Alt Advances in Immunology

1. Auflage 2009
ISBN: 978-0-08-096303-7
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 104, 184 Seiten

Reihe: Advances in Immunology

Advances in Immunology, a long-established and highly respected publication, presents current developments as well as comprehensive reviews in immunology. Articles address the wide range of topics that comprise immunology, including molecular and cellular activation mechanisms, phylogeny and molecular evolution, and clinical modalities. Edited and authored by the foremost scientists in the field, each volume provides up-to-date information and directions for future research. - Contributions from leading authorities and industry experts - Informs and updates on all the latest developments in the field

Autoren/Hrsg.

Alt, Frederick W.

Inhaltsverzeichnis

1;Cover;1
2;Advances in IMMUNOLOGY;4
3;Copyright Page;5
4;Contents;6
5;Contributors;8
6;Chapter 1 Regulation of Gene Expression in Peripheral T Cells by Runx Transcription Factors;10
6.1;1. INTRODUCTION;11
6.2;2. MULTIPLE FACTORS REGULATE TRANSCRIPTION IN EUKARYOTIC ORGANISMS;13
6.3;3. RUNX PROTEINS AS TRANSCRIPTIONAL REGULATORS;14
6.4;4. RUNX PROTEINS REGULATE THYMIC T-CELL DEVELOPMENT;16
6.5;5. RUNX1 AND RUNX3 AT THE Cd4 SILENCER;17
6.6;6. RUNX PROTEINS REGULATE PERIPHERAL CD4+ T-CELL DIFFERENTIATION: THE TH1/TH2 PARADIGM;18
6.7;7. RUNX PROTEINS AND ITREG/TH17 DIFFERENTIATION;22
6.8;8. RUNX PROTEINS AND THE DIFFERENTIATION OF EFFECTOR CD8þ T CELLS;24
6.9;9. CONCLUDING REMARKS-RUNX PROTEINS IN HUMAN DISEASE AND IMMUNITY;26
6.10;ACKNOWLEDGMENTS;27
6.11;REFERENCES;27
7;Chapter 2 Long Noncoding RNAs: Implications for Antigen Receptor Diversification;34
7.1;1. INTRODUCTION;35
7.2;2. NONCODING RNAs;36
7.3;3. ncRNAs AND THE ADAPTIVE IMMUNE SYSTEM;42
7.4;4. PERSPECTIVE;50
7.5;REFERENCES;50
8;Chapter 3 Pathogenic Mechanisms of Allergic Inflammation : Atopic Asthma as a Paradigm;60
8.1;1. INTRODUCTION;62
8.2;2. DEVELOPMENT OF ASTHMA-RELATED PHENOTYPES IN EARLY LIFE;63
8.3;3. DENDRITIC CELLS AND ASTHMA;72
8.4;4. T-REGULATORY (Treg) CELLS;80
8.5;5. INTERACTIONS BETWEEN ANTI-VIRAL AND ATOPIC INFLAMMATORY PATHWAYS: INSIGHT FROM STUDIES ON ACUTE SEVERE ASTHMA EXACERBATIONS IN SCHOOL CHILDREN;88
8.6;6. THE SEARCH FOR NEW ASTHMA DRUG TARGETS WITHIN THE Th2 Cascade;96
8.7;REFERENCES;102
9;Chapter 4 The Amplification Loop of the Complement Pathways;124
9.1;1. THE AMPLIFICATION LOOP: THE C3b FEEDBACK AND BREAKDOWN CYCLES;126
9.2;2. THE EVOLUTIONARY HISTORY OF COMPLEMENT;129
9.3;3. THE ALTERNATIVE PATHWAY: A RATE-GOVERNED REACTION;137
9.4;4. REGULATION OF THE C3B BREAKDOWN CYCLE;141
9.5;5. IMMUNOPATHOLOGY OF THE ALTERNATIVE PATHWAY;144
9.6;ACKNOWLEDGMENTS;151
9.7;REFERENCES;151
10;INDEX;160
11;CONTENTS OF RECENT VOLUMES;172

Leseproben

Regulation of Gene Expression in Peripheral T Cells by Runx Transcription Factors

Ivana M. Djuretic, Fernando Cruz-Guilloty and Anjana Rao

Department of Pathology, Harvard Medical School and Immune Disease Institute and Program in Cellular and Molecular Medicine, Children’s Hospital Boston, Boston, Massachusetts, USA

Members of the Runx family of transcription factors, Runx1-3, are essential regulators of the immune system: a deficiency in one of the members, Runx1, results in complete ablation of hematopoiesis, and all three Runx proteins play important, nonredundant roles in immune system development and function. Here, we review gene regulation by Runx proteins in T lymphocytes, with a focus on their recently emerging roles in the development and function of peripheral CD4+ and CD8+ T lineages.

1. Introduction

The three members of the mammalian family of Runx proteins, Runx1 (also known as AML1/CBF2/PEBP2b), Runx2 (AML3/CBF1/PEBP2a), and Runx3 (AML2/CBF3/PEBP2c), are homologs of Drosophila Runt, share a highly conserved DNA-binding domain called Runt, and play key roles in orchestrating proper gene expression changes during many developmental processes (Lee et al., 2004 and Levanon and Groner, 2004). Runx1 expression is required for definitive hematopoiesis and the emergence of hematopoietic progenitors during mouse development (Chen et al., 2009, Okuda et al., 1996 and Wang et al., 1996). Runx2 is required for osteoblast differentiation from mesenchymal stem cells and proper bone formation (Komori et al., 1997 and Otto et al., 1997). Runx3 expression in dorsal root ganglia proprioceptive neurons is important for their development and in their axon guidance (Inoue et al., 2002 and Levanon et al., 2002). Runx1 and Runx3 also have important roles in the function of the immune system, as discussed below.

The similarity in the structure of the three mammalian Runx genes extends beyond the Runt domain as common features are also found in regions flanking this domain (Fig. 1.1A) (Blyth et al., 2005). Runx3 contains the smallest number of exons, all of which are highly conserved between the three family members, and is therefore considered to be the evolutionary founder of the mammalian Runx family (Fig. 1.1B) (Bangsow et al., 2001). The additional exons in Runx1 and Runx2give rise to a large number of alternatively spliced variants, some of which introduce premature stop codons in the sequence and generate short protein isoforms with distinct biological activities (Levanon et al., 2001). Two promoters, P1 (distal) and P2 (proximal), regulate each of the three genes, resulting in two species with distinct N-terminal regions (Bangsow et al., 2001). In the case of Runx3, P1 and P2 generate p46 and p44 species, respectively, based on their molecular weight in kDa. The biological significance of the various Runx isoforms is not yet fully explored, but it is clear that they offer a complex regulatory potential to this small transcription factor family that can be utilized in different developmental and physiological settings.

Figure 1.1 Functional domains and gene structure of the three mammalian Runx transcription factors. (A) Major domains on the three Runx proteins (Runx1-3) are shown. P1/P2, slightly different N-termini exist for each Runx factor based on the differential promoter (P1 or P2) usage; QA, glutamine/alanine rich region specific to Runx2; AD, activation domain, capable of inducing transcription of heterologous promoters when fused to a DNA-binding domain (Schroeder et al., 2005); ID, inhibitory domain, blocks both DNA bindings which can be relieved by interacting with CBF-? (Kanno et al., 1998); NMTS, nuclear matrix targeting sequence; VWRPY, Groucho/TLE interaction motif. Adapted from Blyth et al. (2005). (B) Genomic structure of the three human Runx gene loci suggests an ancient duplication of this family (neighboring genes are preserved), with Runx3 being the evolutionary founder. Adapted from Levanon and Groner (2004). (C) Transcription factors that interact with Runx2 are listed below their respective interacting domains on Runx2. Adapted from Schroeder et al. (2005).

2. Multiple Factors Regulate Transcription in Eukaryotic Organisms

Although Jacques Monod once famously said “what is true for E. coli is true for an elephant” (Dunn and Kingston, 2007), history has shown that transcriptional regulation in higher eukaryotes is far more complex: it involves fine-tuning of gene activity in the large variety of cell types that make up multicellular organisms, in each case in response to multiple physiological and developmental stimuli. The central players in all organisms are DNA-binding transcription factors which interact with cis-regulatory sequences on DNA, including promoters, enhancers, silencers, and insulators, to orchestrate appropriate gene activation and repression. However, whereas often only one or two regulatory proteins control prokaryotic genes, eukaryotic genes are typically controlled by multiple transcription factors.

In eukaryotes, transcription factors must also interact with chromatin, the DNA-packaging structure that inherently reduces the accessibility of DNA to transcription factors and the RNA polymerase machinery, and thereby constitutes the principal platform for control of gene expression. DNA-binding transcription factors typically lack the enzymatic activities required to modify chromatin structure directly and instead regulate mRNA production by recruiting RNA polymerase or by increasing its processivity on DNA (Narlikar et al., 2002). Additionally, transcription factors modify chromatin and affect transcription indirectly by recruiting chromatin regulatory complexes as well as transcriptional cofactors (coactivators and corepressors). Transcriptional cofactors directly affect chromatin structure by covalently modifying histones or altering the position of the histone octamers around which DNA wraps to form nucleosomes.

One class of chromatin modifiers, the ATP-dependent chromatin remodeling enzymes, is multisubunit complexes that utilize ATP hydrolysis to alter nucleosome positions, thereby rendering nucleosomal DNA sequences on the surface of histone octamers accessible to transcriptional activators (or alternatively, rendering them inaccessible when transcription needs to be repressed) (Narlikar et al., 2002). A second class of chromatin-modifying complexes contains enzymes that covalently modify histones by adding or removing many chemical moieties. The best-studied histone modifications are acetylation, methylation, phosphorylation, and ubiquitination (Li et al., 2007). All of these modifications, with the exception of methylation, result in a change in the net charge of nucleosomes and are postulated to affect chromatin structure directly through loosening of DNA–histone interactions. In addition, because histone modifications can be recognized by other proteins, it has been proposed that individual histone modifications or patterns are read by effector proteins to determine functional outcome (Seet et al., 2006).

Histone acetylation occurs at various lysine residues on histones 3 and 4 and is carried out by complexes containing histone acetyltransferases. Recent genome-wide surveys have confirmed that histone acetylation is unequivocally associated with promoters of transcriptionally active genes and with enhancers (Kim et al., 2005 and Roh et al., 2006). On the other hand, histone methylation, which occurs on both lysines and arginines, can have either activating or repressive effects on gene transcription (Barski et al., 2007 and Berger, 2007). For instance in histone 3 (H3), the most commonly methylated lysine residues are 4, 9, 27, 36, and 79, and their methylation is catalyzed by various histone methyltransferases. Of these, trimethylation of histone 3 at lysine 27 (H3K27me3) and, with some exceptions, at lysine 9 (H3K9me3), is exclusively associated with repressed genes (Barski et al., 2007). The effector proteins of H3K27me3 and H3K9me3 are Polycomb proteins and heterochromatin protein 1, respectively, which mediate the formation of repressive chromatin at the site of their recruitment. The mechanistic details of how these “repressive” histone modifications mediate gene silencing are still unknown, particularly for the H3K27me3 modification and the associated Polycomb-induced gene silencing (Schwartz and Pirrotta, 2007).

How H3K9 and H3K27 methyltransferases get recruited to specific gene targets is even more elusive, as only a handful of interacting proteins have been identified in both cases. An emerging hypothesis is that noncoding RNAs that are differentially expressed in different cell types bind to chromatin-modifying complexes such as Polycomb and guide them to their target genes (Khalil et al., 2009). The most convincing evidence for this idea comes from two recently characterized long noncoding RNAs: HOTAIR and Air RNAs are recruited to Hox loci and an imprinted gene cluster, respectively, and are required for epigenetic silencing of their gene targets by interacting with the repressive chromatin complexes Polycomb and the H3K9 methyl...