Max Planck Institute of Immunobiology

Freiburg, Germany

Max Planck Institute of Immunobiology

Freiburg, Germany

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Sen R.,U.S. National Institute on Aging | Grosschedl R.,Max Planck Institute of Immunobiology
Genes and Development | Year: 2010

Transcriptional enhancers are key determinants of developmentally regulated gene expression. Models of enhancer function must distinguish between analog or digital control of transcription, as well as their requirement to initiate or maintain transcriptional activity of a gene. In light of a recent study by Chong and colleagues (pp. 659-669) providing evidence of a transient requirement of an enhancer associated with the CD4 gene, we discuss possible mechanisms by which transcriptional memory can be propagated in the absence of enhancers.


Feng W.,German Cancer Research Center | Yonezawa M.,Research Institute of Molecular Pathology | Yonezawa M.,Max Planck Institute of Immunobiology | Ye J.,German Cancer Research Center | And 3 more authors.
Nature Structural and Molecular Biology | Year: 2010

Histone lysine methylation is dynamically regulated by lysine methyltransferases and lysine demethylases. Here we show that PHD finger protein 8 (PHF8), a protein containing a PHD finger and a Jumonji C (JmjC) domain, is associated with hypomethylated rRNA genes (rDNA). PHF8 interacts with the RNA polymerase I transcription machinery and with WD repeat-containing protein 5 (WDR5)-containing H3K4 methyltransferase complexes. PHF8 exerts a positive effect on rDNA transcription, with transcriptional activation requiring both the JmjC domain and the PHD finger. PHF8 demethylates H3K9me1/2, and its catalytic activity is stimulated by adjacent H3K4me3. A point mutation within the JmjC domain that is linked to mental retardation with cleft lip and palate (XLMR-CL/P) abolishes demethylase activity and transcriptional activation. Though further work is needed to unravel the contribution of PHF8 activity to mental retardation and cleft lip/palate, our results reveal a functional interplay between H3K4 methylation and H3K9me1/2 demethylation, linking dynamic histone methylation to rDNA transcription and neural disease. © 2010 Nature America, Inc. All rights reserved.


Treiber T.,Max Planck Institute of Immunobiology | Mandel E.M.,Max Planck Institute of Immunobiology | Pott S.,Genome Institute of Singapore | Gyory I.,Max Planck Institute of Immunobiology | And 3 more authors.
Immunity | Year: 2010

The transcription factor early B cell factor-1 (Ebf1) is a key determinant of B lineage specification and differentiation. To gain insight into the molecular basis of Ebf1 function in early-stage B cells, we combined a genome-wide ChIP sequencing analysis with gain- and loss-of-function transcriptome analyses. Among 565 genes that are occupied and transcriptionally regulated by Ebf1, we identified large sets involved in (pre)-B cell receptor and Akt signaling, cell adhesion, and migration. Interestingly, a third of previously described Pax5 targets was found to be occupied by Ebf1. In addition to Ebf1-activated and -repressed genes, we identified targets at which Ebf1 induces chromatin changes that poise the genes for expression at subsequent stages of differentiation. Poised chromatin states on specific targets could also be established by Ebf1 expression in T cells but not in NIH 3T3 cells, suggesting that Ebf1 acts as a " pioneer" factor in a hematopoietic chromatin context. © 2010 Elsevier Inc.


Treiber N.,Max Planck Institute of Immunobiology | Treiber T.,Max Planck Institute of Immunobiology | Zocher G.,University of Tübingen | Grosschedl R.,Max Planck Institute of Immunobiology
Genes and Development | Year: 2010

Early B-cell factor 1 (Ebf1) is a key transcriptional determinant of B-lymphocyte differentiation whose DNA-binding domain has no sequence similarity to other transcription factor families. Here we report the crystal structure of an Ebf1 dimer bound to its palindromic recognition site. The DNA-binding domain adopts a pseudoimmunoglobulin-like fold with novel topology, but is structurally similar to the Rel homology domains of NFAT and NF-κB. Ebf1 contacts the DNA with two loop-based modules and a unique Zn coordination motif whereby each Ebf1 monomer interacts with both palindromic half-sites. This unusual mode of DNA recognition generates an extended contact area that may be crucial for the function of Ebf1 in chromatin. © 2010 by Cold Spring Harbor Laboratory Press.


Fodor B.D.,Max Planck Institute of Immunobiology | Shukeir N.,Max Planck Institute of Immunobiology | Reuter G.,Martin Luther University of Halle Wittenberg | Jenuwein T.,Max Planck Institute of Immunobiology
Annual Review of Cell and Developmental Biology | Year: 2010

Genetic screens in Drosophila have been instrumental in distinguishing approximately 390 loci involved in position effect variegation and heterochromatin stabilization. Most of the identified genes so-called Su(var) and E(var) genes are also conserved in mammals, where more than 50 of their gene products are known to localize to constitutive heterochromatin. From these proteins, approximately 12 core heterochromatin components can be inferred. In addition, there are approximately 30 additional Su(var) and 10 E(var) factors that can, under distinct developmental options, interchange with constitutive heterochromatin and participate in the partitioning of the genome into repressed and active chromatin domains. A significant fraction of the Su(var) and E(var) factors are enzymes that respond to environmental and metabolic signals, thereby allowing both the variation and propagation of epigenetic states to a dynamic chromatin template. Moreover, the misregulation of human SU(VAR) and E(VAR) function can advance cancer and many other human diseases including more complex disorders. As such, mammalian Su(var) and E(var) genes and their products provide a rich source of novel targets for diagnosis of and pharmaceutical intervention in many human diseases. Copyright © 2010 by Annual Reviews. All rights reserved.


Mandel E.M.,Max Planck Institute of Immunobiology | Grosschedl R.,Max Planck Institute of Immunobiology
Current Opinion in Immunology | Year: 2010

Differentiation of B lymphocytes involves the step-wise acquisition of a specialized phenotype that depends on the expression of lineage-specific genes and the repression of genes characteristic of multipotent progenitors and alternate lineages. The early steps of B lineage specification and commitment are, partly, controlled by the well-characterized transcription factors Ikaros, Pu.1, E2A, early B cell factor-1, and Pax5 that act in a complex regulatory network. However, our understanding of B cell differentiation is far from complete. Recent work has shed light on the mechanisms by which transcription factors implement cell type-specific gene expression patterns and epigenetic changes in chromatin that allow for B lineage specification and commitment. © 2010 Elsevier Ltd.


Vogler C.,Max Planck Institute of Immunobiology
PLoS genetics | Year: 2010

The tails of histone proteins are central players for all chromatin-mediated processes. Whereas the N-terminal histone tails have been studied extensively, little is known about the function of the H2A C-terminus. Here, we show that the H2A C-terminal tail plays a pivotal role in regulating chromatin structure and dynamics. We find that cells expressing C-terminally truncated H2A show increased stress sensitivity. Moreover, both the complete and the partial deletion of the tail result in increased histone exchange kinetics and nucleosome mobility in vivo and in vitro. Importantly, our experiments reveal that the H2A C-terminus is required for efficient nucleosome translocation by ISWI-type chromatin remodelers and acts as a novel recognition module for linker histone H1. Thus, we suggest that the H2A C-terminal tail has a bipartite function: stabilisation of the nucleosomal core particle, as well as mediation of the protein interactions that control chromatin dynamics and conformation.


Stemmler M.P.,Max Planck Institute of Immunobiology | Bedzhov I.,Max Planck Institute of Immunobiology
Developmental Dynamics | Year: 2010

The specific roles of classical cadherins at key morphogenetic events during development are still not fully understood. As part of a project to study cadherin function during early mammalian development, we generated mice carrying an HA-epitope tagged Cdh1 (E-cadherin) cDNA knocked into the Cdh1 locus, similar to the previously described mouse mutants in which we forced Cdh2 (N-cadherin) expression in the Cdh1 expression domain. As expected and in contrast to Cdh1Cdh2/Cdh2 and Cdh1-/-, our Cdh1 HA/HA mutant embryos form proper trophectoderm, implant and undergo both gastrulation and neurulation. However, Cdh1HA/HA mice display an unexpected phenotype at embryonic day 10.5. Cdh1HA/HA embryos are smaller, paler and suffer from an insufficient nutrient supply. We detected a reduced expression of Cdh1HA specifically in the extraembryonic ectoderm and in the labyrinth layer, whereas expression in the embryo proper was normal. With this approach, we show for the first time that Cdh1 is essential for the correct formation of the placenta. Placentas without Cdh1 expression are impaired and incapable of establishing a proper connection between the embryonic and the maternal blood vessels for efficient nutrient and oxygen transport. © 2010 Wiley-Liss, Inc.


Tropberger P.,Max Planck Institute of Immunobiology | Schneider R.,Max Planck Institute of Immunobiology
Epigenetics | Year: 2010

Post-translational modifications (PTM) of histones are key regulators of chromatin function. New mass spectrometrical technologies have revealed that PTMs are not restricted to the histone tails, but can also be found in the globular domains, especially at the DNA-binding surface of the nucleosomes. Recent work on this new group of epigenetic marks showed that these modifications have not only the potential to alter the physical properties of the nucleosome, but may act as signals that regulate the recruitment of effector proteins to chromatin as well. © 2010 Landes Bioscience.


Hierholzer A.,Max Planck Institute of Immunobiology | Kemler R.,Max Planck Institute of Immunobiology
Developmental Dynamics | Year: 2010

β-Catenin plays two major roles during the development of multicellular organisms. It is the downstream effector of the canonical Wnt signaling cascade, which is involved in many developmental processes and in tumor formation. Additionally, it is linked to classic cadherins and is required for the correct assembly and function of adherens junctions. β-Catenin loss of function mutants show early gastrulation lethality. To address the role of β-catenin in postgastrulation stages and to overcome the early embryonic lethality, we performed conditional gene targeting, using Cdx1::Cre, a newly established mouse line. By this approach, β-catenin was depleted in the entire posterior embryo after the gastrulation process at embryonic day 8.0, when the three germ layers were established. We observed defects in signaling and adhesion which are temporarily separated. At an early event, known targets of Wnt/β-catenin are down-regulated in the paraxial mesoderm. Moreover, Fgf8 and Wnt3a, the key players of the segmentation process, are down-regulated in the neural ectoderm (NE). Wnt3a expression was rescued in mutant embryos by exogenous Fgf and inhibition of Fgf signaling in wild-type embryos resulted in Wnt3a down-regulation. Based on these results, we assume the existence of an autoregulatory feedback loop in the NE where Fgf8 regulates Wnt3a, which in turn, by means of β-catenin, maintains Fgf8 expression. In later stages, the lack of β-catenin caused a progressive posterior disintegration. We found that β-catenin is required for the correct localization of N-cadherin at the membrane of neural ectodermal cells and that its absence causes a disintegration of the neural tube. © 2009 Wiley-Liss, Inc.

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