. Kirkwood
Keyword(s):  
Mitochondrial Dna ◽  
Energy Production ◽  
Rapid Change ◽  
Eukaryotic Cell ◽  
The Road ◽  
Cell Tissue ◽  
Dna Variants ◽  
A Cell ◽  
The Subject ◽  
Mitochondrial Dna Variants

Mitochondria constitute the major energy-producing compartment of the eukaryotic cell. These organelles contain many molecules of DNA that contribute only a handful of proteins required for energy production. Mutations in the DNA of mitochondria were identified as a cause of human disease a quarter of a century ago, and they have subsequently been implicated in ageing. The process whereby deleterious variants come to dominate a cell, tissue or human is the subject of debate. It is likely to involve multiple, often competing, factors, as selection pressures on mitochondrial DNA can be both indirect and intermittent, and are subjected to rapid change. Here, we assess the different models and the prospects for preventing the accumulation of deleterious mitochondrial DNA variants with time.

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