Myc Transcriptional Functions Controlling Epidermal Stem Cell Self Renewal And Differentiation
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Myc Transcriptional Functions Controlling Epidermal Stem Cell Self Renewal And Differentiation
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Author : Elisabete Nascimento
language : en
Publisher:
Release Date : 2011
Myc Transcriptional Functions Controlling Epidermal Stem Cell Self Renewal And Differentiation written by Elisabete Nascimento and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2011 with categories.
The oncoprotein MYC has long been recognized as an important stem cell regulator, yet its direct biological contributions have been difficult to determine. MYC activation can induce pleiotropic phenotypes and mediates cellular functions as opposing as cell growth and proliferation, metabolism, differentiation and apoptosis. In addition, functional redundancy with MYCL and MYCN proteins as well as dose dependency, complicates the identification of the most relevant biological functions. Studies in tissues with high proliferative capacity and rapid turnover have shown that MYC is a key regulator of homeostasis by balancing stem cell self-renewal, proliferation and differentiation processes. In skin, MYC induces the exit of epidermal stem cells from their niche, increases proliferation of progenitor cells and subsequently stimulates lineage specific differentiation into interfollicular epidermis and sebaceous glands; yet the direct transcriptional roles of MYC in these processes remained elusive. To gain insight into the transcriptional roles of MYC in epidermal stem cell homeostasis, I performed chromatin immunoprecipitation on microarrays (ChIP-on-Chip) using mouse proximal promoter arrays combined with mRNA expression data that was generated using epidermal cells from wild-type and transgenic K14MycER mice, treated in a time-course from zero to six days with tamoxifen, to induce the?Myc? transgene expression in the basal undifferentiated layers of the epidermis. Data analysis revealed that 2187 genes, which corresponds to 15% of the promoter regions covered, were directly regulated by MYC. To identify genes uniquely regulated by MYC in skin, I performed gene expression studies on mouse skin in which MYC was conditionally deleted in the basal layer of the epidermis. Remarkably, I found that 45% of all repressed genes were related to epidermal maintenance and differentiation. To better understand the mechanism of how MYC induces keratinocytes to differentiate specifically into lineages of sebaceous glands and interfollicular epidermis, I analyzed whether MYC might have directly regulated genes involved in skin differentiation. Here, I focused my studies on a single 2.2 Mb locus located on mouse chromosome 3 designated as the epidermal differentiation complex (EDC). To assess how activation of MYC could influence the expression of genes localized to the EDC, I performed ChIP-on-Chip for MYC, H3K4me3, H3K27me3, as well as transcription factors, which have been described to regulate terminal differentiation in skin, such as CEBP?, OVOL-1, KLF4, TCFAP2-? and SIN3A, among others. I demonstrated that MYC recruits a specific set of tissue-specific transcription factors to the EDC, (e.g. KLF4 and OVOL-1) and thereby prevents binding of a different and distinct set of genomic regulators, (e.g. CEBP?, MXI1 and SIN3A). Using a combination of mouse models and systems biology tools, I then identified SIN3A as a key regulator in this MYC-dependent transcriptional network. I found that MYC and SIN3A form a negative feedback loop, which is required to balance proliferation and differentiation in epidermis, and both factors are essential to maintain skin homeostasis.
Transcriptional Functions Of The Corepressor Sin3a In Skin
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Author : Claire Cox
language : en
Publisher:
Release Date : 2013
Transcriptional Functions Of The Corepressor Sin3a In Skin written by Claire Cox and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2013 with categories.
Upon activation in epidermal stem cells, the proto-oncogene c-Myc triggers their exit from the stem cell compartment resulting in an increase in progenitor cell proliferation and an induction in terminal differentiation. Whether c-Myc plays a direct transcriptional role in epidermal stem cell differentiation was unknown. The exploration of c-Myc's transcriptional roles at the epidermal differentiation complex (EDC), a locus essential for skin maturation demonstrated that binding of c-Myc to the EDC can simultaneously recruit and displace specific sets of differentiation-specific transcriptional regulators to EDC genes. Among these factors, Sin3A acts as a transcriptional co-repressor and was initially discovered via its direct interaction with Mxi1 and Mxd1, which are antagonists of the Myc family network. As such, I concentrated on the role of Sin3A as a potential opposing factor to c-Myc activity in the epidermis. To analyse the role of Sin3A in regulating epidermal stem cell fate in vivo, I generated a number of transgenic mouse models. To determine whether Sin3A functions in hair follicle stem cells, I inducibly deleted Sin3A in the hair follicle bulge, where quiescent stem cells reside. However, lack of Sin3A in the hair bulge did not cause any aberrant phenotype and I concluded that Sin3A is dispensable for hair follicle homeostasis. I next analysed a mouse model in which Sin3A is inducibly deleted in the basal layer of the epidermis. Deletion of Sin3A resulted in a severe disruption of epidermal homeostasis-namely due to increases in proliferation and differentiation. Further investigation demonstrated that this phenotype is driven by enhanced genomic recruitment of c-Myc to the epidermal differentiation complex and reactivation of c-Myc target genes involved in cellular proliferation. I found that Sin3A causes de-acetylation of the c-Myc protein to directly repress c-Myc's transcriptional activity and is antagonistic to c-Myc in the interfollicular epidermis. I hypothesised that simultaneous deletion of Sin3A and c-Myc might return the skin to normality. Indeed, when Sin3A and Myc are concurrently deleted, proliferation and differentiation levels returned to normal. These results demonstrate how levels of Sin3A and c-Myc must be carefully balanced for epidermal homeostasis to be maintained. Decreased expression of Sin3A has been linked to tumour susceptibility in other tissues for example in non-small cell lung carcinoma making Sin3A a candidate tumour suppressor gene. I therefore considered that loss of Sin3A may lead to increased susceptibility to skin cancer. To investigate this I performed pilot experiments using UVB irradiation of skin that has one copy of Sin3A deleted in the basal layer of the epidermis. Under normal conditions, these mice have no identifiable phenotype, but pilot experiments demonstrated that after short term and long term UVB irradiation, they exhibit increased epidermal thickness and proliferation relative to controls. This recapitulated the phenotype observed when Sin3A is inducibly deleted in the interfollicular epidermis and further demonstrates the role of SinA as an inhibitor of proliferation in this tissue. Overall, these results demonstrate that an interplay between the opposing functions of Sin3A and c-Myc are necessary to ensure that there is balanced homeostasis in the interfollicular epidermis.
The Keratinocyte Handbook
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Author :
language : en
Publisher: CUP Archive
Release Date : 1994
The Keratinocyte Handbook written by and has been published by CUP Archive this book supported file pdf, txt, epub, kindle and other format this book has been release on 1994 with Keratinocytes categories.
"Keratinocytes, as the main cellular component of the organism/environment interface, perform a vast range of functions in protection, secretion, sensation and self-repair by virtue of their great plasticity in form and development. Indeed recent medical advances in laboratory culture of these cells for use as skin grafts in cases of severe burns or ulceration owe much of their success to this very plasticity. Drawing upon a wide range of international expertise the various interconnected aspects of cell structure, composition and function are laid out in this volume, providing a comprehensive dossier of the keratinocyte and its biological significance."--Pub. desc.
The Myc Max Mad Transcription Factor Network
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Author : Robert N. Eisenman
language : en
Publisher: Springer
Release Date : 2014-09-23
The Myc Max Mad Transcription Factor Network written by Robert N. Eisenman and has been published by Springer this book supported file pdf, txt, epub, kindle and other format this book has been release on 2014-09-23 with Medical categories.
Scientists often look askance at their colleagues whose research appears too strongly focused on a single gene or gene product. We are supposed to be interested in the “big picture” and excessive zeal in pursuit of a single pixel might seem to border on an obsession that is likely to yield only details. However as this volume of Current Topics in Microbiology and Immunology demonstrates, this is certainly not the case for myc. Intense study of this en- matic proto-oncogene over the last twenty years has only broadened our view of its functions and led to insights into mechanisms relating to transcriptional regulation as well as to cell growth, proliferation, differentiation, apoptosis and organismal development. The myc gene originally came to light as a retroviral oncogene (v-myc) associated with a wide range of acute neoplasms. It was later shown to be a virally transduced cellular gene (c-myc) which is a member of family of on- genes (c-myc,N-myc,L-myc). These family members are themselves subject to a bewildering assortment of genetic rearrangements associated with many different types of tumors derived from many different types of cells. These rearrangements (including chromosomal translocation, viral integration, and gene ampli?cation) act to uncouple expression of the myc family genes from their normal physiological regulators. The chapter by LIU and LEVENS - scribes the key pathways leading to regulation of myc expression, showing that such regulation occurs at several different levels and through multiple mechanisms.
Essentials Of Stem Cell Biology
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Author : Robert Lanza
language : en
Publisher: Academic Press
Release Date : 2009-06-05
Essentials Of Stem Cell Biology written by Robert Lanza and has been published by Academic Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2009-06-05 with Science categories.
First developed as an accessible abridgement of the successful Handbook of Stem Cells, Essentials of Stem Cell Biology serves the needs of the evolving population of scientists, researchers, practitioners and students that are embracing the latest advances in stem cells. Representing the combined effort of seven editors and more than 200 scholars and scientists whose pioneering work has defined our understanding of stem cells, this book combines the prerequisites for a general understanding of adult and embryonic stem cells with a presentation by the world's experts of the latest research information about specific organ systems. From basic biology/mechanisms, early development, ectoderm, mesoderm, endoderm, methods to application of stem cells to specific human diseases, regulation and ethics, and patient perspectives, no topic in the field of stem cells is left uncovered. Selected for inclusion in Doody's Core Titles 2013, an essential collection development tool for health sciences libraries Contributions by Nobel Laureates and leading international investigators Includes two entirely new chapters devoted exclusively to induced pluripotent stem (iPS) cells written by the scientists who made the breakthrough Edited by a world-renowned author and researcher to present a complete story of stem cells in research, in application, and as the subject of political debate Presented in full color with glossary, highlighted terms, and bibliographic entries replacing references
Stem Cells In Reproductive Medicine
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Author : Carlos Simón
language : en
Publisher: Cambridge University Press
Release Date : 2013-07-04
Stem Cells In Reproductive Medicine written by Carlos Simón and has been published by Cambridge University Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2013-07-04 with Medical categories.
Stem cell science has the potential to impact human reproductive medicine significantly - cutting edge technologies allow the production and regeneration of viable gametes from human stem cells offering potential to preciously infertile patients. Written by leading experts in the field Stem Cells in Reproductive Medicine brings together chapters on the genetics and epigenetics of both the male and female gametes as well as advice on the production and regeneration of gene cells in men and women, trophoblasts and endometrium from human embryonic and adult stem cells. Although focussing mainly on the practical elements of the use of stem cells in reproductive medicine, the book also contains a section on new developments in stem cell research. The book is essential reading for reproductive medicine clinicians, gynecologists and embryologists who want to keep abreast of practical developments in this rapidly developing field.
Pluripotent Stem Cells
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Author : Deepa Bhartiya
language : en
Publisher: BoD – Books on Demand
Release Date : 2013-08-28
Pluripotent Stem Cells written by Deepa Bhartiya and has been published by BoD – Books on Demand this book supported file pdf, txt, epub, kindle and other format this book has been release on 2013-08-28 with Science categories.
Stem cells have generated a lot of excitement among the researchers, clinicians and the public alike. Various types of stem cells are being evaluated for their regenerative potential. Marginal benefit resulting by transplanting autologus stem cells (deemed to be absolutely safe) in various clinical conditions has been proposed to be a growth factor effect rather than true regeneration. In contrast, various pre-clinical studies have been undertaken, using differentiated cells from embryonic stem cells or induced pluripotent stem cells have shown promise, functional improvement and no signs of teratoma formation. The scientists are not in a rush to reach the clinic but a handful of clinical studies have shown promise. This book is a collection of studies/reviews, beginning with an introduction to the pluripotent stem cells and covering various aspects like derivation, differentiation, ethics, etc., and hence would provide insight into the recent standing on the pluripotent stem cells biology. The chapters have been categorized into three sections, covering subjects ranging from the generation of pluripotent stem cells and various means of their derivation from embryonic as well as adult tissues, the mechanistic understanding of pluripotency and narrating the potential therapeutic implications of these in vitro generated cells in various diseases, in addition to the associated pros and cons in the same.
Neural Crest Stem Cells
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Author : Maya Sieber-Blum
language : en
Publisher: World Scientific
Release Date : 2012
Neural Crest Stem Cells written by Maya Sieber-Blum and has been published by World Scientific this book supported file pdf, txt, epub, kindle and other format this book has been release on 2012 with Medical categories.
Offers readers an understanding of the development of neural crest cells, which is crucial as many birth defects and tumours are of neural crest origin. Delving into stem cells from different locations of the body, this book explores the best possible source of such cells for the use in medical applications.
Cell Cycle Regulation
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Author : Philipp Kaldis
language : en
Publisher: Springer
Release Date : 2010-11-18
Cell Cycle Regulation written by Philipp Kaldis and has been published by Springer this book supported file pdf, txt, epub, kindle and other format this book has been release on 2010-11-18 with Science categories.
This book is a state-of-the-art summary of the latest achievements in cell cycle control research with an outlook on the effect of these findings on cancer research. The chapters are written by internationally leading experts in the field. They provide an updated view on how the cell cycle is regulated in vivo, and about the involvement of cell cycle regulators in cancer.
Transcriptional And Translational Regulation Of Stem Cells
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Author : Gary Hime
language : en
Publisher: Springer Science & Business Media
Release Date : 2013-05-22
Transcriptional And Translational Regulation Of Stem Cells written by Gary Hime and has been published by Springer Science & Business Media this book supported file pdf, txt, epub, kindle and other format this book has been release on 2013-05-22 with Medical categories.
This volume describes the latest findings on transcriptional and translational regulation of stem cells. Both transcriptional activators and repressors have been shown to be crucial for the maintenance of the stem cell state. A key element of stem cell maintenance is repression of differentiation factors or developmental genes – achieved transcriptionally, epigenetically by the Polycomb complex, and post-transcriptionally by RNA-binding proteins and microRNAs. This volume takes two approaches to this topic – (1) illustrating the general principles outlined above through a series of different stem cell examples – embryonic, iPS and adult stem cells, and (2) describing several molecular families that have been shown to have roles in regulation of multiple stem cell populations.