Download or read book The Role of DNA Methylation in Regulating Immunoglobulin Gene Expression During B Cell Differentiation written by Marcia Anne Blackman and published by . This book was released on 1985 with total page 348 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Epigenetics of B Cells and Antibody Responses written by Paolo Casali and published by Frontiers Media SA. This book was released on 2016-04-12 with total page 123 pages. Available in PDF, EPUB and Kindle. Book excerpt: Epigenetics is the study of changes in gene activity that are heritable but not caused by changes in the DNA sequence. By modulating gene activities, epigenetic changes regulate cell functions. They include DNA methylation, histone posttranslational modifications and gene silencing by the action of non-coding RNAs, particularly microRNAs. It is now clear that epigenetic changes regulate B cell development. By acting in concert with networks of transcription factors, they modulate the activation of B cell lineage specific gene programs and repress inappropriate gene transcription in particular B cell differentiation states.

A hallmark of B cell development in the bone marrow is the assembly of the B cell receptor (BCR) for antigen through rearrangement of immunoglobulin heavy (IgH) and light (IgL) chain V(D)J genes, as mediated by RAG1/RAG2 recombinases. Ig V(D)J rearrangement critically times the progression from pro-B cell to pre-B cell and, finally, mature B cell. Such progression is modulated by epigenetic marks, such as DNA methylation and histone posttranslational modifications, that increase chromatin accessibility and target RAG/RAG2 to V, D and J DNA. It is also dependent on the expression of multiple microRNAs. Mice deficient in Ago2, which is essential for microRNA biogenesis and function, have B cell development blocked at the pro-B cell stage. In agreement with this, B cell specific ablation of microRNA by B cell-specific knockout of Dicer virtually blocks B cell differentiation at the pro-B to pre-B cell transition.

After mature B cells encounter antigen, changes of the epigenetic landscape are induced by the same stimuli that drive the antibody response; such epigenetic changes underpin the maturation of the antibody response itself. They instruct those B cell differentiation processes, somatic hypermutation (SHM), class switch DNA recombination (CSR) and plasma cell differentiation, that are central to the maturation of the antibody response as well as differentiation of memory B cells. Inducible histone modifications, together with DNA methylation and microRNAs modulate the transcriptome, particularly the expression of activation-induced cytidine deaminase (AID), central to SHM and CSR, and B lymphocyte-induced maturation protein-1 (Blimp-1), which is central to plasma cell differentiation.

Combinatorial histone modifications also function as histone codes in the targeting of the CSR and, possibly, the SHM machinery to the Ig locus by recruiting specific adaptors (histone code readers) that can in turn target and/or stabilize CSR/SHM factors. Epigenetic alterations in memory B cells contribute to their functionally distinction from their naive counterparts. Memory B cells inherit epigenetic information from their precursors and acquire new epigenetic marks, which make these resting B cells poised to promptly respond to antigen. The cross/feedback regulation of different epigenetic modifications/elements further increases the complexity of the B cell epigenome, which interacts with the genetic information for precise modulation of gene expression. It is increasingly evident that epigenetic dysregulation in B cells, including aberrant expression of microRNAs, can result in aberrant antibody responses to microbial pathogens, emergence of pathogenic autoantibodies or B cell neoplastic transformation. Epigenetic marks are potential targets for new therapeutics in autoimmunity and B cell malignancy.

Download or read book Regulation of Immunoglobulin Transcription During B cell Differentiation written by Mikael Sigvardsson and published by . This book was released on 1995 with total page 140 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Dynamic regulation of DNA methylation in human T cell biology written by Antonio Lentini and published by Linköping University Electronic Press. This book was released on 2019-03-19 with total page 65 pages. Available in PDF, EPUB and Kindle. Book excerpt: T helper cells play a central role in orchestrating immune responses in humans. Upon encountering a foreign antigen, T helper cells are activated followed by a differentiation process where the cells are specialised to help combating the infection. Dysregulation of T helper cell activation, differentiation and function has been implicated in numerous diseases, including autoimmunity and cancer. Whereas gene-regulatory networks help drive T-cell differentiation, acquisition of stable cell states require heritable epigenetic signals, such as DNA methylation. Indeed, the establishment of DNA methylation patterns is a key part of appropriate T-cell differentiation but how this is regulated over time remains unknown. Methylation can be directly attached to cytosine residues in DNA to form 5-methylcytosine (5mC) but the removal of DNA methylation requires multiple enzymatic reactions, commonly initiated by the conversion into 5-hydroxymethylcytosine (5hmC), thus creating a highly complex regulatory system. This thesis aimed to investigate how DNA methylation is dynamically regulated during T-cell differentiation. To this end, we employed large-scale profiling techniques combining gene expression as well as genome-wide 5mC and 5hmC measurements to construct a time-series model of epigenetic regulation of differentiation. This revealed that early T-cell activation was accompanied by extensive genome-wide deposition of 5hmC which resulted in demethylation upon proliferation. Early DNA methylation remodelling through 5hmC was not only indicative of demethylation events during T-cell differentiation but also marked changes persisting longterm in memory T-cell subsets. These results suggest that priming of epigenetic landscapes in T-cells is initiated during early activation events, preceding any establishment of a stable lineage, which are then maintained throughout the cells lifespan. The regions undergoing remodelling were also highly enriched for genetic variants in autoimmune diseases which we show to be functional through disruption of protein binding. These variants could potentially disrupt gene-regulatory networks and the establishment of epigenetic priming, highlighting the complex interplay between genetic and epigenetic layers. In the course of this work, we discovered that a commonly used technique to study genome-wide DNA modifications, DNA immunoprecipitation (DIP)-seq, had a false discovery rate between 50-99% depending on the modification and cell type being assayed. This represented inherent technical errors related to the use of antibodies resulting in off-target binding of repetitive sequences lacking any DNA modifications. These sequences are common in mammalian genomes making robust detection of rare DNA modifications very difficult due to the high background signals. However, offtarget binding could easily be controlled for using a non-specific antibody control which greatly improved data quality and biological insight of the data. Although future studies are advised to use alternative methods where available, error correction is an acceptable alternative which will help fuel new discoveries through the removal of extensive background signals. Taken together, this thesis shows how integrative use of high-resolution epigenomic data can be used to study complex biological systems over time as well as how these techniques can be systematically characterised to identify and correct errors resulting in improved detection.

Download or read book Tracing the Developmental History of B cell Tumors by DNA Methylation written by Martí Duran Ferrer and published by . This book was released on 2021 with total page 317 pages. Available in PDF, EPUB and Kindle. Book excerpt: The DNA from our cells carries the genetic information to build a human being. This information is interpreted through epigenetic marks that lead to tightly coordinated and cell type-specific gene expression programs. One of these marks is DNA methylation, which has been widely reported to regulate gene expression both in physiological and pathological conditions. Initial studies in cancer identified gene promoter methylation as an alternative to genetic alterations in the silencing of tumor suppressor genes. Nonetheless, genome-wide studies published in the last decade uncovered that the majority of DNA methylation changes in cancer are not directly related to gene regulation, and thus do not have an apparent functional impact. Some of these studies focused on the DNA methylome during B-cell development and malignant transformation to major B-cell neoplasms. These reports unveiled a highly dynamic DNA methylome during B-cell development and provided new insights into the cellular origin, pathogenic mechanisms and clinical behavior of B-cell neoplasms. Despite these previous studies targeting specific cancers, a holistic perspective of the DNA methylome during the entire normal cell differentiation program and derived neoplasms was missing. This holistic view was neither available for B cells nor for any other human cell lineage, and therefore was the main goal of this thesis. I exploited previously and newly generated data to dissect the sources of DNA methylation variability of major B-cell tumors spanning the whole maturation spectrum in the context of the entire normal B-cell development. These included B-cell acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL) (Study 1), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). This comprehensive approach using over 2,000 samples showed that the human DNA methylome is more dynamic than previously conceived and uncovered new clinico-biological insights (Study 2). I observed that B-cell tumors display both DNA methylation imprints of normal development and de novo DNA methylation aberrations, which set the basis to build an accurate diagnostic tool for 14 B-cell tumor subtypes with different clinical management. In line with previous knowledge, I identified that most of the DNA methylation changes taking place in individual patients were located in silent chromatin. Remarkably, I could relate this phenomenon to the proliferative history of normal and neoplastic B cells, whereby each cell division seemed to accumulate transcriptionally-inert epigenetic imprints into the genome (Study 3). In general, mitotic activity simultaneously left hyper- and hypomethylation imprints, but some B-cell neoplasms preferentially gained or lost DNA methylation. Based on this data, I built the epiCMIT epigenetic mitotic clock considering both hyper- and hypomethylation imprints related to cell division, which significantly improved the performance of previously reported mitotic clocks. Noticeably, the proliferative history traced by the epiCMIT before treatment was highly predictive of future patient outcome, not only in the B-cell tumors studied but also in other human neoplasias. The accumulation of genetic alterations with positive selection increased the epiCMIT, but some specific drivers seemed to confer a particular proliferative advantage to CLL and MCL cells and distinguished patients with a marked adverse outcome (Study 4). Finally, I compared the epiCMIT mitotic clock with another type of epigenetic clock that estimates the chronological age of a person, the so-called Horvath clock. Interestingly, the epiCMIT was strongly associated with an accelerated epigenetic aging in B-cell tumors measured by the Horvath clock, suggesting a crosstalk between mitotic activity and the aging process (Study 3). In summary, the wealth of data presented in this doctoral thesis uncovers DNA methylation as a holistic tracer of B-cell tumor developmental history and provides new clinico-biological insights for B-cell tumors and cancer in general.

Download or read book The Role of DNA Methylation in Regulation of Gene Expression and Differentiation in Plants written by Gorm Palmgren and published by . This book was released on 1992 with total page 228 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Arginine Methylation by PRMT1 and PRMT5 Regulates B Cell Activation Germinal Center Expansion and Differentiation Into Plasma Cells written by Ludivine Litzler and published by . This book was released on 2018 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Adaptive immunity relies in part on the ability of B cells to generate specific antibodies against foreign antigens. B cells develop in the bone marrow, and once they express a functional antibody at their surface, they reach secondary lymphoid organs where they will be exposed to foreign poly-peptides. Upon encounter with a cognate antigen, B cells proliferate rapidly, migrate to the border of the B cell follicle to receive T cell help and move back within the B cell follicle to form structures called germinal centers (GC). In GCs, B cells undergo affinity maturation, which increase the affinity of the antibodies, and antibody class switching to diversify their function. B cells exit GCs by differentiating into (i) memory B cells that can rapidly be activated following a second encounter with the pathogen or (ii) plasma cells that secrete antibodies in circulation to neutralize and clear pathogens. Post-translational modifications regulate several aspects of B cell biology such as B cell development, activation and differentiation. My thesis investigates the role of arginine methylation in B cells during T-dependant immune responses, focusing on two enzymes: the protein arginine methyltransferases 1 and 5 (PRMT1 and PRMT5), using mice as models. We have uncovered that Prmt5 is necessary during B cell development. In particular, Prmt5 is required at the pro-B cell stage in a p53-dependant manner and at the pre-B cell stage in a p53-independent fashion. Prmt5 is necessary for the expansion of the GC by promoting B cell proliferation and limiting plasma cell differentiation. These functions could originate, among other mechanisms, from the Prmt5 role in enforcing splicing fidelity and regulating gene expression. We have also discovered that Prmt1 is a major negative regulator of plasma cell differentiation, particularly following CD40 stimulation. Furthermore, we obtained evidence that Prmt1 and Prmt5 function synergistically to negatively regulate plasma cell differentiation. Overall arginine methylation by Prmt1 and Prmt5, via different mechanisms, influences GC B cell fate; by promoting B cells to remain in the GC reaction, at least in part by repressing plasma cell differentiation, thereby supporting antibody responses and enhancing affinity maturation.

Download or read book Global DNA Methylation and Gene Expression Analysis in Pre B Cell Acute Lymphoblastic Leukemia written by Md Almamun and published by . This book was released on 2015 with total page 220 pages. Available in PDF, EPUB and Kindle. Book excerpt: Acute lymphoblastic leukemia (ALL) is a fast-growing cancer of lymphoblasts, and is the most common cancer diagnosed in children under the age of 15. Our complete understanding of all mechanisms responsible for ALL induction is inadequate. Moreover, the heritable and potentially stable epigenetic changes occur at a much greater rate than DNA mutations in somatic cells. DNA methylation is an epigenetic modification that plays a significant role in hematopoiesis and malignant transformation. Therefore, the identification of altered DNA methylation on key regulatory regions of the genome is critical to gaining a better understanding of ALL pathogenesis. This dissertation identified the dynamic establishment of DNA methylation during normal B-cell development, and alterations of DNA methylation in the pathogenesis of ALL. First, a protocol to isolate the subsets of precursor B-cells from human umbilical cord blood (HCB) was developed. Using this protocol, we were able to isolate sufficient numbers of pro-B, pre-BI, pre-BII and naïve B-cells from a single HCB unit. This method can be adapted for any type of cell present in HCB at any stage of differentiation. Next, genome-wide DNA methylation profiles using the methylated CpG island recovery assay followed by next generation sequencing (MIRA-seq) were generated for each of the four subsets of precursor B-cells. We report for the first time that hypermethylated loci are associated with the transition of pro-B to pre-BI cells. Differentially methylated regions were identified and the majority of the loci were present within intronic and intergenic regions that harbor putative regulatory elements. The development of methylation profiles in normal precursor B-cells will aid in elucidating the role of altered DNA methylation in the pathogenesis of precursor B-cell related disorders including ALL. In order to identify epigenetic alterations in ALL, we next determined the differentially methylated regions (DMRs) between ALL and healthy precursor B-cells. Further, whole genome transcriptome analysis was performed to determine the regulatory potential of the DMRs. Our studies identified ALL specific epigenetically deregulated genes, novel putative enhancers, and biological pathways that showed concurrent DNA methylation and changes in gene expression during malignant transformation. These altered epigenetic marks could be used as prospective biomarkers for ALL and/or as potential targets to reset the altered DNA methylation in order to modify gene expression which may enhance the present treatment protocol for ALL and eventually improve patient outcome.

Download or read book The Epigenetics of Autoimmune Diseases written by Moncef Zouali and published by John Wiley & Sons. This book was released on 2009-04-01 with total page 472 pages. Available in PDF, EPUB and Kindle. Book excerpt: The role of epigenetic mechanisms in autoimmune disease is only now starting to become clear. Understanding these mechanisms, their effect on cellular function and the role of environmental factors is vital to determining how to manage these often debilitating and fatal diseases. Drawing on the research of leading experts, this book provides a valuable insight into this important new area of autoimmunity research and a clear, up-to-date view on the major advances in the field. Specific coverage includes: How highly developed epigenetic mechanisms are involved in several aspects of normal immune regulation, in addition to maintaining immune tolerance to self-determinants. Specific epigenetic aspects of human autoimmune diseases, including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, autoimmune diabetes, thyroid autoimmunity, inflammatory bowel disease and autoimmune hepatitis. How understanding epigenetic mechanisms can lead to therapeutic strategies based on manipulation of this previously unexploited facet of immune regulation. Discussion of the novel approaches that are being investigated to prevent or treat autoimmune diseases. This book is an essential resource for those actively involved in the field. It is also of interest to basic researchers interested in understanding the origin of autoimmunity and clinical specialists interested in gaining in-depth understanding of the pathogenesis of autoimmune diseases and their treatment.

Download or read book Chromatin and Disease written by Tapas K. Kundu and published by Springer Science & Business Media. This book was released on 2007-05-04 with total page 456 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book includes a collection of articles with the broad theme of disease connection to chromatin structure and function. It elaborates on the molecular pharmacology of the drugs targeting chromatin structure and its components. The book contains up-to-date information about the chromatin structure and chromatin related diseases and drug functions. This work is the first endeavor to present different aspects encompassing the above theme.

Download or read book Molecular Biology of The Cell written by Bruce Alberts and published by . This book was released on 2002 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book The Epstein Barr Virus written by M. A. Epstein and published by Springer Science & Business Media. This book was released on 2012-12-06 with total page 467 pages. Available in PDF, EPUB and Kindle. Book excerpt: The Epstein-Barr virus was discovered 15 years ago. Since that time an immense body of information has been accumu lated on this agent which has come to assume great signifi cance in many different fields of biological science. Thus, the virus has very special relevance in human medicine and oncology, in tumor virology, in immunology, and in mole cular virology, since it is the cause of infectious mononu cleosis and also the first human cancer virus, etiologically related to endemic Burkitt's lymphoma and probably to nasopharyngeal carcinoma. In addition, continuous human lymphoid cell lines initiated and maintained by the transform ing function of the virus genome provide a laboratory tool with wide and ever-growing applications. Innumerable papers on the Epstein-Barr virus have ap peared over recent years and reports of work with this agent now constitute a veritable flood. The present book provides the first and only comprehensive, authoritative over-view of all aspects of the virus by authors who have been the original and major contributors in their particular disciplines. A complete and up-to-date survey of this unique and important agent is thus provided which should be of great interest to experts, teachers, and students engaged in cancer research, virology, immunology, molecular biology, epide miology, and cell culture. Where topics have been dealt with from more than one of these viewpoints, some inevitable overlap and duplication has resulted; although this has been kept to a minimum, it has been retained in some places because of positive usefulness.

Download or read book Normal and Malignant B Cell written by Mourad Aribi and published by BoD – Books on Demand. This book was released on 2020-02-26 with total page 163 pages. Available in PDF, EPUB and Kindle. Book excerpt: Normal and Malignant B-Cell is a collection of harmonious chapters contributed by different authors. This book sets out to describe the B-cell during different stages of ontogeny and the molecular mechanisms of its antigen receptor diversity. It also discusses the main clinical and etiopathogenic aspects when it is transformed into a malignant cell. The book will be interesting and useful for clinicians, biologists, researchers, teachers, and graduate students of both doctoral and master's degrees in the field of immunology.

Download or read book B Cells in Immunity and Tolerance written by Ji-Yang Wang and published by Springer. This book was released on 2021-05-07 with total page 181 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book contains twelve chapters contributed by prestigious international experts who are at the forefront of B cell research, and aims to provide a cutting-edge and comprehensive overview of all aspects of B cells, including B cell development, maturation and activation, germinal center reaction, memory and plasma cell differentiation, and antibody-mediated positive and negative regulation of humoral immune responses. There are also three chapters describing human diseases caused by B cell abnormalities, including primary antibody deficiencies, autoimmune diseases, and B cell malignancies. We hope that this book will become a standard and routine reference for both basic researchers and clinicians.

Download or read book Chronic Graft Versus Host Disease written by Georgia B. Vogelsang and published by Cambridge University Press. This book was released on 2009-04-20 with total page 427 pages. Available in PDF, EPUB and Kindle. Book excerpt: Chronic graft versus host disease (GVHD) is the most common complication of allogenic bone marrow transplantation. Because of the protracted clinical course of chronic GVHD, transplant centers and hematology/oncology offices are inadequately equipped to manage these immuno-incompetent patients with a multi-system disorder. Practitioners need to be able to recognize and effectively manage chronic GVHD as a late effect of more than half of allogenic transplantations. The text is oriented for the clinician, with chapters covering staging, organ site and system-specific manifestations, treatment options, and supportive care. Drs Georgia B. Vogelsang and Steven Z. Pavletic have been pioneers in the recognition of the multi-organ complexity of this disease and have gathered the input of a variety of subspecialist physicians for this book. This book fills the gap in practical literature on chronic GVHD, providing a comprehensive, up-to-date, and clinically relevant resource for anyone who deals with cancer patients post-transplant.

Download or read book Human Herpesviruses written by Ann Arvin and published by Cambridge University Press. This book was released on 2007-08-16 with total page 1325 pages. Available in PDF, EPUB and Kindle. Book excerpt: This comprehensive account of the human herpesviruses provides an encyclopedic overview of their basic virology and clinical manifestations. This group of viruses includes human simplex type 1 and 2, Epstein–Barr virus, Kaposi's Sarcoma-associated herpesvirus, cytomegalovirus, HHV6A, 6B and 7, and varicella-zoster virus. The viral diseases and cancers they cause are significant and often recurrent. Their prevalence in the developed world accounts for a major burden of disease, and as a result there is a great deal of research into the pathophysiology of infection and immunobiology. Another important area covered within this volume concerns antiviral therapy and the development of vaccines. All these aspects are covered in depth, both scientifically and in terms of clinical guidelines for patient care. The text is illustrated generously throughout and is fully referenced to the latest research and developments.

Download or read book Biomedical Index to PHS supported Research pt A Subject access A H written by and published by . This book was released on 1994 with total page 1398 pages. Available in PDF, EPUB and Kindle. Book excerpt: