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López de Mingo I, Rivera González MX, Ramos Gómez M, Maestú Unturbe C. The Frequency of a Magnetic Field Reduces the Viability and Proliferation of Numerous Tumor Cell Lines. Biomolecules 2025; 15:503. [PMID: 40305213 PMCID: PMC12024963 DOI: 10.3390/biom15040503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 03/24/2025] [Accepted: 03/26/2025] [Indexed: 05/02/2025] Open
Abstract
The frequency of a magnetic field has led to the development of physicochemical interaction models and to the consideration of the role of frequency as a fundamental parameter in the change of cell behavior. The main objective of this article is to find a frequency window to decrease the viability and proliferation of different tumor cell lines to compare the frequency response of each. For this purpose, tumor cell lines PC12 (rat), B16F10 (mouse), SKBR3 (human), MDA-MB-231 (human), and the non-tumor cell line 3T3 (mouse) are exposed to a magnetic field of 100 µT for 24, 48, and 72 hours in frequency windows contained in the range [20-100] Hz, and their viability and proliferation behavior is evaluated. The results show a frequency-, exposure-time-, and cell-line-dependent behavior, with the most pronounced changes for most cell lines at frequencies of 45, 50, and 55 Hz. It is concluded that each cell type could respond to specific frequency codes that allow the modification of its behavior in vital cellular processes related to tumor development. Knowledge of these codes would allow for the therapeutic application of magnetic fields in oncological pathologies.
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Affiliation(s)
- Isabel López de Mingo
- Escuela Técnica Superior de Ingenieros de Telecomunicación (ETSIT), Universidad Politécnica de Madrid, 28223 Madrid, Spain;
- Centro de Tecnología Biomédica (CTB), Universidad Politécnica de Madrid (UPM), Avda. Campus de Montegancedo, M40 Km38, Pozuelo de Alarcón, 28223 Madrid, Spain; (M.X.R.G.); (C.M.U.)
| | - Marco Xavier Rivera González
- Centro de Tecnología Biomédica (CTB), Universidad Politécnica de Madrid (UPM), Avda. Campus de Montegancedo, M40 Km38, Pozuelo de Alarcón, 28223 Madrid, Spain; (M.X.R.G.); (C.M.U.)
- Escuela Técnica Superior de Ingenieros Informáticos (ETSIINF), Universidad Politécnica de Madrid, 28223 Madrid, Spain
| | - Milagros Ramos Gómez
- Escuela Técnica Superior de Ingenieros de Telecomunicación (ETSIT), Universidad Politécnica de Madrid, 28223 Madrid, Spain;
- Centro de Tecnología Biomédica (CTB), Universidad Politécnica de Madrid (UPM), Avda. Campus de Montegancedo, M40 Km38, Pozuelo de Alarcón, 28223 Madrid, Spain; (M.X.R.G.); (C.M.U.)
- Centro de Investigación Biomédica en Red (CIBER-BBN), 28029 Madrid, Spain
| | - Ceferino Maestú Unturbe
- Centro de Tecnología Biomédica (CTB), Universidad Politécnica de Madrid (UPM), Avda. Campus de Montegancedo, M40 Km38, Pozuelo de Alarcón, 28223 Madrid, Spain; (M.X.R.G.); (C.M.U.)
- Centro de Investigación Biomédica en Red (CIBER-BBN), 28029 Madrid, Spain
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Barbieri M. The concepts of code biology. Biosystems 2025; 248:105400. [PMID: 39826706 DOI: 10.1016/j.biosystems.2025.105400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 01/15/2025] [Accepted: 01/15/2025] [Indexed: 01/22/2025]
Abstract
Today there are two dominant paradigms in Biology: the idea that 'Life is Chemistry' and the idea that 'Life is Chemistry plus Information'. There is also a third paradigm, the idea that 'Life is Chemistry, Information and Meaning' but today this is a minority view, despite the fact that meaning is produced by codes and there is ample experimental evidence that hundreds of codes exist in living systems. This is because that evidence has not yet reached the university books, but what exists in nature is bound to exist, one day, also in our books and at that point the codes will become an integral part of biology. This paper is a brief description of the key concepts of that third paradigm that has become known as Code Biology.
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Affiliation(s)
- Marcello Barbieri
- Dipartimento di Morfologia ed Embriologia, University of Ferrara, Italy.
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3
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Sizer RE, Ingram RM, White RJ. Barriers Composed of tRNA Genes Can Complement the Benefits of a Ubiquitous Chromatin Opening Element to Enhance Transgene Expression. Biotechnol J 2025; 20:e202400455. [PMID: 39956936 PMCID: PMC11830863 DOI: 10.1002/biot.202400455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 12/18/2024] [Accepted: 12/20/2024] [Indexed: 02/18/2025]
Abstract
Random integration of transgenes into host cell genomes often occurs in epigenetically unstable regions, leading to variable and unreliable transgene expression. To address this, biomanufacturing organizations frequently employ barrier elements, such as the widely-used ubiquitous chromatin opening element (UCOE). We have compared UCOE barrier activity against a barrier provided by tRNA genes. We demonstrate that the tRNA genes provide a more effective barrier than a UCOE in preventing transgene silencing in Chinese hamster ovary (CHO) cells. Nevertheless, the UCOE offers other benefits, increasing expression strongly, albeit transiently, and reducing production variability. Both the UCOE and tRNA genes counteract the repressive heterochromatin mark H3K9me3, but only the tRNA genes sustain euchromatic H3K27ac and recruitment of RNA polymerase II (Pol II) throughout long-term culture. A hybrid combining these distinct types of elements can provide benefits of both, enhancing expression in a more enduring manner. This synthetic hybrid offers potential for biomanufacturing applications.
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Bondhus L, Nava AA, Liu IS, Arboleda VA. Epigene functional diversity: isoform usage, disordered domain content, and variable binding partners. Epigenetics Chromatin 2025; 18:8. [PMID: 39893491 PMCID: PMC11786378 DOI: 10.1186/s13072-025-00571-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 01/21/2025] [Indexed: 02/04/2025] Open
Abstract
BACKGROUND Epigenes are defined as proteins that perform post-translational modification of histones or DNA, reading of post-translational modifications, form complexes with epigenetic factors or changing the general structure of chromatin. This specialized group of proteins is responsible for controlling the organization of genomic DNA in a cell-type specific fashion, controlling normal development in a spatial and temporal fashion. Moreover, mutations in epigenes have been implicated as causal in germline pediatric disorders and as driver mutations in cancer. Despite their importance to human disease, to date, there has not been a systematic analysis of the sources of functional diversity for epigenes at large. Epigenes' unique functions that require the assembly of pools within the nucleus suggest that their structure and amino acid composition would have been enriched for features that enable efficient assembly of chromatin and DNA for transcription, splicing, and post-translational modifications. RESULTS In this study, we assess the functional diversity stemming from gene structure, isoforms, protein domains, and multiprotein complex formation that drive the functions of established epigenes. We found that there are specific structural features that enable epigenes to perform their variable roles depending on the cellular and environmental context. First, epigenes are significantly larger and have more exons compared with non-epigenes which contributes to increased isoform diversity. Second epigenes participate in more multimeric complexes than non-epigenes. Thirdly, given their proposed importance in membraneless organelles, we show epigenes are enriched for substantially larger intrinsically disordered regions (IDRs). Additionally, we assessed the specificity of their expression profiles and showed epigenes are more ubiquitously expressed consistent with their enrichment in pediatric syndromes with intellectual disability, multiorgan dysfunction, and developmental delay. Finally, in the L1000 dataset, we identify drugs that can potentially be used to modulate expression of these genes. CONCLUSIONS Here we identify significant differences in isoform usage, disordered domain content, and variable binding partners between human epigenes and non-epigenes using various functional genomics datasets from Ensembl, ENCODE, GTEx, HPO, LINCS L1000, and BrainSpan. Our results contribute new knowledge to the growing field focused on developing targeted therapies for diseases caused by epigene mutations, such as chromatinopathies and cancers.
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Affiliation(s)
- Leroy Bondhus
- Department of Human Genetics, David Geffen School of Medicine, UCLA, 615 Charles E. Young Drive South, Los Angeles, CA, 90095, USA
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA
- Department of Computational Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA
| | - Aileen A Nava
- Department of Human Genetics, David Geffen School of Medicine, UCLA, 615 Charles E. Young Drive South, Los Angeles, CA, 90095, USA
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA
- Department of Computational Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA
| | - Isabelle S Liu
- Department of Human Genetics, David Geffen School of Medicine, UCLA, 615 Charles E. Young Drive South, Los Angeles, CA, 90095, USA
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA
- Department of Computational Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA
| | - Valerie A Arboleda
- Department of Human Genetics, David Geffen School of Medicine, UCLA, 615 Charles E. Young Drive South, Los Angeles, CA, 90095, USA.
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA.
- Department of Computational Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA.
- Molecular Biology Institute, UCLA, Los Angeles, CA, 90095, USA.
- Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, 90095, USA.
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Butterfield SP, Sizer RE, Saunders FL, White RJ. Selective Recruitment of a Synthetic Histone Acetyltransferase Can Boost CHO Cell Productivity. Biotechnol J 2024; 19:e202400474. [PMID: 39655408 PMCID: PMC11629143 DOI: 10.1002/biot.202400474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 10/16/2024] [Accepted: 11/21/2024] [Indexed: 12/12/2024]
Abstract
Industrial production of biologics typically involves the integration of transgenes into host cell genomes, most often Chinese hamster ovary (CHO) cells. Epigenetic control of transgene expression is a major determinant of production titers. Although the cytomegalovirus (CMV) promoter has long been used to drive industrial transgene expression, we found that its associated histones are suboptimally acetylated in CHO cells, providing an opportunity to enhance productivity through epigenetic manipulation. Expression of monoclonal antibody mRNAs increased up to 12-fold when a CRISPR-dCas9 system delivered the catalytic domain of a histone acetyltransferase to the CMV promoter. This effect was far stronger than when promoter DNA was selectively demethylated using dCas9 fused to a 5-methylcytosine dioxygenase. Mechanistically, acetylation-mediated transcriptional activation involved heightened phosphorylation and activity of RNA polymerase II, enabling it to escape promoter-proximal pausing at the transgene. This approach almost doubled the titer and specific productivity of antibody-producing CHO cells, demonstrating the potential for biomanufacturing.
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Murgas L, Pollastri G, Riquelme E, Sáez M, Martin AJM. Understanding relationships between epigenetic marks and their application to robust assignment of chromatin states. Brief Bioinform 2024; 26:bbae638. [PMID: 39658206 PMCID: PMC11631260 DOI: 10.1093/bib/bbae638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 09/09/2024] [Accepted: 12/02/2024] [Indexed: 12/12/2024] Open
Abstract
Structural changes of chromatin modulate access to DNA for the molecular machinery involved in the control of transcription. These changes are linked to variations in epigenetic marks that allow to classify chromatin in different functional states depending on the pattern of these histone marks. Importantly, alterations in chromatin states are known to be linked with various diseases, and their changes are known to explain processes such as cellular proliferation. For most of the available samples, there are not enough epigenomic data available to accurately determine chromatin states for the cells affected in each of them. This is mainly due to high costs of performing this type of experiments but also because of lack of a sufficient amount of sample or its degradation. In this work, we describe a cascade method based on a random forest algorithm to infer epigenetic marks, and by doing so, to identify relationships between different histone marks. Importantly, our approach also reduces the number of experimentally determined marks required to assign chromatin states. Moreover, in this work we have identified several relationships between patterns of different histone marks, which strengthens the evidence in favor of a redundant epigenetic code.
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Affiliation(s)
- Leandro Murgas
- Programa de Doctorado en Genómica Integrativa, Vicerrectoría de investigación, Universidad Mayor, Camino La Pirámide 5750, 8580745 Huechuraba, Chile
- Laboratorio de Redes Biológicas, Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Avda. del Valle 725, 8580702 Huechuraba, Chile
| | - Gianluca Pollastri
- School of Computer Science, University College Dublin, Belfield, Dublin 4, Dublin D04 C1P1, Ireland
| | - Erick Riquelme
- Department of Respiratory Diseases, Facultad de Medicina, Pontificia Universidad Católica, Avda. Libertador Bernando O’Higgins 340, 8331150 Santiago, Chile
| | - Mauricio Sáez
- Laboratorio de Investigación en Salud de Precisión, Departamento de Procesos Diagnósticos y Evaluación, Facultad de Ciencias de la Salud, Universidad Católica de Temuco, Manuel Montt 56, 4813302 Temuco, Chile
| | - Alberto J M Martin
- Laboratorio de Redes Biológicas, Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Avda. del Valle 725, 8580702 Huechuraba, Chile
- Escuela de Ingeniería, Facultad de Ingeniería, Arquitectura y Diseño, Universidad San Sebastián, Bellavista 7, 8420524 Santiago, Chile
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7
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Tvardovskiy A, Lukauskas S, Bartke T. Breaking the epigenetic code with MARCS: the Modification Atlas of Regulation by Chromatin States. Epigenomics 2024; 16:1061-1065. [PMID: 39229639 PMCID: PMC11418295 DOI: 10.1080/17501911.2024.2387527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 07/30/2024] [Indexed: 09/05/2024] Open
Affiliation(s)
- Andrey Tvardovskiy
- Institute of Functional Epigenetics, Helmholtz Zentrum München, 85764, Neuherberg, Germany
| | - Saulius Lukauskas
- Institute of Functional Epigenetics, Helmholtz Zentrum München, 85764, Neuherberg, Germany
| | - Till Bartke
- Institute of Functional Epigenetics, Helmholtz Zentrum München, 85764, Neuherberg, Germany
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8
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Alexanian AR. Epigenetic inheritance of acquired traits via stem cells dedifferentiation/differentiation or transdifferentiation cycles. Cells Dev 2024; 179:203928. [PMID: 38768658 DOI: 10.1016/j.cdev.2024.203928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 04/20/2024] [Accepted: 05/17/2024] [Indexed: 05/22/2024]
Abstract
Inheritance of acquired characteristics is the once widely accepted idea that multiple modifications acquired by an organism during its life, can be inherited by the offspring. This belief is at least as old as Hippocrates and became popular in early 19th century, leading Lamarck to suggest his theory of evolution. Charles Darwin, along with other thinkers of the time attempted to explain the mechanism of acquired traits' inheritance by proposing the theory of pangenesis. While later this and similar theories were rejected because of the lack of hard evidence, the studies aimed at revealing the mechanism by which somatic information can be passed to germ cells have continued up to the present. In this paper, we present a new theory and provide supporting literature to explain this phenomenon. We hypothesize existence of pluripotent adult stem cells that can serve as collectors and carriers of new epigenetic traits by entering different developmentally active organ/tissue compartments through blood circulation and acquiring new epigenetic marks though cycles of differentiation/dedifferentiation or transdifferentiation. During gametogenesis, these epigenetically modified cells are attracted by gonads, transdifferentiate into germ cells, and pass the acquired epigenetic modifications collected from the entire body's somatic cells to the offspring.
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Affiliation(s)
- Arshak R Alexanian
- Cell Reprogramming & Therapeutics LLC, Wauwatosa (Milwaukee County), WI 53226, USA.
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9
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Alcaráz N, Salcedo-Tello P, González-Barrios R, Torres-Arciga K, Guzmán-Ramos K. Underlying Mechanisms of the Protective Effects of Lifestyle Factors On Age-Related Diseases. Arch Med Res 2024; 55:103014. [PMID: 38861840 DOI: 10.1016/j.arcmed.2024.103014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 05/15/2024] [Accepted: 05/30/2024] [Indexed: 06/13/2024]
Abstract
The rise in life expectancy has significantly increased the occurrence of age-related chronic diseases, leading to escalating expenses for both society and individuals. Among the main factors influencing health and lifespan, lifestyle takes a forefront position. Specifically, nutrition, mental activity, and physical exercise influence the molecular and functional mechanisms that contribute to the prevention of major age-related diseases. Gaining deeper insights into the mechanisms that drive the positive effects of healthy lifestyles is valuable for creating interventions to prevent or postpone the development of chronic degenerative diseases. This review summarizes the main mechanisms that underlie the positive effect of lifestyle factors in counteracting the major age-related diseases involving brain health, musculoskeletal function, cancer, frailty, and cardiovascular diseases, among others. This knowledge will help to identify high-risk populations for targeted intervention trials and discover new biomarkers associated with healthy aging.
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Affiliation(s)
- Nicolás Alcaráz
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Pamela Salcedo-Tello
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Rodrigo González-Barrios
- Instituto Nacional de Cancerología, Laboratorio de regulación de la cromatina y genómica, Mexico City, México
| | - Karla Torres-Arciga
- Instituto Nacional de Cancerología, Laboratorio de regulación de la cromatina y genómica, Mexico City, México; Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Kioko Guzmán-Ramos
- Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana, Unidad Lerma, Mexico State, Mexico.
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10
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Wazahat R, Zaidi R, Kumar P. Epigenetic regulations in Mycobacterium tuberculosis infection. Indian J Tuberc 2024; 71:204-212. [PMID: 38589125 DOI: 10.1016/j.ijtb.2023.06.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/02/2023] [Accepted: 06/22/2023] [Indexed: 04/10/2024]
Abstract
Mycobacterium tuberculosis (Mtb) employs several sophisticated strategies to evade host immunity and facilitate its intracellular survival. One of them is the epigenetic manipulation of host chromatin by three strategies i.e., DNA methylation, histone modifications and miRNA involvement. A host-directed therapeutic can be an attractive approach that targets these host epigenetics or gene regulations and circumvent manipulation of host cell machinery by Mtb. Given the complexity of the nature of intracellular infection by Mtb, there are challenges in identifying the important host proteins, non-coding RNA or the secretory proteins of Mtb itself that directly or indirectly bring upon the epigenetic modifications in the host chromatin. Equally challenging is developing the methods of targeting these epigenetic factors through chemical or non-chemical approaches as host-directed therapeutics. The current review article briefly summarizes several of the epigenetic factors that serve to bring upon potential changes in the host transcriptional machinery and targets the immune system for immunosuppression and disease progression in Mtb infection.
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Affiliation(s)
- Rushna Wazahat
- Department of Biochemistry, Jamia Hamdard, New Delhi 110062, India.
| | - Rana Zaidi
- Department of Biochemistry, Jamia Hamdard, New Delhi 110062, India
| | - Pankaj Kumar
- Department of Biochemistry, Jamia Hamdard, New Delhi 110062, India.
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11
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Camerini L, Zurchimitten G, Bock B, Xavier J, Bastos CR, Martins E, Ardais AP, Dos Santos Motta JV, Pires AJ, de Matos MB, de Ávila Quevedo L, Pinheiro RT, Ghisleni G. Genetic Variations in Elements of the Oxytocinergic Pathway are Associated with Attention/Hyperactivity Problems and Anxiety Problems in Childhood. Child Psychiatry Hum Dev 2024; 55:552-563. [PMID: 36087156 DOI: 10.1007/s10578-022-01419-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 08/03/2022] [Accepted: 08/17/2022] [Indexed: 11/28/2022]
Abstract
Genetic alterations related to oxytocin system seem to influence the neurobiology of attention-deficit hyperactivity disorder and anxiety problems leading to greater functional, social and emotional impairment. Here, we analyzed the association of OXTR rs2254298 and CD38 rs6449182 variants with attention/hyperactivity problems and anxiety problems in children. The study enrolled 292 children and adjusted regression model revealed OXTR rs2254298 AA genotype as a risk factor for attention deficit/hyperactivity problems (PR: 2.37; PadjFDR = 0.006), attention problems (PR: 2.71; PadjFDR = 0.003) and anxiety problems (PR: 1.92; PadjFDR = 0.018). CD38 rs6449182 G allele showed as a risk factor for attention deficit/hyperactivity problems (PR: 1.56; PadjFDR = 0.028). Moreover, in silico approach for regulatory roles found markers that influence chromatin accessibility and transcription capacity. Together, these data provide genetic information of oxytocin in developmental and behavioral disorders opening a range of opportunities for future studies that clarify their neurobiology in childhood.
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Affiliation(s)
- Laísa Camerini
- Postgraduate Program in Health and Behavior, Catholic University of Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Gabriel Zurchimitten
- Postgraduate Program in Health and Behavior, Catholic University of Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Bertha Bock
- Postgraduate Program in Health and Behavior, Catholic University of Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Janaína Xavier
- Postgraduate Program in Health and Behavior, Catholic University of Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Clarissa Ribeiro Bastos
- Department of Neurosciences, Federal University of Santa Catarina, Florianopolis, Santa Catarina, Brazil
| | - Evânia Martins
- Postgraduate Program in Health and Behavior, Catholic University of Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Ana Paula Ardais
- Postgraduate Program in Health and Behavior, Catholic University of Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | | | - Andressa Jacondino Pires
- Postgraduate Program in Health and Behavior, Catholic University of Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Mariana Bonati de Matos
- Postgraduate Program in Health and Behavior, Catholic University of Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Luciana de Ávila Quevedo
- Postgraduate Program in Health and Behavior, Catholic University of Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Ricardo Tavares Pinheiro
- Postgraduate Program in Health and Behavior, Catholic University of Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Gabriele Ghisleni
- Postgraduate Program in Health and Behavior, Catholic University of Pelotas, Pelotas, Rio Grande do Sul, Brazil.
- Post-Graduation Program of Health and Behavior, Laboratory of Clinical Neuroscience, Catholic University of Pelotas - UCPel, Center of Health Science, Rua Gonçalves Chaves 373, sala 324, CEP 96010-280, Pelotas, RS, Brasil.
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12
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Girard C. The tri-flow adaptiveness of codes in major evolutionary transitions. Biosystems 2024; 237:105133. [PMID: 38336225 DOI: 10.1016/j.biosystems.2024.105133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 01/26/2024] [Accepted: 01/27/2024] [Indexed: 02/12/2024]
Abstract
Life codes increase in both number and variety with biological complexity. Although our knowledge of codes is constantly expanding, the evolutionary progression of organic, neural, and cultural codes in response to selection pressure remains poorly understood. Greater clarification of the selective mechanisms is achieved by investigating how major evolutionary transitions reduce spatiotemporal and energetic constraints on transmitting heritable code to offspring. Evolution toward less constrained flows is integral to enduring flow architecture everywhere, in both engineered and natural flow systems. Beginning approximately 4 billion years ago, the most basic level for transmitting genetic material to offspring was initiated by protocell division. Evidence from ribosomes suggests that protocells transmitted comma-free or circular codes, preceding the evolution of standard genetic code. This rudimentary information flow within protocells is likely to have first emerged within the geo-energetic and geospatial constraints of hydrothermal vents. A broad-gauged hypothesis is that major evolutionary transitions overcame such constraints with tri-flow adaptations. The interconnected triple flows incorporated energy-converting, spatiotemporal, and code-based informational dynamics. Such tri-flow adaptations stacked sequence splicing code on top of protein-DNA recognition code in eukaryotes, prefiguring the transition to sexual reproduction. Sex overcame the spatiotemporal-energetic constraints of binary fission with further code stacking. Examples are tubulin code and transcription initiation code in vertebrates. In a later evolutionary transition, language reduced metabolic-spatiotemporal constraints on inheritance by stacking phonetic, phonological, and orthographic codes. In organisms that reproduce sexually, each major evolutionary transition is shown to be a tri-flow adaptation that adds new levels of code-based informational exchange. Evolving biological complexity is also shown to increase the nongenetic transmissibility of code.
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Affiliation(s)
- Chris Girard
- Department of Global and Sociocultural Studies, Florida International University, Miami, FL 33199, United States.
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Ferrer P, Upadhyay S, Cai JJ, Clement TM. Novel Nuclear Roles for Testis-Specific ACTL7A and ACTL7B Supported by In Vivo Characterizations and AI Facilitated In Silico Mechanistic Modeling with Implications for Epigenetic Regulation in Spermiogenesis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.29.582797. [PMID: 38464253 PMCID: PMC10925299 DOI: 10.1101/2024.02.29.582797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
A mechanistic role for nuclear function of testis-specific actin related proteins (ARPs) is proposed here through contributions of ARP subunit swapping in canonical chromatin regulatory complexes. This is significant to our understanding of both mechanisms controlling regulation of spermiogenesis, and the expanding functional roles of the ARPs in cell biology. Among these roles, actins and ARPs are pivotal not only in cytoskeletal regulation, but also in intranuclear chromatin organization, influencing gene regulation and nucleosome remodeling. This study focuses on two testis-specific ARPs, ACTL7A and ACTL7B, exploring their intranuclear activities and broader implications utilizing combined in vivo, in vitro, and in silico approaches. ACTL7A and ACTL7B, previously associated with structural roles, are hypothesized here to serve in chromatin regulation during germline development. This study confirms the intranuclear presence of ACTL7B in spermatocytes and round spermatids, revealing a potential role in intranuclear processes, and identifies a putative nuclear localization sequence conserved across mammalian ACTL7B, indicating a potentially unique mode of nuclear transport which differs from conventional actin. Ablation of ACTL7B leads to varied transcriptional changes reported here. Additionally, in the absence of ACTL7A or ACTL7B there is a loss of intranuclear localization of HDAC1 and HDAC3, which are known regulators of epigenetic associated acetylation changes that in turn regulate gene expression. Thus, these HDACs are implicated as contributors to the aberrant gene expression observed in the KO mouse testis transcriptomic analysis. Furthermore, this study employed and confirmed the accuracy of in silico models to predict ARP interactions with Helicase-SANT-associated (HSA) domains, uncovering putative roles for testis-specific ARPs in nucleosome remodeling complexes. In these models, ACTL7A and ACTL7B were found capable of binding to INO80 and SWI/SNF nucleosome remodeler family members in a manner akin to nuclear actin and ACTL6A. These models thus implicate germline-specific ARP subunit swapping within chromatin regulatory complexes as a potential regulatory mechanism for chromatin and associated molecular machinery adaptations in nuclear reorganizations required during spermiogenesis. These results hold implications for male fertility and epigenetic programing in the male-germline that warrant significant future investigation. In summary, this study reveals that ACTL7A and ACTL7B play intranuclear gene regulation roles in male gametogenesis, adding to the multifaceted roles identified also spanning structural, acrosomal, and flagellar stability. ACTL7A and ACTL7B unique nuclear transport, impact on HDAC nuclear associations, impact on transcriptional processes, and proposed mechanism for involvement in nucleosome remodeling complexes supported by AI facilitated in silico modeling contribute to a more comprehensive understanding of the indispensable functions of ARPs broadly in cell biology, and specifically in male fertility.
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Affiliation(s)
- Pierre Ferrer
- Interdisciplinary Faculty of Toxicology Program, Texas A&M University, College Station, TX 77843
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843
| | - Srijana Upadhyay
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843
| | - James J Cai
- Department of Veterinary Integrative Biosciences, School of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843
| | - Tracy M Clement
- Interdisciplinary Faculty of Toxicology Program, Texas A&M University, College Station, TX 77843
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843
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14
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DeLorenzo L, Powder KE. Epigenetics and the evolution of form: Experimental manipulation of a chromatin modification causes species-specific changes to the craniofacial skeleton. Evol Dev 2024; 26:e12461. [PMID: 37850843 PMCID: PMC10842503 DOI: 10.1111/ede.12461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 08/18/2023] [Accepted: 10/05/2023] [Indexed: 10/19/2023]
Abstract
A central question in biology is the molecular origins of phenotypic diversity. While genetic changes are key to the genotype-phenotype relationship, alterations to chromatin structure and the physical packaging of histone proteins may also be important drivers of vertebrate divergence. We investigate the impact of such an epigenetic mechanism, histone acetylation, within a textbook example of an adaptive radiation. Cichlids of Lake Malawi have adapted diverse craniofacial structures, and here we investigate how histone acetylation influences morphological variation in these fishes. Specifically, we assessed the effect of inhibiting histone deacetylation using the drug trichostatin A (TSA) on developing facial structures. We examined this during three critical developmental windows in two cichlid species with alternate adult morphologies. Exposure to TSA during neural crest cell (NCC) migration and as postmigratory NCCs proliferate in the pharyngeal arches resulted in significant changes in lateral and ventral shape in Maylandia, but not in Tropheops. This included an overall shortening of the head, widening of the lower jaw, and steeper craniofacial profile, all of which are paedomorphic morphologies. In contrast, treatment with TSA during early chondrogenesis did not result in significant morphological changes in either species. Together, these data suggest a sensitivity to epigenetic alterations that are both time- and species-dependent. We find that morphologies are due to nonautonomous or potentially indirect effects on NCC development, including in part a global developmental delay. Our research bolsters the understanding that proper histone acetylation is essential for early craniofacial development and identifies a species-specific robustness to developmental change. Overall, this study demonstrates how epigenetic regulation may play an important role in both generating and buffering morphological variation.
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Affiliation(s)
- Leah DeLorenzo
- Department of Biological Sciences, Clemson University, Clemson, SC 29634, USA
| | - Kara E. Powder
- Department of Biological Sciences, Clemson University, Clemson, SC 29634, USA
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15
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Xiong D, Zhang L, Sun ZJ. Targeting the epigenome to reinvigorate T cells for cancer immunotherapy. Mil Med Res 2023; 10:59. [PMID: 38044445 PMCID: PMC10694991 DOI: 10.1186/s40779-023-00496-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 11/14/2023] [Indexed: 12/05/2023] Open
Abstract
Cancer immunotherapy using immune-checkpoint inhibitors (ICIs) has revolutionized the field of cancer treatment; however, ICI efficacy is constrained by progressive dysfunction of CD8+ tumor-infiltrating lymphocytes (TILs), which is termed T cell exhaustion. This process is driven by diverse extrinsic factors across heterogeneous tumor immune microenvironment (TIME). Simultaneously, tumorigenesis entails robust reshaping of the epigenetic landscape, potentially instigating T cell exhaustion. In this review, we summarize the epigenetic mechanisms governing tumor microenvironmental cues leading to T cell exhaustion, and discuss therapeutic potential of targeting epigenetic regulators for immunotherapies. Finally, we outline conceptual and technical advances in developing potential treatment paradigms involving immunostimulatory agents and epigenetic therapies.
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Affiliation(s)
- Dian Xiong
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 430079, China
| | - Lu Zhang
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 430079, China.
| | - Zhi-Jun Sun
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 430079, China.
- Department of Oral Maxillofacial-Head Neck Oncology, School and and Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.
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16
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Serio S, Pagiatakis C, Musolino E, Felicetta A, Carullo P, Laura Frances J, Papa L, Rozzi G, Salvarani N, Miragoli M, Gornati R, Bernardini G, Condorelli G, Papait R. Cardiac Aging Is Promoted by Pseudohypoxia Increasing p300-Induced Glycolysis. Circ Res 2023; 133:687-703. [PMID: 37681309 DOI: 10.1161/circresaha.123.322676] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 08/30/2023] [Indexed: 09/09/2023]
Abstract
BACKGROUND Heart failure is typical in the elderly. Metabolic remodeling of cardiomyocytes underlies inexorable deterioration of cardiac function with aging: glycolysis increases at the expense of oxidative phosphorylation, causing an energy deficit contributing to impaired contractility. Better understanding of the mechanisms of this metabolic switching could be critical for reversing the condition. METHODS To investigate the role of 3 histone modifications (H3K27ac, H3K27me3, and H3K4me1) in the metabolic remodeling occurring in the aging heart, we cross-compared epigenomic, transcriptomic, and metabolomic data from mice of different ages. In addition, the role of the transcriptional coactivator p300 (E1A-associated binding protein p300)/CBP (CREB binding protein) in cardiac aging was investigated using a specific inhibitor of this histone acetyltransferase enzyme. RESULTS We report a set of species-conserved enhancers associated with transcriptional changes underlying age-related metabolic remodeling in cardiomyocytes. Activation of the enhancer region of Hk2-a key glycolysis pathway gene-was fostered in old age-onset mouse heart by pseudohypoxia, wherein hypoxia-related genes are expressed under normal O2 levels, via increased activity of P300/CBP. Pharmacological inhibition of this transcriptional coactivator before the onset of cardiac aging led to a more aerobic, less glycolytic, metabolic state, improved heart contractility, and overall blunting of cardiac decline. CONCLUSIONS Taken together, our results suggest how epigenetic dysregulation of glycolysis pathway enhancers could potentially be targeted to treat heart failure in the elderly.
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Affiliation(s)
- Simone Serio
- Department of Cardiovascular Medicine, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano (MI), Italy (S.S., C.P., A.F., P.C., J.L.F., L.P., G.R., N.S., M.M., G.C., R.P.)
- Department of Biomedical Sciences, Humanitas University, via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy (S.S., G.C.)
| | - Christina Pagiatakis
- Department of Cardiovascular Medicine, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano (MI), Italy (S.S., C.P., A.F., P.C., J.L.F., L.P., G.R., N.S., M.M., G.C., R.P.)
- Department of Biotechnology and Life Sciences, University of Insubria, via J.H. Dunant 3, 21100, Varese, Italy (C.P., E.M., R.G., G.B., R.P.)
| | - Elettra Musolino
- Department of Biotechnology and Life Sciences, University of Insubria, via J.H. Dunant 3, 21100, Varese, Italy (C.P., E.M., R.G., G.B., R.P.)
| | - Arianna Felicetta
- Department of Cardiovascular Medicine, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano (MI), Italy (S.S., C.P., A.F., P.C., J.L.F., L.P., G.R., N.S., M.M., G.C., R.P.)
| | - Pierluigi Carullo
- Department of Cardiovascular Medicine, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano (MI), Italy (S.S., C.P., A.F., P.C., J.L.F., L.P., G.R., N.S., M.M., G.C., R.P.)
| | - Javier Laura Frances
- Department of Cardiovascular Medicine, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano (MI), Italy (S.S., C.P., A.F., P.C., J.L.F., L.P., G.R., N.S., M.M., G.C., R.P.)
| | - Laura Papa
- Department of Cardiovascular Medicine, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano (MI), Italy (S.S., C.P., A.F., P.C., J.L.F., L.P., G.R., N.S., M.M., G.C., R.P.)
| | - Giacomo Rozzi
- Department of Cardiovascular Medicine, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano (MI), Italy (S.S., C.P., A.F., P.C., J.L.F., L.P., G.R., N.S., M.M., G.C., R.P.)
| | - Nicolò Salvarani
- Department of Cardiovascular Medicine, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano (MI), Italy (S.S., C.P., A.F., P.C., J.L.F., L.P., G.R., N.S., M.M., G.C., R.P.)
- Institute of Genetic and Biomedical Research, UOS of Milan, National Research Council of Italy (N.S.)
| | - Michele Miragoli
- Department of Cardiovascular Medicine, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano (MI), Italy (S.S., C.P., A.F., P.C., J.L.F., L.P., G.R., N.S., M.M., G.C., R.P.)
- Department of Medicine and Surgery, University of Parma, Italy (M.M.)
| | - Rosalba Gornati
- Department of Biotechnology and Life Sciences, University of Insubria, via J.H. Dunant 3, 21100, Varese, Italy (C.P., E.M., R.G., G.B., R.P.)
| | - Giovanni Bernardini
- Department of Biotechnology and Life Sciences, University of Insubria, via J.H. Dunant 3, 21100, Varese, Italy (C.P., E.M., R.G., G.B., R.P.)
| | - Gianluigi Condorelli
- Department of Cardiovascular Medicine, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano (MI), Italy (S.S., C.P., A.F., P.C., J.L.F., L.P., G.R., N.S., M.M., G.C., R.P.)
- Department of Biomedical Sciences, Humanitas University, via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy (S.S., G.C.)
| | - Roberto Papait
- Department of Cardiovascular Medicine, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano (MI), Italy (S.S., C.P., A.F., P.C., J.L.F., L.P., G.R., N.S., M.M., G.C., R.P.)
- Department of Biotechnology and Life Sciences, University of Insubria, via J.H. Dunant 3, 21100, Varese, Italy (C.P., E.M., R.G., G.B., R.P.)
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17
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Pierzynska-Mach A, Cainero I, Oneto M, Ferrando-May E, Lanzanò L, Diaspro A. Imaging-based study demonstrates how the DEK nanoscale distribution differentially correlates with epigenetic marks in a breast cancer model. Sci Rep 2023; 13:12749. [PMID: 37550322 PMCID: PMC10406876 DOI: 10.1038/s41598-023-38685-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 07/12/2023] [Indexed: 08/09/2023] Open
Abstract
Epigenetic dysregulation of chromatin is one of the hallmarks of cancer development and progression, and it is continuously investigated as a potential general bio-marker of this complex disease. One of the nuclear factors involved in gene regulation is the unique DEK protein-a histone chaperon modulating chromatin topology. DEK expression levels increase significantly from normal to cancer cells, hence raising the possibility of using DEK as a tumor marker. Although DEK is known to be implicated in epigenetic and transcriptional regulation, the details of these interactions and their relevance in cancer development remain largely elusive. In this work, we investigated the spatial correlation between the nuclear distribution of DEK and chromatin patterns-alongside breast cancer progression-leveraging image cross-correlation spectroscopy (ICCS) coupled with Proximity Ligation Assay (PLA) analysis. We performed our study on the model based on three well-established human breast cell lines to consider this tumor's heterogeneity (MCF10A, MCF7, and MDA-MB-231 cells). Our results show that overexpression of DEK correlates with the overall higher level of spatial proximity between DEK and histone marks corresponding to gene promoters regions (H3K9ac, H3K4me3), although it does not correlate with spatial proximity between DEK and gene enhancers (H3K27ac). Additionally, we observed that colocalizing fractions of DEK and histone marks are lower for the non-invasive cell subtype than for the highly invasive cell line (MDA-MB-231). Thus, this study suggests that the role of DEK on transcriptionally active chromatin regions varies depending on the subtype of the breast cancer cell line.
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Affiliation(s)
| | - Isotta Cainero
- Nanoscopy and NIC @ IIT, Istituto Italiano di Tecnologia, Via Enrico Melen, 83, 16152, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, Italy
| | - Michele Oneto
- Nanoscopy and NIC @ IIT, Istituto Italiano di Tecnologia, Via Enrico Melen, 83, 16152, Genoa, Italy
| | - Elisa Ferrando-May
- Department of Biology, University of Konstanz, Konstanz, Germany
- German Cancer Research Center, Heidelberg, Germany
| | - Luca Lanzanò
- Nanoscopy and NIC @ IIT, Istituto Italiano di Tecnologia, Via Enrico Melen, 83, 16152, Genoa, Italy
- Department of Physics and Astronomy, University of Catania, Catania, Italy
| | - Alberto Diaspro
- Nanoscopy and NIC @ IIT, Istituto Italiano di Tecnologia, Via Enrico Melen, 83, 16152, Genoa, Italy.
- DIFILAB, Department of Physics, University of Genoa, Genoa, Italy.
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18
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Jia X, Lin W, Wang W. Regulation of chromatin organization during animal regeneration. CELL REGENERATION (LONDON, ENGLAND) 2023; 12:19. [PMID: 37259007 DOI: 10.1186/s13619-023-00162-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 03/21/2023] [Indexed: 06/02/2023]
Abstract
Activation of regeneration upon tissue damages requires the activation of many developmental genes responsible for cell proliferation, migration, differentiation, and tissue patterning. Ample evidence revealed that the regulation of chromatin organization functions as a crucial mechanism for establishing and maintaining cellular identity through precise control of gene transcription. The alteration of chromatin organization can lead to changes in chromatin accessibility and/or enhancer-promoter interactions. Like embryogenesis, each stage of tissue regeneration is accompanied by dynamic changes of chromatin organization in regeneration-responsive cells. In the past decade, many studies have been conducted to investigate the contribution of chromatin organization during regeneration in various tissues, organs, and organisms. A collection of chromatin regulators were demonstrated to play critical roles in regeneration. In this review, we will summarize the progress in the understanding of chromatin organization during regeneration in different research organisms and discuss potential common mechanisms responsible for the activation of regeneration response program.
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Affiliation(s)
- Xiaohui Jia
- National Institute of Biological Sciences, Beijing, 102206, China
- China Agricultural University, Beijing, 100083, China
| | - Weifeng Lin
- National Institute of Biological Sciences, Beijing, 102206, China
- Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, 100084, China
| | - Wei Wang
- National Institute of Biological Sciences, Beijing, 102206, China.
- Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, 100084, China.
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19
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Kong C, Zhao G, Gao L, Kong X, Wang D, Liu X, Jia J. Epigenetic Landscape Is Largely Shaped by Diversiform Transposons in Aegilops tauschii. Int J Mol Sci 2023; 24:9349. [PMID: 37298301 PMCID: PMC10253722 DOI: 10.3390/ijms24119349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/21/2023] [Accepted: 05/23/2023] [Indexed: 06/12/2023] Open
Abstract
Transposons (TEs) account for more than 80% of the wheat genome, the highest among all known crop species. They play an important role in shaping the elaborate genomic landscape, which is the key to the speciation of wheat. In this study, we analyzed the association between TEs, chromatin states, and chromatin accessibility in Aegilops tauschii, the D genome donor of bread wheat. We found that TEs contributed to the complex but orderly epigenetic landscape as chromatin states showed diverse distributions on TEs of different orders or superfamilies. TEs also contributed to the chromatin state and openness of potential regulatory elements, affecting the expression of TE-related genes. Some TE superfamilies, such as hAT-Ac, carry active/open chromatin regions. In addition, the histone mark H3K9ac was found to be associated with the accessibility shaped by TEs. These results suggest the role of diversiform TEs in shaping the epigenetic landscape and in gene expression regulation in Aegilops tauschii. This has positive implications for understanding the transposon roles in Aegilops tauschii or the wheat D genome.
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Affiliation(s)
- Chuizheng Kong
- National Key Facility for Crop Gene Resources and Genetic Improvement, Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (C.K.); (G.Z.); (L.G.); (X.K.)
| | - Guangyao Zhao
- National Key Facility for Crop Gene Resources and Genetic Improvement, Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (C.K.); (G.Z.); (L.G.); (X.K.)
| | - Lifeng Gao
- National Key Facility for Crop Gene Resources and Genetic Improvement, Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (C.K.); (G.Z.); (L.G.); (X.K.)
| | - Xiuying Kong
- National Key Facility for Crop Gene Resources and Genetic Improvement, Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (C.K.); (G.Z.); (L.G.); (X.K.)
| | - Daowen Wang
- State Key Laboratory of Wheat and Maize Crop Science, College of Agronomy, Henan Agricultural University, Zhengzhou 450002, China;
| | - Xu Liu
- National Key Facility for Crop Gene Resources and Genetic Improvement, Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (C.K.); (G.Z.); (L.G.); (X.K.)
| | - Jizeng Jia
- National Key Facility for Crop Gene Resources and Genetic Improvement, Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (C.K.); (G.Z.); (L.G.); (X.K.)
- State Key Laboratory of Wheat and Maize Crop Science, College of Agronomy, Henan Agricultural University, Zhengzhou 450002, China;
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20
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Prinz R. Nothing in evolution makes sense except in the light of code biology. Biosystems 2023; 229:104907. [PMID: 37207840 DOI: 10.1016/j.biosystems.2023.104907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 04/29/2023] [Accepted: 05/02/2023] [Indexed: 05/21/2023]
Abstract
This article highlights the potential contribution of biological codes to the course and dynamics of evolution. The concept of organic codes, developed by Marcello Barbieri, has fundamentally changed our view of how living systems function. The notion that molecular interactions built on adaptors that arbitrarily link molecules from different "worlds" in a conventional, i.e., rule-based way, departs significantly from the law-based constraints imposed on livening things by physical and chemical mechanisms. In other words, living and non-living things behave like rules and laws, respectively, but this important distinction is rarely considered in current evolutionary theory. The many known codes allow quantification of codes that relate to a cell, or comparisons between different biological systems and may pave the way to a quantitative and empirical research agenda in code biology. A starting point for such an endeavour is the introduction of a simple dichotomous classification of structural and regulatory codes. This classification can be used as a tool to analyse and quantify key organising principles of the living world, such as modularity, hierarchy, and robustness, based on organic codes. The implications for evolutionary research are related to the unique dynamics of codes, or ´Eigendynamics´ (self-momentum) and how they determine the behaviour of biological systems from within, whereas physical constraints are imposed mainly from without. A speculation on the drivers of macroevolution in light of codes is followed by the conclusion that a meaningful and comprehensive understanding of evolution depends including codes into the equation of life.
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21
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Cuevas-Diaz Duran R, Li Y, Garza Carbajal A, You Y, Dessauer CW, Wu J, Walters ET. Major Differences in Transcriptional Alterations in Dorsal Root Ganglia Between Spinal Cord Injury and Peripheral Neuropathic Pain Models. J Neurotrauma 2023; 40:883-900. [PMID: 36178348 PMCID: PMC10150729 DOI: 10.1089/neu.2022.0238] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Chronic, often intractable, pain is caused by neuropathic conditions such as traumatic peripheral nerve injury (PNI) and spinal cord injury (SCI). These conditions are associated with alterations in gene and protein expression correlated with functional changes in somatosensory neurons having cell bodies in dorsal root ganglia (DRGs). Most studies of DRG transcriptional alterations have utilized PNI models where axotomy-induced changes important for neural regeneration may overshadow changes that drive neuropathic pain. Both PNI and SCI produce DRG neuron hyperexcitability linked to pain, but contusive SCI produces little peripheral axotomy or peripheral nerve inflammation. Thus, comparison of transcriptional signatures of DRGs across PNI and SCI models may highlight pain-associated transcriptional alterations in sensory ganglia that do not depend on peripheral axotomy or associated effects such as peripheral Wallerian degeneration. Data from our rat thoracic SCI experiments were combined with meta-analysis of published whole-DRG RNA-seq datasets from prominent rat PNI models. Striking differences were found between transcriptional responses to PNI and SCI, especially in regeneration-associated genes (RAGs) and long noncoding RNAs (lncRNAs). Many transcriptomic changes after SCI also were found after corresponding sham surgery, indicating they were caused by injury to surrounding tissue, including bone and muscle, rather than to the spinal cord itself. Another unexpected finding was of few transcriptomic similarities between rat neuropathic pain models and the only reported transcriptional analysis of human DRGs linked to neuropathic pain. These findings show that DRGs exhibit complex transcriptional responses to central and peripheral neural injury and associated tissue damage. Although only a few genes in DRG cells exhibited similar changes in expression across all the painful conditions examined here, these genes may represent a core set whose transcription in various DRG cell types is sensitive to significant bodily injury, and which may play a fundamental role in promoting neuropathic pain.
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Affiliation(s)
- Raquel Cuevas-Diaz Duran
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Leon, Mexico
| | - Yong Li
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Anibal Garza Carbajal
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Yanan You
- Department of Neurosurgery, The University of Texas Health Science Center at Houston, Houston, Texas, USA
- Center for Stem Cell and Regenerative Medicine, UT Brown Foundation Institute of Molecular Medicine, Houston, Texas, USA
| | - Carmen W. Dessauer
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Jiaqian Wu
- Department of Neurosurgery, The University of Texas Health Science Center at Houston, Houston, Texas, USA
- Center for Stem Cell and Regenerative Medicine, UT Brown Foundation Institute of Molecular Medicine, Houston, Texas, USA
| | - Edgar T. Walters
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas, USA
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22
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Ren N, Dai S, Ma S, Yang F. Strategies for activity analysis of single nucleotide polymorphisms associated with human diseases. Clin Genet 2023; 103:392-400. [PMID: 36527336 DOI: 10.1111/cge.14282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/10/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022]
Abstract
Genome-wide association studies (GWAS) have identified a large number of single nucleotide polymorphism (SNP) sites associated with human diseases. In the annotation of human diseases, especially cancers, SNPs, as an important component of genetic factors, have gained increasing attention. Given that most of the SNPs are located in non-coding regions, the functional verification of these SNPs is a great challenge. The key to functional annotation for risk SNPs is to screen SNPs with regulatory activity from thousands of disease associated-SNPs. In this review, we systematically recapitulate the characteristics and functional roles of SNP sites, discuss three parallel reporter screening strategies in detail based on barcode tag classification, and recommend the common in silico strategies to help supplement the annotation of SNP sites with epigenetic activity analysis, prediction of target genes and trans-acting factors. We hope that this review will contribute to this exuberant research field by providing robust activity analysis strategies that can facilitate the translation of GWAS results into personalized diagnosis and prevention measures for human diseases.
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Affiliation(s)
- Naixia Ren
- School of Life Sciences and Medicine, Shandong University of Technology, Zibo, China
| | - Shangkun Dai
- School of Life Sciences and Medicine, Shandong University of Technology, Zibo, China
| | - Shumin Ma
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
| | - Fengtang Yang
- School of Life Sciences and Medicine, Shandong University of Technology, Zibo, China
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23
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Use of ubiquitous chromatin opening elements (UCOE) as tools to maintain transgene expression in biotechnology. Comput Struct Biotechnol J 2022; 21:275-283. [PMID: 36582439 PMCID: PMC9764128 DOI: 10.1016/j.csbj.2022.11.059] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/28/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022] Open
Abstract
Amongst the most important outputs of the biopharmaceutical industry are recombinant proteins, many of which are produced by integrating transgenes into the genomes of mammalian cells. However, expression is highly variable and can be unstable during prolonged culture. This is often due to epigenetic mechanisms silencing the transgenes. To combat this problem, vectors have been engineered to include ubiquitous chromatin opening elements (UCOEs) that protect against silencing. Here, we recount the evidence that UCOEs can modify chromatin environments and benefit biomanufacturing.
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24
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Ketone Bodies as Metabolites and Signalling Molecules at the Crossroad between Inflammation and Epigenetic Control of Cardiometabolic Disorders. Int J Mol Sci 2022; 23:ijms232314564. [PMID: 36498891 PMCID: PMC9740056 DOI: 10.3390/ijms232314564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/17/2022] [Accepted: 11/20/2022] [Indexed: 11/24/2022] Open
Abstract
For many years, it has been clear that a Western diet rich in saturated fats and sugars promotes an inflammatory environment predisposing a person to chronic cardiometabolic diseases. In parallel, the emergence of ketogenic diets, deprived of carbohydrates and promoting the synthesis of ketone bodies imitating the metabolic effects of fasting, has been shown to provide a possible nutritional solution to alleviating diseases triggered by an inflammatory environment. The main ketone body, β-hydroxybutyrate (BHB), acts as an alternative fuel, and also as a substrate for a novel histone post-translational modification, β-hydroxybutyrylation. β-hydroxybutyrylation influences the state of chromatin architecture and promotes the transcription of multiple genes. BHB has also been shown to modulate inflammation in chronic diseases. In this review, we discuss, in the pathological context of cardiovascular risks, the current understanding of how ketone bodies, or a ketogenic diet, are able to modulate, trigger, or inhibit inflammation and how the epigenome and chromatin remodeling may be a key contributor.
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25
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Fouque KJD, Miller SA, Pham K, Bhanu NV, Cintron-Diaz YL, Leyva D, Kaplan D, Voinov VG, Ridgeway ME, Park MA, Garcia BA, Fernandez-Lima F. Top-"Double-Down" Mass Spectrometry of Histone H4 Proteoforms: Tandem Ultraviolet-Photon and Mobility/Mass-Selected Electron Capture Dissociations. Anal Chem 2022; 94:15377-15385. [PMID: 36282112 PMCID: PMC11037235 DOI: 10.1021/acs.analchem.2c03147] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Post-translational modifications (PTMs) on intact histones play a major role in regulating chromatin dynamics and influence biological processes such as DNA transcription, replication, and repair. The nature and position of each histone PTM is crucial to decipher how this information is translated into biological response. In the present work, the potential of a novel tandem top-"double-down" approach─ultraviolet photodissociation followed by mobility and mass-selected electron capture dissociation and mass spectrometry (UVPD-TIMS-q-ECD-ToF MS/MS)─is illustrated for the characterization of HeLa derived intact histone H4 proteoforms. The comparison between q-ECD-ToF MS/MS spectra and traditional Fourier-transform-ion cyclotron resonance-ECD MS/MS spectra of a H4 standard showed a similar sequence coverage (∼75%) with significant faster data acquisition in the ToF MS/MS platform (∼3 vs ∼15 min). Multiple mass shifts (e.g., 14 and 42 Da) were observed for the HeLa derived H4 proteoforms for which the top-down UVPD and ECD fragmentation analysis were consistent in detecting the presence of acetylated PTMs at the N-terminus and Lys5, Lys8, Lys12, and Lys16 residues, as well as methylated, dimethylated, and trimethylated PTMs at the Lys20 residue with a high sequence coverage (∼90%). The presented top-down results are in good agreement with bottom-up TIMS ToF MS/MS experiments and allowed for additional description of PTMs at the N-terminus. The integration of a 213 nm UV laser in the present platform allowed for UVPD events prior to the ion mobility-mass precursor separation for collision-induced dissociation (CID)/ECD-ToF MS. Selected c305+ UVPD fragments, from different H4 proteoforms (e.g., Ac + Me2, 2Ac + Me2 and 3Ac + Me2), exhibited multiple IMS bands for which similar CID/ECD fragmentation patterns per IMS band pointed toward the presence of conformers, adopting the same PTM distribution, with a clear assignment of the PTM localization for each of the c305+ UVPD fragment H4 proteoforms. These results were consistent with the biological "zip" model, where acetylation proceeds in the Lys16 to Lys5 direction. This novel platform further enhances the structural toolbox with alternative fragmentation mechanisms (UVPD, CID, and ECD) in tandem with fast, high-resolution mobility separations and shows great promise for global proteoform analysis.
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Affiliation(s)
- Kevin Jeanne Dit Fouque
- Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, United States
| | - Samuel A. Miller
- Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, United States
| | - Khoa Pham
- Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, United States
| | - Natarajan V. Bhanu
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States
| | - Yarixa L. Cintron-Diaz
- Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, United States
| | - Dennys Leyva
- Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, United States
| | | | | | | | - Melvin A. Park
- Bruker Daltonics Inc., Billerica, MA 01821, United States
| | - Benjamin A. Garcia
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States
| | - Francisco Fernandez-Lima
- Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, United States
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26
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Talon I, Janiszewski A, Theeuwes B, Lefevre T, Song J, Bervoets G, Vanheer L, De Geest N, Poovathingal S, Allsop R, Marine JC, Rambow F, Voet T, Pasque V. Enhanced chromatin accessibility contributes to X chromosome dosage compensation in mammals. Genome Biol 2021; 22:302. [PMID: 34724962 PMCID: PMC8558763 DOI: 10.1186/s13059-021-02518-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 10/13/2021] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Precise gene dosage of the X chromosomes is critical for normal development and cellular function. In mice, XX female somatic cells show transcriptional X chromosome upregulation of their single active X chromosome, while the other X chromosome is inactive. Moreover, the inactive X chromosome is reactivated during development in the inner cell mass and in germ cells through X chromosome reactivation, which can be studied in vitro by reprogramming of somatic cells to pluripotency. How chromatin processes and gene regulatory networks evolved to regulate X chromosome dosage in the somatic state and during X chromosome reactivation remains unclear. RESULTS Using genome-wide approaches, allele-specific ATAC-seq and single-cell RNA-seq, in female embryonic fibroblasts and during reprogramming to pluripotency, we show that chromatin accessibility on the upregulated mammalian active X chromosome is increased compared to autosomes. We further show that increased accessibility on the active X chromosome is erased by reprogramming, accompanied by erasure of transcriptional X chromosome upregulation and the loss of increased transcriptional burst frequency. In addition, we characterize gene regulatory networks during reprogramming and X chromosome reactivation, revealing changes in regulatory states. Our data show that ZFP42/REX1, a pluripotency-associated gene that evolved specifically in placental mammals, targets multiple X-linked genes, suggesting an evolutionary link between ZFP42/REX1, X chromosome reactivation, and pluripotency. CONCLUSIONS Our data reveal the existence of intrinsic compensatory mechanisms that involve modulation of chromatin accessibility to counteract X-to-Autosome gene dosage imbalances caused by evolutionary or in vitro X chromosome loss and X chromosome inactivation in mammalian cells.
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Affiliation(s)
- Irene Talon
- Department of Development and Regeneration, Laboratory of Cellular Reprogramming and Epigenetic Regulation, KU Leuven – University of Leuven, Herestraat 49, 3000 Leuven, Belgium
- KU Leuven Institute for Single Cell Omics (LISCO), 3000 Leuven, Belgium
- Leuven Stem Cell Institute (SCIL), 3000 Leuven, Belgium
| | - Adrian Janiszewski
- Department of Development and Regeneration, Laboratory of Cellular Reprogramming and Epigenetic Regulation, KU Leuven – University of Leuven, Herestraat 49, 3000 Leuven, Belgium
- KU Leuven Institute for Single Cell Omics (LISCO), 3000 Leuven, Belgium
- Leuven Stem Cell Institute (SCIL), 3000 Leuven, Belgium
| | - Bart Theeuwes
- Department of Development and Regeneration, Laboratory of Cellular Reprogramming and Epigenetic Regulation, KU Leuven – University of Leuven, Herestraat 49, 3000 Leuven, Belgium
- Leuven Stem Cell Institute (SCIL), 3000 Leuven, Belgium
| | - Thomas Lefevre
- Laboratory of Reproductive Genomics, Centre for Human Genetics, KU Leuven, 3000 Leuven, Belgium
| | - Juan Song
- Department of Development and Regeneration, Laboratory of Cellular Reprogramming and Epigenetic Regulation, KU Leuven – University of Leuven, Herestraat 49, 3000 Leuven, Belgium
- Leuven Stem Cell Institute (SCIL), 3000 Leuven, Belgium
| | - Greet Bervoets
- Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, VIB, 3000 Leuven, Belgium
- Department of Oncology, Laboratory for Molecular Cancer Biology, KU Leuven, 3000 Leuven, Belgium
| | - Lotte Vanheer
- Department of Development and Regeneration, Laboratory of Cellular Reprogramming and Epigenetic Regulation, KU Leuven – University of Leuven, Herestraat 49, 3000 Leuven, Belgium
- KU Leuven Institute for Single Cell Omics (LISCO), 3000 Leuven, Belgium
- Leuven Stem Cell Institute (SCIL), 3000 Leuven, Belgium
| | - Natalie De Geest
- Department of Development and Regeneration, Laboratory of Cellular Reprogramming and Epigenetic Regulation, KU Leuven – University of Leuven, Herestraat 49, 3000 Leuven, Belgium
- Leuven Stem Cell Institute (SCIL), 3000 Leuven, Belgium
| | - Suresh Poovathingal
- KU Leuven Institute for Single Cell Omics (LISCO), 3000 Leuven, Belgium
- VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium
| | - Ryan Allsop
- Department of Development and Regeneration, Laboratory of Cellular Reprogramming and Epigenetic Regulation, KU Leuven – University of Leuven, Herestraat 49, 3000 Leuven, Belgium
- KU Leuven Institute for Single Cell Omics (LISCO), 3000 Leuven, Belgium
- Leuven Stem Cell Institute (SCIL), 3000 Leuven, Belgium
| | - Jean-Christophe Marine
- KU Leuven Institute for Single Cell Omics (LISCO), 3000 Leuven, Belgium
- Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, VIB, 3000 Leuven, Belgium
- Department of Oncology, Laboratory for Molecular Cancer Biology, KU Leuven, 3000 Leuven, Belgium
| | - Florian Rambow
- KU Leuven Institute for Single Cell Omics (LISCO), 3000 Leuven, Belgium
- Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, VIB, 3000 Leuven, Belgium
| | - Thierry Voet
- KU Leuven Institute for Single Cell Omics (LISCO), 3000 Leuven, Belgium
- Laboratory of Reproductive Genomics, Centre for Human Genetics, KU Leuven, 3000 Leuven, Belgium
| | - Vincent Pasque
- Department of Development and Regeneration, Laboratory of Cellular Reprogramming and Epigenetic Regulation, KU Leuven – University of Leuven, Herestraat 49, 3000 Leuven, Belgium
- KU Leuven Institute for Single Cell Omics (LISCO), 3000 Leuven, Belgium
- Leuven Stem Cell Institute (SCIL), 3000 Leuven, Belgium
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27
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Zhao C, Zhang Y, Zheng H. The Effects of Interferons on Allogeneic T Cell Response in GVHD: The Multifaced Biology and Epigenetic Regulations. Front Immunol 2021; 12:717540. [PMID: 34305954 PMCID: PMC8297501 DOI: 10.3389/fimmu.2021.717540] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 06/25/2021] [Indexed: 12/19/2022] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. This beneficial effect is derived mainly from graft-versus-leukemia (GVL) effects mediated by alloreactive T cells. However, these alloreactive T cells can also induce graft-versus-host disease (GVHD), a life-threatening complication after allo-HSCT. Significant progress has been made in the dissociation of GVL effects from GVHD by modulating alloreactive T cell immunity. However, many factors may influence alloreactive T cell responses in the host undergoing allo-HSCT, including the interaction of alloreactive T cells with both donor and recipient hematopoietic cells and host non-hematopoietic tissues, cytokines, chemokines and inflammatory mediators. Interferons (IFNs), including type I IFNs and IFN-γ, primarily produced by monocytes, dendritic cells and T cells, play essential roles in regulating alloreactive T cell differentiation and function. Many studies have shown pleiotropic effects of IFNs on allogeneic T cell responses during GVH reaction. Epigenetic mechanisms, such as DNA methylation and histone modifications, are important to regulate IFNs’ production and function during GVHD. In this review, we discuss recent findings from preclinical models and clinical studies that characterize T cell responses regulated by IFNs and epigenetic mechanisms, and further discuss pharmacological approaches that modulate epigenetic effects in the setting of allo-HSCT.
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Affiliation(s)
- Chenchen Zhao
- Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA, United States
| | - Yi Zhang
- Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, United States
| | - Hong Zheng
- Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA, United States
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28
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Heng J, Heng HH. Karyotype coding: The creation and maintenance of system information for complexity and biodiversity. Biosystems 2021; 208:104476. [PMID: 34237348 DOI: 10.1016/j.biosystems.2021.104476] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/02/2021] [Accepted: 07/03/2021] [Indexed: 12/22/2022]
Abstract
The mechanism of biological information flow is of vital importance. However, traditional research surrounding the genetic code that follows the central dogma to a phenotype faces challengers, including missing heritability and two-phased evolution. Here, we propose the karyotype code, which by organizing genes along chromosomes at once preserves species genome information and provides a platform for other genetic and nongenetic information to develop and accumulate. This specific genome-level code, which exists in all living systems, is compared to the genetic code and other organic codes in the context of information management, leading to the concept of hierarchical biological codes and an 'extended' definition of adaptor where the adaptors of a code can be not only molecular structures but also, more commonly, biological processes. Notably, different levels of a biosystem have their own mechanisms of information management, and gene-coded parts inheritance preserves "parts information" while karyotype-coded system inheritance preserves the "system information" which organizes parts information. The karyotype code prompts many questions regarding the flow of biological information, including the distinction between information creation, maintenance, modification, and usage, along with differences between living and non-living systems. How do biological systems exist, reproduce, and self-evolve for increased complexity and diversity? Inheritance is mediated by organic codes which function as informational tools to organize chemical reactions, create new information, and preserve frozen accidents, transforming historical miracles into biological routines.
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Affiliation(s)
- Julie Heng
- Harvard College, 86 Brattle Street Cambridge, MA, 02138, USA
| | - Henry H Heng
- Molecular Medicine and Genomics, Wayne State University School of Medicine, Detroit, MI, 48201, USA; Department of Pathology, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
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29
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Jeanne Dit Fouque K, Kaplan D, Voinov VG, Holck FHV, Jensen ON, Fernandez-Lima F. Proteoform Differentiation using Tandem Trapped Ion Mobility, Electron Capture Dissociation, and ToF Mass Spectrometry. Anal Chem 2021; 93:9575-9582. [PMID: 34170114 DOI: 10.1021/acs.analchem.1c01735] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Comprehensive characterization of post-translationally modified histone proteoforms is challenging due to their high isobaric and isomeric content. Trapped ion mobility spectrometry (TIMS), implemented on a quadrupole/time-of-flight (Q-ToF) mass spectrometer, has shown great promise in discriminating isomeric complete histone tails. The absence of electron activated dissociation (ExD) in the current platform prevents the comprehensive characterization of unknown histone proteoforms. In the present work, we report for the first time the use of an electromagnetostatic (EMS) cell devised for nonergodic dissociation based on electron capture dissociation (ECD), implemented within a nESI-TIMS-Q-ToF mass spectrometer for the characterization of acetylated (AcK18 and AcK27) and trimethylated (TriMetK4, TriMetK9 and TriMetK27) complete histone tails. The integration of the EMS cell in a TIMS-q-TOF MS permitted fast mobility-selected top-down ECD fragmentation with near 10% efficiency overall. The potential of this coupling was illustrated using isobaric (AcK18/TriMetK4) and isomeric (AcK18/AcK27 and TriMetK4/TriMetK9) binary H3 histone tail mixtures, and the H3.1 TriMetK27 histone tail structural diversity (e.g., three IMS bands at z = 7+). The binary isobaric and isomeric mixtures can be separated in the mobility domain with RIMS > 100 and the nonergodic ECD fragmentation permitted the PTM localization (sequence coverage of ∼86%). Differences in the ECD patterns per mobility band of the z = 7+ H3 TriMetK27 molecular ions suggested that the charge location is responsible for the structural differences observed in the mobility domain. This coupling further enhances the structural toolbox with fast, high resolution mobility separations in tandem with nonergodic fragmentation for effective proteoform differentiation.
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Affiliation(s)
- Kevin Jeanne Dit Fouque
- Department of Chemistry and Biochemistry, Florida International University, Miami, Florida 33199, United States.,Biomolecular Sciences Institute, Florida International University, Miami, Florida 33199, United States
| | - Desmond Kaplan
- KapScience, LLC., Tewksbury, Massachusetts 01876, United States
| | - Valery G Voinov
- e-MSion, Inc., Corvallis, Oregon 97330, United States.,Linus Pauling Institute and Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon 97331, United States
| | - Frederik H V Holck
- Department of Biochemistry & Molecular Biology and VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, DK-5230 Odense M, Denmark
| | - Ole N Jensen
- Department of Biochemistry & Molecular Biology and VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, DK-5230 Odense M, Denmark
| | - Francisco Fernandez-Lima
- Department of Chemistry and Biochemistry, Florida International University, Miami, Florida 33199, United States.,Biomolecular Sciences Institute, Florida International University, Miami, Florida 33199, United States
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30
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Waghmare SG, Samarin AM, Samarin AM, Danielsen M, Møller HS, Policar T, Linhart O, Dalsgaard TK. Histone Acetylation Dynamics during In Vivo and In Vitro Oocyte Aging in Common Carp Cyprinus carpio. Int J Mol Sci 2021; 22:ijms22116036. [PMID: 34204879 PMCID: PMC8199789 DOI: 10.3390/ijms22116036] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 05/26/2021] [Accepted: 05/29/2021] [Indexed: 11/28/2022] Open
Abstract
Aging is the most critical factor that influences the quality of post-ovulatory oocytes. Age-related molecular pathways remain poorly understood in fish oocytes. In this study, we examined the effect of oocyte aging on specific histone acetylation in common carp Cyprinus carpio. The capacity to progress to the larval stage in oocytes that were aged for 28 h in vivo and in vitro was evaluated. Global histone modifications and specific histone acetylation (H3K9ac, H3K14ac, H4K5ac, H4K8ac, H4K12ac, and H4K16ac) were investigated during oocyte aging. Furthermore, the activity of histone acetyltransferase (HAT) was assessed in fresh and aged oocytes. Global histone modifications did not exhibit significant alterations during 8 h of oocyte aging. Among the selected modifications, H4K12ac increased significantly at 28 h post-stripping (HPS). Although not significantly different, HAT activity exhibited an upward trend during oocyte aging. Results of our current study indicate that aging of common carp oocytes for 12 h results in complete loss of egg viability rates without any consequence in global and specific histone modifications. However, aging oocytes for 28 h led to increased H4K12ac. Thus, histone acetylation modification as a crucial epigenetic mediator may be associated with age-related defects, particularly in oocytes of a more advanced age.
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Affiliation(s)
- Swapnil Gorakh Waghmare
- South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Research Institute of Fish Culture and Hydrobiology, Faculty of Fisheries and Protection of Waters, University of South Bohemia in Ceske Budejovice, 389 25 Vodňany, Czech Republic; (A.M.S.); a (A.M.S.); (T.P.); (O.L.)
- Correspondence:
| | - Azin Mohagheghi Samarin
- South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Research Institute of Fish Culture and Hydrobiology, Faculty of Fisheries and Protection of Waters, University of South Bohemia in Ceske Budejovice, 389 25 Vodňany, Czech Republic; (A.M.S.); a (A.M.S.); (T.P.); (O.L.)
| | - Azadeh Mohagheghi Samarin
- South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Research Institute of Fish Culture and Hydrobiology, Faculty of Fisheries and Protection of Waters, University of South Bohemia in Ceske Budejovice, 389 25 Vodňany, Czech Republic; (A.M.S.); a (A.M.S.); (T.P.); (O.L.)
| | - Marianne Danielsen
- Department of Food Science, Aarhus University, Agro Food Park 48, 8200 Aarhus, Denmark; (M.D.); (H.S.M.); (T.K.D.)
- Center of Innovative Food Research, Aarhus University Centre for Innovative Food Research, 8000 Aarhus, Denmark
- CBIO, Aarhus University Centre for Circular Bioeconomy, 8000 Aarhus, Denmark
| | - Hanne Søndergård Møller
- Department of Food Science, Aarhus University, Agro Food Park 48, 8200 Aarhus, Denmark; (M.D.); (H.S.M.); (T.K.D.)
| | - Tomáš Policar
- South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Research Institute of Fish Culture and Hydrobiology, Faculty of Fisheries and Protection of Waters, University of South Bohemia in Ceske Budejovice, 389 25 Vodňany, Czech Republic; (A.M.S.); a (A.M.S.); (T.P.); (O.L.)
| | - Otomar Linhart
- South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Research Institute of Fish Culture and Hydrobiology, Faculty of Fisheries and Protection of Waters, University of South Bohemia in Ceske Budejovice, 389 25 Vodňany, Czech Republic; (A.M.S.); a (A.M.S.); (T.P.); (O.L.)
| | - Trine Kastrup Dalsgaard
- Department of Food Science, Aarhus University, Agro Food Park 48, 8200 Aarhus, Denmark; (M.D.); (H.S.M.); (T.K.D.)
- Center of Innovative Food Research, Aarhus University Centre for Innovative Food Research, 8000 Aarhus, Denmark
- CBIO, Aarhus University Centre for Circular Bioeconomy, 8000 Aarhus, Denmark
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31
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Prosdocimi F, de Farias ST. Life and living beings under the perspective of organic macrocodes. Biosystems 2021; 206:104445. [PMID: 34033908 DOI: 10.1016/j.biosystems.2021.104445] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/17/2021] [Accepted: 05/18/2021] [Indexed: 11/16/2022]
Abstract
A powerful and concise concept of life is crucial for studies aiming to understand the characteristics that emerged from an inorganic world. Among biologists, the most accepted argument define life under a top-down strategy by looking into the shared characteristics observed in all cellular organisms. This is often made highlighting (i) autonomy and (ii) evolutionary capacity as fundamental characteristics observed in all cellular organisms. Along the present work, we assume the framework of code biology considering that biology started with the emergence of the first organic code by self-organization. We reinforces that the conceptual structure of life should be reallocated from the ontology class of Matter to its sister class of Process. Along the emergence and early evolution of biological systems, biological codes changed from open systems of "naked" molecules (at the progenote era), to close, encapsulated systems (at the organismic era). Living beings appeared at the very moment when nucleic acids with coding properties became encapsulated. This led to the origin of viruses and, then, to the origin of cells. In this context, we propose that the single character that makes a clear distinction between the abiotic and the biotic world is the capacity to process organic codes. Thus, life appears with the self-assembly of a genetic code and evolves by the emergence of other overlapping codes. Once life has been clearly conceptualized, we go further to conceptualize organisms, parents, lineages, and species in terms of code biology.
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Affiliation(s)
- Francisco Prosdocimi
- Laboratório de Biologia Teórica e de Sistemas, Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Sávio Torres de Farias
- Laboratório de Genética Evolutiva Paulo Leminski, Centro de Ciências Exatas e da Natureza, Universidade Federal da Paraíba, João Pessoa, Paraíba, Brazil; Network of Researchers on the Chemical Evolution of Life (NoRCEL), Leeds, LS7 3RB, UK.
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Coates JTT, Pirovano G, El Naqa I. Radiomic and radiogenomic modeling for radiotherapy: strategies, pitfalls, and challenges. J Med Imaging (Bellingham) 2021; 8:031902. [PMID: 33768134 PMCID: PMC7985651 DOI: 10.1117/1.jmi.8.3.031902] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 01/12/2021] [Indexed: 12/14/2022] Open
Abstract
The power of predictive modeling for radiotherapy outcomes has historically been limited by an inability to adequately capture patient-specific variabilities; however, next-generation platforms together with imaging technologies and powerful bioinformatic tools have facilitated strategies and provided optimism. Integrating clinical, biological, imaging, and treatment-specific data for more accurate prediction of tumor control probabilities or risk of radiation-induced side effects are high-dimensional problems whose solutions could have widespread benefits to a diverse patient population-we discuss technical approaches toward this objective. Increasing interest in the above is specifically reflected by the emergence of two nascent fields, which are distinct but complementary: radiogenomics, which broadly seeks to integrate biological risk factors together with treatment and diagnostic information to generate individualized patient risk profiles, and radiomics, which further leverages large-scale imaging correlates and extracted features for the same purpose. We review classical analytical and data-driven approaches for outcomes prediction that serve as antecedents to both radiomic and radiogenomic strategies. Discussion then focuses on uses of conventional and deep machine learning in radiomics. We further consider promising strategies for the harmonization of high-dimensional, heterogeneous multiomics datasets (panomics) and techniques for nonparametric validation of best-fit models. Strategies to overcome common pitfalls that are unique to data-intensive radiomics are also discussed.
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Affiliation(s)
- James T. T. Coates
- Massachusetts General Hospital & Harvard Medical School, Center for Cancer Research, Boston, Massachusetts, United States
| | - Giacomo Pirovano
- Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, New York, United States
| | - Issam El Naqa
- Moffitt Cancer Center and Research Institute, Department of Machine Learning, Tampa, Florida, United States
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Piferrer F, Anastasiadi D. Do the Offspring of Sex Reversals Have Higher Sensitivity to Environmental Perturbations? Sex Dev 2021; 15:134-147. [PMID: 33910195 DOI: 10.1159/000515192] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 12/04/2020] [Indexed: 11/19/2022] Open
Abstract
Sex determination systems in vertebrates vary along a continuum from genetic (GSD) to environmental sex determination (ESD). Individuals that show a sexual phenotype opposite to their genotypic sex are called sex reversals. Aside from genetic elements, temperature, sex steroids, and exogenous chemicals are common factors triggering sex reversal, a phenomenon that may occur even in strict GSD species. In this paper, we review the literature on instances of sex reversal in fish, amphibians, reptiles, birds, and mammals. We focus on the offspring of sex-reversed parents in the instances that they can be produced, and show that in all cases studied the offspring of these sex-reversed parents exhibit a higher sensitivity to environmental perturbations than the offspring of non-sex-reversed parents. We suggest that the inheritance of this sensitivity, aside from possible genetic factors, is likely to be mediated by epigenetic mechanisms such as DNA methylation, since these mechanisms are responsive to environmental cues, and epigenetic modifications can be transmitted to the subsequent generations. Species with a chromosomal GSD system with environmental sensitivity and availability of genetic sex markers should be employed to further test whether offspring of sex-reversed parents have greater sensitivity to environmental perturbations. Future studies could also benefit from detailed whole-genome data in order to elucidate the underlying molecular mechanisms. Finally, we discuss the consequences of such higher sensitivity in the context of global climate change.
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Affiliation(s)
- Francesc Piferrer
- Institut de Ciències del Mar (ICM), Spanish National Research Council (CSIC), Barcelona, Spain
| | - Dafni Anastasiadi
- The New Zealand Institute for Plant and Food Research Limited, Nelson, New Zealand
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Guo Z, Mo Z. Regulation of endothelial cell differentiation in embryonic vascular development and its therapeutic potential in cardiovascular diseases. Life Sci 2021; 276:119406. [PMID: 33785330 DOI: 10.1016/j.lfs.2021.119406] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 03/05/2021] [Accepted: 03/14/2021] [Indexed: 12/17/2022]
Abstract
During vertebrate development, the cardiovascular system begins operating earlier than any other organ in the embryo. Endothelial cell (EC) forms the inner lining of blood vessels, and its extensive proliferation and migration are requisite for vasculogenesis and angiogenesis. Many aspects of cellular biology are involved in vasculogenesis and angiogenesis, including the tip versus stalk cell specification. Recently, epigenetics has attracted growing attention in regulating embryonic vascular development and controlling EC differentiation. Some proteins that regulate chromatin structure have been shown to be directly implicated in human cardiovascular diseases. Additionally, the roles of important EC signaling such as vascular endothelial growth factor and its receptors, angiopoietin-1 and tyrosine kinase containing immunoglobulin and epidermal growth factor homology domain-2, and transforming growth factor-β in EC differentiation during embryonic vasculature development are briefly discussed in this review. Recently, the transplantation of human induced pluripotent stem cell (iPSC)-ECs are promising approaches for the treatment of ischemic cardiovascular disease including myocardial infarction. Patient-specific iPSC-derived EC is a potential new target to study differences in gene expression or response to drugs. However, clinical application of the iPSC-ECs in regenerative medicine is often limited by the challenges of maintaining cell viability and function. Therefore, novel insights into the molecular mechanisms underlying EC differentiation might provide a better understanding of embryonic vascular development and bring out more effective EC-based therapeutic strategies for cardiovascular diseases.
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Affiliation(s)
- Zi Guo
- Department of Endocrinology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhaohui Mo
- Department of Endocrinology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
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Chenarani N, Emamjomeh A, Allahverdi A, Mirmostafa S, Afsharinia MH, Zahiri J. Bioinformatic tools for DNA methylation and histone modification: A survey. Genomics 2021; 113:1098-1113. [PMID: 33677056 DOI: 10.1016/j.ygeno.2021.03.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 10/10/2020] [Accepted: 03/02/2021] [Indexed: 01/19/2023]
Abstract
Epigenetic inheritance occurs due to different mechanisms such as chromatin and histone modifications, DNA methylation and processes mediated by non-coding RNAs. It leads to changes in gene expressions and the emergence of new traits in different organisms in many diseases such as cancer. Recent advances in experimental methods led to the identification of epigenetic target sites in various organisms. Computational approaches have enabled us to analyze mass data produced by these methods. Next-generation sequencing (NGS) methods have been broadly used to identify these target sites and their patterns. By using these patterns, the emergence of diseases could be prognosticated. In this study, target site prediction tools for two major epigenetic mechanisms comprising histone modification and DNA methylation are reviewed. Publicly accessible databases are reviewed as well. Some suggestions regarding the state-of-the-art methods and databases have been made, including examining patterns of epigenetic changes that are important in epigenotypes detection.
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Affiliation(s)
- Nasibeh Chenarani
- Department of Plant Breeding and Biotechnology (PBB), Faculty of Agriculture, University of Zabol, Zabol, Iran
| | - Abbasali Emamjomeh
- Department of Plant Breeding and Biotechnology (PBB), Faculty of Agriculture, University of Zabol, Zabol, Iran; Laboratory of Computational Biotechnology and Bioinformatics (CBB), Department of Bioinformatics, Faculty of Basic Sciences, University of Zabol, Zabol, Iran.
| | - Abdollah Allahverdi
- Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - SeyedAli Mirmostafa
- Bioinformatics and Computational Omics Lab (BioCOOL), Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohammad Hossein Afsharinia
- Bioinformatics and Computational Omics Lab (BioCOOL), Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Javad Zahiri
- Bioinformatics and Computational Omics Lab (BioCOOL), Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran; Department of Neuroscience, University of California, San Diego, USA.
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36
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Pike JW, Lee SM, Benkusky NA, Meyer MB. Genomic Mechanisms Governing Mineral Homeostasis and the Regulation and Maintenance of Vitamin D Metabolism. JBMR Plus 2021; 5:e10433. [PMID: 33553989 PMCID: PMC7839818 DOI: 10.1002/jbm4.10433] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/30/2020] [Accepted: 11/08/2020] [Indexed: 01/08/2023] Open
Abstract
Our recent genomic studies identified a complex kidney‐specific enhancer module located within the introns of adjacent Mettl1 (M1) and Mettl21b (M21) genes that mediate basal and PTH induction of Cyp27b1, as well as suppression by FGF23 and 1,25‐dihydroxyvitamin D3 [1,25(OH)2D3]. The tissue specificity for this regulatory module appears to be localized exclusively to renal proximal tubules. Gross deletion of these segments in mice has severe consequences on skeletal health, and directly affects Cyp27b1 expression in the kidney. Deletion of both the M1 and M21 submodules together almost completely eliminates basal Cyp27b1 expression in the kidney, creating a renal specific pseudo‐null mouse, resulting in a systemic and skeletal phenotype similar to that of the Cyp27b1‐KO mouse caused by high levels of both 25‐hydroxyvitamin D3 [25(OH)D3] and PTH and depletion of 1,25(OH)2D3. Cyp24a1 levels in the double KO mouse also decrease because of compensatory downregulation of the gene by elevated PTH and reduced FGF23 that is mediated by an intergenic module located downstream of the Cyp24a1 gene. Outside of the kidney in nonrenal target cells (NRTCs), expression of Cyp27b1 in these mutant mice was unaffected. Dietary normalization of calcium, phosphate, PTH, and FGF23 rescues the aberrant phenotype of this mouse and normalizes the skeleton. In addition, both the high levels of 25(OH)D3 were reduced and the low levels of 1,25(OH)2D3 were fully eliminated in these mutant mice as a result of the rescue‐induced normalization of renal Cyp24a1. Thus, these hormone‐regulated enhancers for both Cyp27b1 and Cyp24a1 in the kidney are responsible for the circulating levels of 1,25(OH)2D3 in the blood. The retention of Cyp27b1 and Cyp24a1 expression in NRTCs of these endocrine 1,25(OH)2D3‐deficient mice suggests that this Cyp27b1 pseudo‐null mouse will provide a model for the future exploration of the role of NRTC‐produced 1,25(OH)2D3 in the hormone's diverse noncalcemic actions in both health and disease. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- J Wesley Pike
- Department of Biochemistry University of Wisconsin-Madison Madison WI USA
| | - Seong Min Lee
- Department of Biochemistry University of Wisconsin-Madison Madison WI USA
| | - Nancy A Benkusky
- Department of Biochemistry University of Wisconsin-Madison Madison WI USA
| | - Mark B Meyer
- Department of Biochemistry University of Wisconsin-Madison Madison WI USA
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Minnoye L, Marinov GK, Krausgruber T, Pan L, Marand AP, Secchia S, Greenleaf WJ, Furlong EEM, Zhao K, Schmitz RJ, Bock C, Aerts S. Chromatin accessibility profiling methods. NATURE REVIEWS. METHODS PRIMERS 2021; 1:10. [PMID: 38410680 PMCID: PMC10895463 DOI: 10.1038/s43586-020-00008-9] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 12/01/2020] [Indexed: 02/06/2023]
Abstract
Chromatin accessibility, or the physical access to chromatinized DNA, is a widely studied characteristic of the eukaryotic genome. As active regulatory DNA elements are generally 'accessible', the genome-wide profiling of chromatin accessibility can be used to identify candidate regulatory genomic regions in a tissue or cell type. Multiple biochemical methods have been developed to profile chromatin accessibility, both in bulk and at the single-cell level. Depending on the method, enzymatic cleavage, transposition or DNA methyltransferases are used, followed by high-throughput sequencing, providing a view of genome-wide chromatin accessibility. In this Primer, we discuss these biochemical methods, as well as bioinformatics tools for analysing and interpreting the generated data, and insights into the key regulators underlying developmental, evolutionary and disease processes. We outline standards for data quality, reproducibility and deposition used by the genomics community. Although chromatin accessibility profiling is invaluable to study gene regulation, alone it provides only a partial view of this complex process. Orthogonal assays facilitate the interpretation of accessible regions with respect to enhancer-promoter proximity, functional transcription factor binding and regulatory function. We envision that technological improvements including single-molecule, multi-omics and spatial methods will bring further insight into the secrets of genome regulation.
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Affiliation(s)
- Liesbeth Minnoye
- Center for Brain & Disease Research, VIB-KU Leuven, Leuven, Belgium
- Department of Human Genetics, KU Leuven, Leuven, Belgium
| | | | - Thomas Krausgruber
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Lixia Pan
- Laboratory of Epigenome Biology, Systems Biology Center, Division of Intramural Research, National Heart, Lung and Blood Institute, NIH, Bethesda, MD, USA
| | | | - Stefano Secchia
- European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany
| | | | - Eileen E M Furlong
- European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany
| | - Keji Zhao
- Laboratory of Epigenome Biology, Systems Biology Center, Division of Intramural Research, National Heart, Lung and Blood Institute, NIH, Bethesda, MD, USA
| | | | - Christoph Bock
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Institute of Artificial Intelligence and Decision Support, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Stein Aerts
- Center for Brain & Disease Research, VIB-KU Leuven, Leuven, Belgium
- Department of Human Genetics, KU Leuven, Leuven, Belgium
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Leng X, Liu M, Tao D, Yang B, Zhang Y, He T, Xie S, Wang Z, Liu Y, Yang Y. Epigenetic modification-dependent androgen receptor occupancy facilitates the ectopic TSPY1 expression in prostate cancer cells. Cancer Sci 2020; 112:691-702. [PMID: 33185915 PMCID: PMC7894013 DOI: 10.1111/cas.14731] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 10/27/2020] [Accepted: 11/07/2020] [Indexed: 02/06/2023] Open
Abstract
Testis‐specific protein Y‐encoded 1 (TSPY1), a Y chromosome‐linked oncogene, is frequently activated in prostate cancers (PCa) and its expression is correlated with the poor prognosis of PCa. However, the cause of the ectopic transcription of TSPY1 in PCa remains unclear. Here, we observed that the methylation status in the CpG islands (CGI) of the TSPY1 promoter was negatively correlated with its expression level in different human samples. The acetyl‐histone H4 and trimethylated histone H3‐lysine 4, two post–translational modifications of histones occupying the TSPY1 promoter, facilitated the TSPY1 expression in PCa cells. In addition, we found that androgen accelerated the TSPY1 transcription on the condition of hypomethylated of TSPY1‐CGI and promoted PCa cell proliferation. Moreover, the binding of androgen receptor (AR) to the TSPY1 promoter, enhancing TSPY1 transcription, was detected in PCa cells. Taken together, our findings identified the regulation of DNA methylation, acting as a primary mechanism, on TSPY1 expression in PCa, and revealed that TSPY1 is an androgen‐AR axis‐regulated oncogene, suggesting a novel and potential target for PCa therapy.
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Affiliation(s)
- Xiangyou Leng
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Mohan Liu
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Dachang Tao
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Bo Yang
- Department of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Yangwei Zhang
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Tianrong He
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Shengyu Xie
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Zhaokun Wang
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Yunqiang Liu
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Yuan Yang
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
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Pal P, Hales K, Hales DB. The pro-apoptotic actions of 2-methoxyestradiol against ovarian cancer involve catalytic activation of PKCδ signaling. Oncotarget 2020; 11:3646-3659. [PMID: 33088425 PMCID: PMC7546757 DOI: 10.18632/oncotarget.27760] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 09/10/2020] [Indexed: 02/02/2023] Open
Abstract
Background: 2-methoxyestradiol (2MeOE2) is a natural metabolite of estradiol, which is generated by the action of CYP1A1 enzyme in the liver. We have previously shown that a flaxseed-supplemented diet decreases both the incidence and severity of ovarian cancer in laying hens, also induces CYP1A1 expression in liver. Recently, we have shown that as a biologically derived active component of flax diet, 2MeOE2 induces apoptosis in ovarian cancer cells which is partially dependent on p38 MAPK. The objective of this study was to elucidate the molecular mechanism of actions of 2MeOE2, a known microtubule disrupting agent, in inducing apoptosis in ovarian tumors. Results: 2MeOE2 induces γH2Ax expression and apoptotic histone modifications in ovarian cancer cells, which are predicted downstream targets of protein kinase Cδ (PKCδ) during apoptosis. Overexpressing full length PKCδ alone does not induce apoptosis but potentiates 2MeOE2-mediated apoptosis. C3-domain mutated dominant-negative PKCδ (PKCδDN) significantly reduces 2MeOE2-induced caspase-3 cleavage and apoptotic histone modification. Silencing PKCδ diminishes 2MeOE2-mediated apoptosis. The catalytic fragment of PKCδ (PKCδCAT) evokes pro-apoptotic effects which are principally dependent on p38 MAPK phosphorylation. Conclusions: The pro-apoptotic actions of 2MeOE2 are in part dependent on catalytic activation of PKCδ. Catalytic activation of PKCδ accelerates the 2MeOE2-induced apoptotic cascade. This study describes a novel molecular action of flaxseed diet in ovarian cancer.
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Affiliation(s)
- Purab Pal
- Department of Physiology, Southern Illinois University, Carbondale, IL 62901, USA
| | - Karen Hales
- Department of Obstetrics and Gynecology, Southern Illinois University School of Medicine, Springfield, IL 62702, USA
| | - Dale Buchanan Hales
- Department of Physiology, Southern Illinois University, Carbondale, IL 62901, USA.,Department of Obstetrics and Gynecology, Southern Illinois University School of Medicine, Springfield, IL 62702, USA
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40
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Ishikawa Y, Nakai K. A hypothetical trivalent epigenetic code that affects the nature of human ESCs. PLoS One 2020; 15:e0238742. [PMID: 32911515 PMCID: PMC7482980 DOI: 10.1371/journal.pone.0238742] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 08/21/2020] [Indexed: 02/07/2023] Open
Abstract
It has been suggested that DNA methylation can work in concert with other epigenetic factors, leading to changes in cellular phenotypes. For example, DNA demethylation modifications producing 5-hydroxymethylcytosine (5hmC) are thought to interact with histone modifications to influence the acquisition of embryonic stem cell (ESC) potency. However, the mechanism by which this occurs is still unknown. Thus, we systematically analysed the co-occurrence of DNA and histone modifications at genic regions as well as their relationship with ESC-specific expression using a number of heterogeneous public datasets. From a set of 19 epigenetic factors, we found remarkable co-occurrence of 5hmC and H4K8ac, accompanied by H3K4me1. This enrichment was more prominent at gene body regions. The results were confirmed using data obtained from different detection methods and species. Our analysis shows that these marks work cooperatively to influence ESC-specific gene expression. We also found that this trivalent mark is relatively enriched in genes related with immunity, which is a bit specific in ESCs. We propose that a trivalent epigenetic mark, composed of 5hmC, H4K8ac and H3K4me1, regulates gene expression and modulates the nature of human ESCs as a novel epigenetic code.
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Affiliation(s)
- Yasuhisa Ishikawa
- Department of Computational Biology and Medical Sciences, the University of Tokyo, Kashiwa-shi, Chiba, Japan
| | - Kenta Nakai
- Department of Computational Biology and Medical Sciences, the University of Tokyo, Kashiwa-shi, Chiba, Japan
- Human Genome Center, the Institute of Medical Science, the University of Tokyo, Tokyo, Japan
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Exploring DNA Methylation Diversity in the Honey Bee Brain by Ultra-Deep Amplicon Sequencing. EPIGENOMES 2020; 4:epigenomes4020010. [PMID: 34968244 PMCID: PMC8594699 DOI: 10.3390/epigenomes4020010] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 06/17/2020] [Accepted: 06/22/2020] [Indexed: 02/04/2023] Open
Abstract
Understanding methylation dynamics in organs or tissues containing many different cell types is a challenging task that cannot be efficiently addressed by the low-depth bisulphite sequencing of DNA extracted from such sources. Here we explored the feasibility of ultra-deep bisulphite sequencing of long amplicons to reveal the brain methylation patterns in three selected honey bee genes analysed across five distinct conditions on the Illumina MiSeq platform. By combing 15 libraries in one run we achieved a very high sequencing depth of 240,000–340,000 reads per amplicon, suggesting that most of the cell types in the honey bee brain, containing approximately 1 million neurons, are represented in this dataset. We found a small number of gene-specific patterns for each condition in individuals of different ages and performing distinct tasks with 80–90% of those were represented by no more than a dozen patterns. One possibility is that such a small number of frequent patterns is the result of differentially methylated epialleles, whereas the rare and less frequent patterns reflect activity-dependent modifications. The condition-specific methylation differences within each gene appear to be position-dependent with some CpGs showing significant changes and others remaining stable in a methylated or non-methylated state. Interestingly, no significant loss of methylation was detected in very old individuals. Our findings imply that these diverse patterns represent a special challenge in the analyses of DNA methylation in complex tissues and organs that cannot be investigated by low-depth genome-wide bisulphite sequencing. We conclude that ultra-deep sequencing of gene-specific amplicons combined with genotyping of differentially methylated epialleles is an effective way to facilitate more advanced neuro-epigenomic studies in honey bees and other insects.
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Calder ED, Skwarska A, Sneddon D, Folkes LK, Mistry IN, Conway SJ, Hammond EM. Hypoxia-activated pro-drugs of the KDAC inhibitor vorinostat (SAHA). Tetrahedron 2020. [DOI: 10.1016/j.tet.2020.131170] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Dompe C, Janowicz K, Hutchings G, Moncrieff L, Jankowski M, Nawrocki MJ, Józkowiak M, Mozdziak P, Petitte J, Shibli JA, Dyszkiewicz-Konwińska M, Bruska M, Piotrowska-Kempisty H, Kempisty B, Nowicki M. Epigenetic Research in Stem Cell Bioengineering-Anti-Cancer Therapy, Regenerative and Reconstructive Medicine in Human Clinical Trials. Cancers (Basel) 2020; 12:E1016. [PMID: 32326172 PMCID: PMC7226111 DOI: 10.3390/cancers12041016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 04/14/2020] [Accepted: 04/15/2020] [Indexed: 12/12/2022] Open
Abstract
The epigenome denotes all the information related to gene expression that is not contained in the DNA sequence but rather results from chemical changes to histones and DNA. Epigenetic modifications act in a cooperative way towards the regulation of gene expression, working at the transcriptional or post-transcriptional level, and play a key role in the determination of phenotypic variations in cells containing the same genotype. Epigenetic modifications are important considerations in relation to anti-cancer therapy and regenerative/reconstructive medicine. Moreover, a range of clinical trials have been performed, exploiting the potential of epigenetics in stem cell engineering towards application in disease treatments and diagnostics. Epigenetic studies will most likely be the basis of future cancer therapies, as epigenetic modifications play major roles in tumour formation, malignancy and metastasis. In fact, a large number of currently designed or tested clinical approaches, based on compounds regulating epigenetic pathways in various types of tumours, employ these mechanisms in stem cell bioengineering.
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Affiliation(s)
- Claudia Dompe
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (C.D.); (L.M.); (M.N.)
- The School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; (K.J.); (G.H.)
| | - Krzysztof Janowicz
- The School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; (K.J.); (G.H.)
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.J.); (M.J.N.); (M.D.-K.); (M.B.)
| | - Greg Hutchings
- The School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; (K.J.); (G.H.)
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.J.); (M.J.N.); (M.D.-K.); (M.B.)
| | - Lisa Moncrieff
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (C.D.); (L.M.); (M.N.)
- The School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; (K.J.); (G.H.)
| | - Maurycy Jankowski
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.J.); (M.J.N.); (M.D.-K.); (M.B.)
| | - Mariusz J. Nawrocki
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.J.); (M.J.N.); (M.D.-K.); (M.B.)
| | - Małgorzata Józkowiak
- Department of Toxicology, Poznan University of Medical Sciences, 61-631 Poznan, Poland; (M.J.); (H.P.-K.)
| | - Paul Mozdziak
- Physiology Graduate Program, North Carolina State University, Raleigh, NC 27695, USA;
| | - Jim Petitte
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA;
| | - Jamil A. Shibli
- Department of Periodontology and Oral Implantology, Dental Research Division, University of Guarulhos, São Paulo 07023-070, Brazil;
| | - Marta Dyszkiewicz-Konwińska
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.J.); (M.J.N.); (M.D.-K.); (M.B.)
- Department of Biomaterials and Experimental Dentistry, Poznan University of Medical Sciences, 61 701 Poznan, Poland
| | - Małgorzata Bruska
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.J.); (M.J.N.); (M.D.-K.); (M.B.)
| | - Hanna Piotrowska-Kempisty
- Department of Toxicology, Poznan University of Medical Sciences, 61-631 Poznan, Poland; (M.J.); (H.P.-K.)
| | - Bartosz Kempisty
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (C.D.); (L.M.); (M.N.)
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.J.); (M.J.N.); (M.D.-K.); (M.B.)
- Department of Obstetrics and Gynaecology, University Hospital and Masaryk University, 602 00 Brno, Czech Republic
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87 100 Torun, Poland
| | - Michał Nowicki
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (C.D.); (L.M.); (M.N.)
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Barbieri M. The semantic theory of language. Biosystems 2020; 190:104100. [DOI: 10.1016/j.biosystems.2020.104100] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 01/09/2020] [Accepted: 01/09/2020] [Indexed: 12/17/2022]
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Jones DP, Cohn BA. A vision for exposome epidemiology: The pregnancy exposome in relation to breast cancer in the Child Health and Development Studies. Reprod Toxicol 2020; 92:4-10. [PMID: 32197999 PMCID: PMC7306421 DOI: 10.1016/j.reprotox.2020.03.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Etiology of complex diseases, such as breast cancer, involves multiple genetic, behavioral and environmental factors. Gene sequencing enabled detection of genetic risks with relatively small effect size, and high-resolution metabolomics (HRM) to provide omics level data for exposures is poised to do the same for environmental epidemiology. Coupling HRM to the Child Health and Development Studies (CHDS) cohort combines two unique resources to create a prototype for exposome epidemiology, in which omics scale measures of exposure are used for study of distribution and determinants of health and disease. Using this approach, exposures and biologic responses during pregnancy have been linked to breast cancer in the CHDS. With improved chemical coverage and extension to larger populations and other disease processes, development of exposome epidemiology portends discovery of new disease-associated environment factors with small effect size as well as new capabilities to disentangle these from behavioral and other risk factors.
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Affiliation(s)
- Dean P Jones
- Department of Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA.
| | - Barbara A Cohn
- Child Health and Development Studies, Public Health Institute, 1683 Shattuck Avenue, Suite B, Berkeley, CA 94709, USA
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Meyer MB, Pike JW. Mechanistic homeostasis of vitamin D metabolism in the kidney through reciprocal modulation of Cyp27b1 and Cyp24a1 expression. J Steroid Biochem Mol Biol 2020; 196:105500. [PMID: 31629064 PMCID: PMC6954286 DOI: 10.1016/j.jsbmb.2019.105500] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 10/07/2019] [Accepted: 10/14/2019] [Indexed: 01/08/2023]
Abstract
Cyp27b1 and Cyp24a1 are reciprocally regulated in the kidney by the key hormones PTH, FGF23, and 1,25(OH)2D3. Our recent genomic studies in mice identified a complex kidney-specific enhancer module located within the introns of adjacent Mettl1 (M1) and Mettl21b (M21) genes that mediate basal and PTH induction of Cyp27b1 as well as suppression by FGF23 and 1,25(OH)2D3. Gross deletion of these segments in mice has severe consequences on skeletal health, and directly affects Cyp27b1 expression in the kidney. Deletion of both M1 and M21 submodules together fully eliminates basal Cyp27b1 expression in the kidney, leading to a systemic and skeletal phenotype similar to that of the Cyp27b1-KO mouse due to depletion of 1,25(OH)2D3 and high PTH. Cyp24a1 levels in the double KO mouse were low due to compensatory regulation by elevated PTH and reduced FGF23. However, expression of Cyp27b1 and retention of its regulation by inflammation (LPS) in the NRTCs remained unperturbed. Dietary normalization of calcium, phosphate, PTH, and FGF23 rescues this aberrant phenotype and normalizes the skeletal issues. Cyp24a1 is controlled by its own unique enhancers for 1,25(OH)2D3, FGF23, and PTH. We were also able to eliminate these activities in mice. Collectively, the hormone-mediated enhancer regulation of both Cyp27b1 and Cyp24a1 in the kidney is responsible for the circulating levels of 1,25(OH)2D3 in the blood which in turn primarily affects calcium and phosphate regulation. Importantly, we can now manipulate this system with our enhancer deletion animal models to study 1,25(OH)2D3 production in non-renal target cells and tissues not only in disease, where it is known to affect the immune system, but also in healthy individuals. Here we will review our studies that have defined a finely balanced homeostatic control mechanism employed by PTH and FGF23 with catastrophic toxicity protection from 1,25(OH)2D3 in the genomic regulation of vitamin D metabolism and its accompanied control of mineral maintenance.
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Affiliation(s)
- Mark B Meyer
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA.
| | - J Wesley Pike
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA
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Zaghi M, Broccoli V, Sessa A. H3K36 Methylation in Neural Development and Associated Diseases. Front Genet 2020; 10:1291. [PMID: 31998360 PMCID: PMC6962298 DOI: 10.3389/fgene.2019.01291] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 11/25/2019] [Indexed: 12/14/2022] Open
Abstract
Post-translational methylation of H3 lysine 36 (H3K36) is an important epigenetic marker that majorly contributes to the functionality of the chromatin. This mark is interpreted by the cell in several crucial biological processes including gene transcription and DNA methylation. The homeostasis of H3K36 methylation is finely regulated by different enzyme classes which, when impaired, lead to a plethora of diseases; ranging from multi-organ syndromes to cancer, to pure neurological diseases often associated with brain development. This mini-review summarizes current knowledge on these important epigenetic signals with emphasis on the molecular mechanisms that (i) regulate their abundance, (ii) are influenced by H3K36 methylation, and (iii) the associated diseases.
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Affiliation(s)
- Mattia Zaghi
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
| | - Vania Broccoli
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.,Concilio Nazionale Delle Ricerche (CNR), Instituto di Neuroscienze, Milan, Italy
| | - Alessandro Sessa
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
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Molecular Approaches for Analyzing Environmental Chaetomium Diversity and Exploitation of Chaetomium thermophilum for Biochemical Analyses. Fungal Biol 2020. [DOI: 10.1007/978-3-030-31612-9_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Gupta J, Sharma S, Sharma NR, Kabra D. Phytochemicals enriched in spices: a source of natural epigenetic therapy. Arch Pharm Res 2019; 43:171-186. [DOI: 10.1007/s12272-019-01203-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 12/06/2019] [Indexed: 02/07/2023]
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Dantas A, Al Shueili B, Yang Y, Nabbi A, Fink D, Riabowol K. Biological Functions of the ING Proteins. Cancers (Basel) 2019; 11:E1817. [PMID: 31752342 PMCID: PMC6896041 DOI: 10.3390/cancers11111817] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 11/07/2019] [Indexed: 02/06/2023] Open
Abstract
The proteins belonging to the inhibitor of growth (ING) family of proteins serve as epigenetic readers of the H3K4Me3 histone mark of active gene transcription and target histone acetyltransferase (HAT) or histone deacetylase (HDAC) protein complexes, in order to alter local chromatin structure. These multidomain adaptor proteins interact with numerous other proteins to facilitate their localization and the regulation of numerous biochemical pathways that impinge upon biological functions. Knockout of some of the ING genes in murine models by various groups has verified their status as tumor suppressors, with ING1 knockout resulting in the formation of large clear-cell B-lymphomas and ING2 knockout increasing the frequency of ameloblastomas, among other phenotypic effects. ING4 knockout strongly affects innate immunity and angiogenesis, and INGs1, ING2, and ING4 have been reported to affect apoptosis in different cellular models. Although ING3 and ING5 knockouts have yet to be published, preliminary reports indicate that ING3 knockout results in embryonic lethality and that ING5 knockout may have postpartum effects on stem cell maintenance. In this review, we compile the known information on the domains of the INGs and the effects of altering ING protein expression, to better understand the functions of this adaptor protein family and its possible uses for targeted cancer therapy.
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Affiliation(s)
- Arthur Dantas
- Arnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, 374 HMRB, 3330 Hospital Dr. NW, Calgary, AB T2N 4N1, Canada; (A.D.); (B.A.S.); (Y.Y.)
| | - Buthaina Al Shueili
- Arnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, 374 HMRB, 3330 Hospital Dr. NW, Calgary, AB T2N 4N1, Canada; (A.D.); (B.A.S.); (Y.Y.)
| | - Yang Yang
- Arnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, 374 HMRB, 3330 Hospital Dr. NW, Calgary, AB T2N 4N1, Canada; (A.D.); (B.A.S.); (Y.Y.)
| | - Arash Nabbi
- Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada
| | - Dieter Fink
- Institute of Laboratory Animal Science, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, 1210 Vienna, Austria;
| | - Karl Riabowol
- Arnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, 374 HMRB, 3330 Hospital Dr. NW, Calgary, AB T2N 4N1, Canada; (A.D.); (B.A.S.); (Y.Y.)
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