Showing papers by "Peter D. Adams published in 2014"

EZH2 in normal and malignant hematopoiesis.

Abstract: The histone methyltransferase Enhancer of Zeste Homologue 2 (EZH2), a component of the polycomb group complex, is vital for stem cell development, including hematopoiesis. Its primary function, to deposit the histone mark H3K27me3, promotes transcriptional repression. The activity of EZH2 influences cell fate regulation, namely the balance between self-renewal and differentiation. The contribution of aberrant EZH2 expression to tumorigenesis by directing cells toward a cancer stem cell (CSC) state is increasingly recognized. However, its role in hematological malignancies is complex. Point mutations, resulting in gain-of-function, and inactivating mutations, reported in lymphoma and leukemia, respectively, suggest that EZH2 may serve a dual purpose as an oncogene and tumor-suppressor gene. The reduction of CSC self-renewal via EZH2 inhibition offers a potentially attractive therapeutic approach to counter the aberrant activation found in lymphoma and leukemia. The discovery of small molecules that specifically inhibit EZH2 raises the exciting possibility of exploiting the oncogenic addiction of tumor cells toward this protein. However, interference with the tumor-suppressor role of wild-type EZH2 must be avoided. This review examines the role of EZH2 in normal and malignant hematopoiesis and recent developments in harnessing the therapeutic potential of EZH2 inhibition.

HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia.

Abstract: Cellular senescence is a stable proliferation arrest that suppresses tumorigenesis. Cellular senescence and associated tumor suppression depend on control of chromatin. Histone chaperone HIRA deposits variant histone H3.3 and histone H4 into chromatin in a DNA replication-independent manner. Appropriately for a DNA replication-independent chaperone, HIRA is involved in control of chromatin in nonproliferating senescent cells, although its role is poorly defined. Here, we show that nonproliferating senescent cells express and incorporate histone H3.3 and other canonical core histones into a dynamic chromatin landscape. Expression of canonical histones is linked to alternative mRNA splicing to eliminate signals that confer mRNA instability in nonproliferating cells. Deposition of newly synthesized histones H3.3 and H4 into chromatin of senescent cells depends on HIRA. HIRA and newly deposited H3.3 colocalize at promoters of expressed genes, partially redistributing between proliferating and senescent cells to parallel changes in expression. In senescent cells, but not proliferating cells, promoters of active genes are exceptionally enriched in H4K16ac, and HIRA is required for retention of H4K16ac. HIRA is also required for retention of H4K16ac in vivo and suppression of oncogene-induced neoplasia. These results show that HIRA controls a specialized, dynamic H4K16ac-decorated chromatin landscape in senescent cells and enforces tumor suppression.

DNMT inhibitors reverse a specific signature of aberrant promoter DNA methylation and associated gene silencing in AML

Abstract: Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are neoplastic disorders of hematopoietic stem cells. DNA methyltransferase inhibitors, 5-azacytidine and 5-aza-2′-deoxycytidine (decitabine), benefit some MDS/AML patients. However, the role of DNA methyltransferase inhibitor-induced DNA hypomethylation in regulation of gene expression in AML is unclear. We compared the effects of 5-azacytidine on DNA methylation and gene expression using whole-genome single-nucleotide bisulfite-sequencing and RNA-sequencing in OCI-AML3 cells. For data analysis, we used an approach recently developed for discovery of differential patterns of DNA methylation associated with changes in gene expression, that is tailored to single-nucleotide bisulfite-sequencing data (Washington University Interpolated Methylation Signatures). Using this approach, we find that a subset of genes upregulated by 5-azacytidine are characterized by 5-azacytidine-induced signature methylation loss flanking the transcription start site. Many of these genes show increased methylation and decreased expression in OCI-AML3 cells compared to normal hematopoietic stem and progenitor cells. Moreover, these genes are preferentially upregulated by decitabine in human primary AML blasts, and control cell proliferation, death, and development. Our approach identifies a set of genes whose methylation and silencing in AML is reversed by DNA methyltransferase inhibitors. These genes are good candidates for direct regulation by DNA methyltransferase inhibitors, and their reactivation by DNA methyltransferase inhibitors may contribute to therapeutic activity.

The effects of aging on the expression of Wnt pathway genes in mouse tissues.

Abstract: The Wnt signaling pathway is involved in the regulation of tissue patterning and organ development during embryogenesis and continues to contribute to the maintenance of tissue homeostasis in adulthood. Recently, Wnt signaling has also been implicated in the establishment and progression of replicative cellular senescence. Given the known roles of tissue homeostasis and cellular senescence in aging, we sought to determine whether Wnt signaling changes with age. We examined the expression of 84 Wnt pathway-related genes in the liver, lung, skeletal muscle, and brain tissue from young and old mice. Expression changes were compared with those seen in cellular senescence, and transcription factors that might mediate these changes were predicted bioinformatically. In aggregate, our data are indicative of a general decrease in Wnt signaling with age, especially in the lung and brain. Furthermore, the set of genes that are differentially expressed with age is distinct from the genes differentially expressed in cellular senescence. The transcription factors predicted to regulate these changes, Nf-κB, Myb, Nkx2-1, Nr5a2, and Ep300, are known to regulate inflammation, differentiation, lipid metabolism, and chromatin remodeling, all of which have previously been implicated in aging. Although our study does not address whether altered Wnt signaling is a cause or an effect of aging, the presence of a relationship between the two provides a starting point for further investigation.

Phase II trial of vorinostat in advanced melanoma

Abstract: Introduction Vorinostat is a small molecule inhibitor of class I and II histone deacetylases with preclinical activity in melanoma. Methods We evaluated 32 patients with advanced primary cutaneous or ocular melanoma in a multi-institutional setting (PMH Phase II Consortium) with continuous daily oral vorinostat 400 mg. The primary endpoint was response rate by RECIST, with time to progression as a secondary endpoint. The study was designed to distinguish a response rate of 20 % from a RR of 5 % and to distinguish a 2 month median progression-free survival (PFS), from one of 3.1 months. The study proceeded to stage 2 following 2 of 16 responses.. We also assessed VEGF, FGF levels, P52 polymorphisms and chromatin-associated proteins as potential biomarkers. Results Therapy was associated with significant side effects, including fatigue, nausea, lymphopenia, and hyperglycemia. Eleven patients experienced at least one grade 3 or higher adverse event. There were two confirmed PRs in patients with cutaneous melanoma. Sixteen patients had stable disease and 14 patients had progressive disease for best response. In addition, two patients with cutaneous melanoma scored as stable disease had early unconfirmed partial responses with subsequent progression. Patients with stable disease or partial response (n = 18) had a median progression free survival of 5 months. (range 2–12 months). Conclusions Vorinostat demonstrated some early responses and a high proportion of patients with stable disease, but did not meet its primary endpoint of response. Different schedules of this agent with BRAF mutation status and markers of histone acetylation could be explored in melanoma.

A comparison of oncogene-induced senescence and replicative senescence: implications for tumor suppression and aging

Abstract: Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway, the senescence-associated secretory phenotype. However, cellular senescence is initiated by diverse molecular triggers, such as activated oncogenes and shortened telomeres, and is associated with varied and complex physiological endpoints, such as tumor suppression and tissue aging. The extent to which distinct triggers activate divergent modes of senescence that might be associated with different physiological endpoints is largely unknown. To begin to address this, we performed gene expression profiling to compare the senescence programs associated with two different modes of senescence, oncogene-induced senescence (OIS) and replicative senescence (RS [in part caused by shortened telomeres]). While both OIS and RS are associated with many common changes in gene expression compared to control proliferating cells, they also exhibit substantial differences. These results are discussed in light of potential physiological consequences, tumor suppression and aging.

Transcription factor EKLF (KLF1) recruitment of the histone chaperone HIRA is essential for β-globin gene expression

Abstract: The binding of chromatin-associated proteins and incorporation of histone variants correlates with alterations in gene expression. These changes have been particularly well analyzed at the mammalian β-globin locus, where transcription factors such as erythroid Kruppel-like factor (EKLF), which is also known as Kruppel-like factor 1 (KLF1), play a coordinating role in establishing the proper chromatin structure and inducing high-level expression of adult β-globin. We had previously shown that EKLF preferentially interacts with histone H3 and that the H3.3 variant is differentially recruited to the β-globin promoter. We now find that a novel interaction between EKLF and the histone cell cycle regulation defective homolog A (HIRA) histone chaperone accounts for these effects. HIRA is not only critical for β-globin expression but is also required for activation of the erythropoietic regulators EKLF and GATA binding protein 1 (GATA1). Our results provide a mechanism by which transcription factor-directed recruitment of a generally expressed histone chaperone can lead to tissue-restricted changes in chromatin components, structure, and transcription at specific genomic sites during differentiation.

Aging Cell: open access to all.

Abstract: Since its launch in 2002, Aging Cell has strived to publish the highest caliber research in biogerontology (now often referred to as the biology of aging). Aging Cell has rapidly established itself as a highly respected and reputable journal and has maintained its leadership role in publishing some of the most important and exciting research in this field. As we enter 2014 (the thirteenth year of our publication), Aging Cell will undergo some changes that we wish to introduce here to our readership. An important goal of the editors-in-chief has always been to ensure that Aging Cell remains current and relevant to the scientific community at large. With a steady increase in the submission and publication of articles from many countries around the globe, we recognize the importance of maximizing the accessibility and impact of the research published in the journal. To maintain and promote our leading position, the publishers, with the support of the editorial team, and the Anatomical Society, have decided to convert Aging Cell to an author-pays open access model. This change will not only comply with funder mandates, but more importantly, it will allow anyone and everyone around the world with internet access to read all material in Aging Cell, irrespective of field, host institution, location, or mode of internet access. Articles will be published under a Creative Commons license, and authors will be the copyright holders. All other editorial policies, such as those concerning the scope of the journal, the review process, and the length, number, and quality of accepted articles, will remain in place (visit our website, http://www.aging-cell.com/, for additional details). We have also made a number of important changes to the Aging Cell website which we believe will enhance the experience of accessing content in the journal. The new website is more attractive visually and provides constantly updated information on features of interest in the journal as well as the aging field at large. To complement this, the content of Aging Cell and articles of interest in other journals can be followed on Twitter (https://twitter.com/AgingCell). Through an improved website and by keeping pace with social media, Aging Cell aims to develop into an online interaction hub for the aging research community. An important strength of Aging Cell has always been its editorial team and policies, in particular the large and diverse editorial board. This board is comprised of internationally recognized leaders in all the subfields of biogerontology who act as supervising editors, managing the entire review process of assigned papers (including the choice of reviewers and rendering decisions). Hence, papers reviewed by Aging Cell receive personal attention from the top experts in the field. This rigorous process often necessitates extensive revisions and ensures that only the highest quality papers are published in the journal. Many authors have commented on the dramatic improvement of their papers during the review process. The membership of the editorial board is continuously updated, with several new members joining us in 2013 (visit our website, http://www.aging-cell.com/, for additional details). We hope that all of you will share our excitement in these new developments. We would also like to take this opportunity to sincerely thank all the authors, reviewers, editorial board members, and managing editorial team for their hard work and dedication, and for making Aging Cell what it is: the flagship journal of the biology of aging. Above all, we would like to thank our readership – we hope you have found the content of the journal informative as well as important for your research. We welcome any comments or suggestions, and as always, we welcome your best papers.

Chapter 4 – Epigenetics

Abstract: Epigenetics is the study of heritable genome functions that do not depend directly on DNA sequence. Commonly studied epigenetic mechanisms include DNA methylation, histone variants and histone modifications. This chapter will describe the basic mechanisms underlying DNA methylation, histone structure and variants and post translational modifications. A summary of the known effects and disease relationships will be provided and methods of measuring and manipulating these epigenetic marks will be discussed. Finally, a number of epigenetic disorders and emerging therapies will be presented.