Bernhard G Herrmann

Charité Universitätsmedizin Berlin, Berlín, Berlin, Germany

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Publications (83)693.04 Total impact

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    ABSTRACT: During somitogenesis differential gene expression can be observed for so-called cyclic genes, which display expression changes with a periodicity of 120min in the mouse. In screens to identify novel cyclic genes in murine embryos, Fam181b was predicted to be an oscillating gene in the presomitic mesoderm (psm). This gene, and its closely related paralogue Fam181a, belong to the thus far uncharacterized Fam181 gene family. Here we describe the expression of Fam181b and Fam181a during murine embryonic development. In addition, we confirm oscillation of Fam181b in the psm in-phase with targets of, and regulated by, Notch signaling. Fam181b expression in the psm, as well as in the lateral plate mesoderm, was found to be affected by genetic background. We show that Fam181a and b exhibit partially overlapping mRNA expression patterns, and encode for proteins containing highly-conserved motifs, which predominantly localize to the nucleus. A Fam181b loss-of-function model was generated and found to result in no obvious phenotype.
    No preview · Article · Sep 2015 · Gene
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    ABSTRACT: Congenital anomalies of the kidney and urinary tract (CAKUT) account for 40-50 % of chronic kidney disease that manifests in the first two decades of life. Thus far, 31 monogenic causes of isolated CAKUT have been described, explaining ~12 % of cases. To identify additional CAKUT-causing genes, we performed whole-exome sequencing followed by a genetic burden analysis in 26 genetically unsolved families with CAKUT. We identified two heterozygous mutations in SRGAP1 in 2 unrelated families. SRGAP1 is a small GTPase-activating protein in the SLIT2-ROBO2 signaling pathway, which is essential for development of the metanephric kidney. We then examined the pathway-derived candidate gene SLIT2 for mutations in cohort of 749 individuals with CAKUT and we identified 3 unrelated individuals with heterozygous mutations. The clinical phenotypes of individuals with mutations in SLIT2 or SRGAP1 were cystic dysplastic kidneys, unilateral renal agenesis, and duplicated collecting system. We show that SRGAP1 is expressed in early mouse nephrogenic mesenchyme and that it is coexpressed with ROBO2 in SIX2-positive nephron progenitor cells of the cap mesenchyme in developing rat kidney. We demonstrate that the newly identified mutations in SRGAP1 lead to an augmented inhibition of RAC1 in cultured human embryonic kidney cells and that the SLIT2 mutations compromise the ability of the SLIT2 ligand to inhibit cell migration. Thus, we report on two novel candidate genes for causing monogenic isolated CAKUT in humans.
    Full-text · Article · May 2015 · Human Genetics
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    ABSTRACT: The segmental body pattern of vertebrates is established during embryonic development by the process of somitogenesis. Blocks of epithelial cells, the somites, bud off from the anterior tip of the presomitic mesoderm (PSM) in an anterior-to-posterior fashion. The periodicity of somitogenesis is thought to be based on a molecular oscillator, called the segmentation clock, which leads to periodic expression of certain genes in the PSM that correlates with morphological somite formation. Within a screen to identify new genes with such an expression pattern, we identified Fam181b (A). Here we show preliminary results for the analysis of this, as yet uncharacterized, gene.
    Full-text · Conference Paper · Mar 2015
  • Phillip Grote · Bernhard G Herrmann
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    ABSTRACT: A large proportion of the cellular transcriptome of higher vertebrates consists of non-protein coding transcripts, among them the long noncoding RNAs (lncRNAs). Although lncRNAs are functionally extremely divergent, many ncRNAs have been shown to interact with chromatin modifying complexes and/or with transcriptional regulators. Via such interactions, many lncRNAs are involved in controlling the activity and expression level of target genes, including important regulators of embryonic processes, and thereby fine-tune gene regulatory networks controlling cell fate, lineage balance, and organogenesis. Intriguingly, an increase in organ complexity during evolution parallels a rise in lncRNA abundance. The current data suggest that lncRNAs support the generation of cell diversity and organ complexity during embryogenesis, and thereby have promoted the evolution of more complex organisms. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Mar 2015 · Trends in Genetics
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    ABSTRACT: The bladder exstrophy-epispadias complex (BEEC) represents the severe end of the uro-rectal malformation spectrum, and is thought to result from aberrant embryonic morphogenesis of the cloacal membrane and the urorectal septum. The most common form of BEEC is isolated classic bladder exstrophy (CBE). To identify susceptibility loci for CBE, we performed a genome-wide association study (GWAS) of 110 CBE patients and 1,177 controls of European origin. Here, an association was found with a region of approximately 220kb on chromosome 5q11.1. This region harbors the ISL1 (ISL LIM homeobox 1) gene. Multiple markers in this region showed evidence for association with CBE, including 84 markers with genome-wide significance. We then performed a meta-analysis using data from a previous GWAS by our group of 98 CBE patients and 526 controls of European origin. This meta-analysis also implicated the 5q11.1 locus in CBE risk. A total of 138 markers at this locus reached genome-wide significance in the meta-analysis, and the most significant marker (rs9291768) achieved a P value of 2.13 × 10-12. No other locus in the meta-analysis achieved genome-wide significance. We then performed murine expression analyses to follow up this finding. Here, Isl1 expression was detected in the genital region within the critical time frame for human CBE development. Genital regions with Isl1 expression included the peri-cloacal mesenchyme and the urorectal septum. The present study identified the first genome-wide significant locus for CBE at chromosomal region 5q11.1, and provides strong evidence for the hypothesis that ISL1 is the responsible candidate gene in this region.
    Full-text · Article · Mar 2015 · PLoS Genetics
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    ABSTRACT: The mesothelium, the lining of the coelomic cavities, and the urothelium, the inner lining of the urinary drainage system, are highly specialized epithelia that protect the underlying tissues from mechanical stress and seal them from the overlying fluid space. The development of these epithelia from simple precursors and the molecular characteristics of the mature tissues are poorly analyzed. Here, we show that uroplakin 3B (Upk3b), which encodes an integral membrane protein of the tetraspanin superfamily, is specifically expressed both in development as well as under homeostatic conditions in adult mice in the mesothelia of the body cavities, i.e., the epicardium and pericardium, the pleura and the peritoneum, and in the urothelium of the urinary tract. To analyze Upk3b function, we generated a creERT2 knock-in allele by homologous recombination in embryonic stem cells. We show that Upk3bcreERT2 represents a null allele despite the lack of creERT2 expression from the mutated locus. Morphological, histological and molecular analyses of Upk3b-deficient mice did not detect changes in differentiation or integrity of the urothelium and the mesothelia that cover internal organs. Upk3b is coexpressed with the closely related Upk3a gene in the urothelium but not in the mesothelium, leaving the possibility of a functional redundancy between the two genes in the urothelium only.
    Full-text · Article · Nov 2014 · PLoS ONE
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    ABSTRACT: Bladder exstrophy-epispadias complex (BEEC), the severe end of the urorectal malformation spectrum, has a profound impact on continence as well as sexual and renal functions. It is widely accepted that for the majority of cases the genetic basis appears to be multifactorial. Here, we report the first study which utilizes genome-wide association methods to analyze a cohort comprising patients presenting the most common BEEC form, classic bladder exstrophy (CBE), to identify common variation associated with risk for isolated CBE. We employed discovery and follow-up samples comprising 218 cases/865 controls and 78 trios in total, all of European descent. Our discovery sample identified a marker near SALL1, showing genome-wide significant association with CBE. However, analyses performed on follow-up samples did not add further support to these findings. We were also able to identify an association with CBE across our study samples (discovery: P = 8.88 × 10−5; follow-up: P = 0.0025; combined: 1.09 × 10−6) in a highly conserved 32 kb intergenic region containing regulatory elements between WNT3 and WNT9B. Subsequent analyses in mice revealed expression for both genes in the genital region during stages relevant to the development of CBE in humans. Unfortunately, we were not able to replicate the suggestive signal for WNT3 and WNT9B in a sample that was enriched for non-CBE BEEC cases (P = 0.51). Our suggestive findings support the hypothesis that larger samples are warranted to identify association of common variation with CBE.
    Full-text · Article · Oct 2014 · Human Molecular Genetics
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    ABSTRACT: The pathogenesis of complex diseases, such as type 1 diabetes (T1D), derives from interactions between host genetics and environmental factors. Previous studies have suggested that viral infection plays a significant role in initiation of T1D in genetically predisposed individuals. T1D susceptibility loci may therefore be enriched in previously uncharacterized genes functioning in antiviral defense pathways. To identify genes involved in antiviral immunity, we performed an image-based high-throughput genetic screen using short hairpin RNAs (shRNAs) against 161 genes within T1D susceptibility loci. RAW 264.7 cells transduced with shRNAs were infected with GFP-expressing herpes simplex virus type 1 (HSV-1) and fluorescent microscopy was performed to assess the viral infectivity by fluorescence reporter activity. Of the 14 candidates identified with high confidence, two candidates were selected for further investigation, Il27 and Tagap. Administration of recombinant IL-27 during viral infection was found to act synergistically with interferon gamma (IFN-γ) to activate expression of type I IFNs and proinflammatory cytokines, and to enhance the activities of interferon regulatory factor 3 (IRF3). Consistent with a role in antiviral immunity, Tagap-deficient macrophages demonstrated increased viral replication, reduced expression of proinflammatory chemokines and cytokines, and decreased production of IFN-β. Taken together, our unbiased loss-of-function genetic screen identifies genes that play a role in host antiviral immunity and delineates roles for IL-27 and Tagap in the production of antiviral cytokines.
    Full-text · Article · Sep 2014 · PLoS ONE
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    ABSTRACT: Candidaemia is the fourth most common cause of bloodstream infection, with a high mortality rate of up to 40%. Identification of host genetic factors that confer susceptibility to candidaemia may aid in designing adjunctive immunotherapeutic strategies. Here we hypothesize that variation in immune genes may predispose to candidaemia. We analyse 118,989 single-nucleotide polymorphisms (SNPs) across 186 loci known to be associated with immune-mediated diseases in the largest candidaemia cohort to date of 217 patients of European ancestry and a group of 11,920 controls. We validate the significant associations by comparison with a disease-matched control group. We observe significant association between candidaemia and SNPs in the CD58 (P=1.97 × 10-11; odds ratio (OR)=4.68), LCE4A-C1orf68 (P=1.98 × 10-10; OR=4.25) and TAGAP (P=1.84 × 10-8; OR=2.96) loci. Individuals carrying two or more risk alleles have an increased risk for candidaemia of 19.4-fold compared with individuals carrying no risk allele. We identify three novel genetic risk factors for candidaemia, which we subsequently validate for their role in antifungal host defence.
    Full-text · Article · Sep 2014 · Nature Communications
  • P Riemer · A Sreekumar · S Reinke · R Rad · R Schäfer · C Sers · H Bläker · B G Herrmann · M Morkel
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    ABSTRACT: Colon cancer cells frequently carry mutations that activate the β-catenin and mitogen-activated protein kinase (MAPK) signaling cascades. Yet how oncogenic alterations interact to control cellular hierarchies during tumor initiation and progression is largely unknown. We found that oncogenic BRAF modulates gene expression associated with cell differentiation in colon cancer cells. We therefore engineered a mouse with an inducible oncogenic BRAF transgene, and analyzed BRAF effects on cellular hierarchies in the intestinal epithelium in vivo and in primary organotypic culture. We demonstrate that transgenic expression of oncogenic BRAF in the mouse strongly activated MAPK signal transduction, resulted in the rapid development of generalized serrated dysplasia, but unexpectedly also induced depletion of the intestinal stem cell (ISC) pool. Histological and gene expression analyses indicate that ISCs collectively converted to short-lived progenitor cells after BRAF activation. As Wnt/β-catenin signals encourage ISC identity, we asked whether β-catenin activity could counteract oncogenic BRAF. Indeed, we found that intestinal organoids could be partially protected from deleterious oncogenic BRAF effects by Wnt3a or by small-molecule inhibition of GSK3β. Similarly, transgenic expression of stabilized β-catenin in addition to oncogenic BRAF partially prevented loss of stem cells in the mouse intestine. We also used BRAF(V637E) knock-in mice to follow changes in the stem cell pool during serrated tumor progression and found ISC marker expression reduced in serrated hyperplasia forming after BRAF activation, but intensified in progressive dysplastic foci characterized by additional mutations that activate the Wnt/β-catenin pathway. Our study suggests that oncogenic alterations activating the MAPK and Wnt/β-catenin pathways must be consecutively and coordinately selected to assure stem cell maintenance during colon cancer initiation and progression. Notably, loss of stem cell identity upon induction of BRAF/MAPK activity may represent a novel fail-safe mechanism protecting intestinal tissue from oncogene activation.Oncogene advance online publication, 11 August 2014; doi:10.1038/onc.2014.247.
    No preview · Article · Aug 2014 · Oncogene
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    ABSTRACT: Mesoderm formation in the mouse embryo initiates around E6.5 at the primitive streak and continues until the end of axis extension at E12.5. It requires the process of epithelial-to-mesenchymal transition (EMT), wherein cells detach from the epithelium, adopt mesenchymal cell morphology, and gain competence to migrate. It was shown previously that, prior to mesoderm formation, the transcription factor SRF (Serum Response Factor) is essential for the formation of the primitive streak. To elucidate the role of murine Srf in mesoderm formation during axis extension we conditionally inactivated Srf in nascent mesoderm using the T(s)::Cre driver mouse. Defects in mutant embryos became apparent at E8.75 in the heart and in the allantois. From E9.0 onwards body axis elongation was arrested. Using genome-wide expression analysis, combined with SRF occupancy data from ChIP-seq analysis, we identified a set of direct SRF target genes acting in posterior nascent mesoderm which are enriched for transcripts associated with migratory function. We further show that cell migration is impaired in Srf mutant embryos. Thus, the primary role for SRF in the nascent mesoderm during elongation of the embryonic body axis is the activation of a migratory program, which is a prerequisite for axis extension.
    No preview · Article · Aug 2014 · Mechanisms of Development
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    ABSTRACT: Background Classic bladder exstrophy (CBE) is the most common form of the bladder exstrophy and epispadias complex. Previously, we and others have identified four patients with a duplication of 22q11.21 among a total of 96 unrelated CBE patients.Methods Here, we investigated whether this chromosomal aberration was commonly associated with CBE/bladder exstrophy and epispadias complex in an extended case-control sample. Multiplex ligation-dependent probe amplification and microarray-based analysis were used to identify 22q11.21 duplications in 244 unrelated bladder exstrophy and epispadias complex patients (including 217 CBE patients) and 665 healthy controls.ResultsNew duplications of variable size were identified in four CBE patients and one control. Pooling of our previous and present data (eight duplications in 313 CBE patients) yielded a combined odds ratio of 31.86 (95% confidence interval, 4.24–1407.97). Array-based sequence capture and high-throughput targeted re-sequencing established that all breakpoints resided within the low-copy repeats 22A to 22D. Comparison of the eight duplications revealed a 414 kb phenocritical region harboring 12 validated RefSeq genes. Characterization of these 12 candidate genes through whole-mount in situ hybridization of mouse embryos at embryonic day 9.5 suggested that CRKL, THAP7, and LZTR1 are CBE candidate genes.Conclusion Our data suggest that duplication of 22q11.21 increases CBE risk and implicate a phenocritical region in disease formation. Birth Defects Research (Part A), 2014. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Jun 2014 · Birth Defects Research Part A Clinical and Molecular Teratology
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    Martin Werber · Lars Wittler · Bernd Timmermann · Phillip Grote · Bernhard G Herrmann
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    ABSTRACT: Differential gene expression is a prerequisite for the formation of multiple cell types from the fertilized egg during embryogenesis. Understanding the gene regulatory networks controlling cellular differentiation requires the identification of crucial differentially expressed control genes and, ideally, the determination of the complete transcriptomes of each individual cell type. Here, we have analyzed the transcriptomes of six major tissues dissected from mid-gestational (TS12) mouse embryos. Approximately one billion reads derived by RNA-seq analysis provided extended transcript lengths, novel first exons and alternative transcripts of known genes. We have identified 1375 genes showing tissue-specific expression, providing gene signatures for each of the six tissues. In addition, we have identified 1403 novel putative long noncoding RNA gene loci, 439 of which show differential expression. Our analysis provides the first complete transcriptome data for the mouse embryo. It offers a rich data source for the analysis of individual genes and gene regulatory networks controlling mid-gestational development.
    Full-text · Article · May 2014 · Development
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    ABSTRACT: Congenital abnormalities of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease and they are the most frequent cause of end-stage renal disease in children in the US. However, its genetic etiology remains mostly elusive. VACTERL association is a rare disorder that involves congenital abnormalities in multiple organs including the kidney and urinary tract in up to 60% of the cases. By homozygosity mapping and whole-exome resequencing combined with high-throughput mutation analysis by array-based multiplex PCR and next-generation sequencing, we identified recessive mutations in the gene TNF receptor-associated protein 1 (TRAP1) in two families with isolated CAKUT and three families with VACTERL association. TRAP1 is a heat-shock protein 90-related mitochondrial chaperone possibly involved in antiapoptotic and endoplasmic reticulum stress signaling. Trap1 is expressed in renal epithelia of developing mouse kidney E13.5 and in the kidney of adult rats, most prominently in proximal tubules and in thick medullary ascending limbs of Henle's loop. Thus, we identified mutations in TRAP1 as highly likely causing CAKUT or VACTERL association with CAKUT.Kidney International advance online publication, 23 October 2013; doi:10.1038/ki.2013.417.
    Full-text · Article · Oct 2013 · Kidney International
  • Phillip Grote · Bernhard G Herrmann
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    ABSTRACT: Epigenetic control mechanisms determine active and silenced regions of the genome. It is known that the Polycomb Repressive Complex 2 (PRC2) and the Trithorax group/Mixed lineage leukemia (TrxG/Mll) complex are able to set repressive and active histone marks, respectively. Long non-coding RNAs (lncRNAs) can interact with either of these complexes and guide them to regulatory elements, thereby modifying the expression levels of target genes. The lncRNA Fendrr is transiently expressed in lateral mesoderm of mid-gestational mouse embryos and was shown to interact with both PRC2 and TrxG/Mll complexes in vivo. Gene targeting revealed that loss of Fendrr results in impaired differentiation of tissues derived from lateral mesoderm, the heart and the body wall, ultimately leading to embryonic death. Molecular data suggests that Fendrr acts via dsDNA/RNA triplex formation at target regulatory elements, and directly increases PRC2 occupancy at these sites. This, in turn, modifies the ratio of repressive to active marks, adjusting the expression levels of Fendrr target genes in lateral mesoderm. We propose that Fendrr also mediates long-term epigenetic marks to define expression levels of its target genes within the descendants of lateral mesoderm cells. Here we discuss approaches for lncRNA gene knockouts in the mouse, and suggest a model how Fendrr and possibly other lncRNAs act during embryogenesis.
    No preview · Article · Aug 2013 · RNA biology
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    ABSTRACT: The acronym VATER/VACTERL association describes the combination of at least three of the following congenital anomalies: vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). We aimed to identify highly penetrant de novo copy number variations (CNVs) that contribute to VATER/VACTERL association. Array-based molecular karyotyping was performed in a cohort of 41 patients with VATER/VACTERL association and 6 patients with VATER/VACTERL-like phenotype including all of the patients' parents. Three de novo CNVs were identified involving chromosomal regions 1q41, 2q37.3, and 8q24.3 comprising one (SPATA17), two (CAPN10, GPR35), and three (EPPK1, PLEC, PARP10) genes, respectively. Pre-existing data from the literature prompted us to choose GPR35 and EPPK1 for mouse expression studies. Based on these studies, we prioritized GPR35 for sequencing analysis in an extended cohort of 192 patients with VATER/VACTERL association and VATER/VACTERL-like phenotype. Although no disease-causing mutation was identified, our mouse expression studies suggest GPR35 to be involved in the development of the VATER/VACTERL phenotype. Follow-up of GPR35 and the other genes comprising the identified duplications is warranted.European Journal of Human Genetics advance online publication, 3 April 2013; doi:10.1038/ejhg.2013.58.
    Full-text · Article · Apr 2013 · European journal of human genetics: EJHG
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    ABSTRACT: Background: The exstrophy-epispadias complex (BEEC) is a urogenital birth defect of varying severity. The causes of the BEEC are likely to be heterogeneous, with individual environmental or genetic risk factors still being largely unknown. In this study, we aimed to identify de novo causative copy number variations (CNVs) that contribute to the BEEC. Methods: Array-based molecular karyotyping was performed to screen 110 individuals with BEEC. Promising CNVs were tested for de novo occurrence by investigating parental DNAs. Genes located in regions of rearrangements were prioritized through expression analysis in mice to be sequenced in the complete cohort, to identify high-penetrance mutations involving small sequence changes. Results: A de novo 0.9 Mb microduplication involving chromosomal region 19p13.12 was identified in a single patient. This region harbors 20 validated RefSeq genes, and in situ hybridization data showed specific expression of the Wiz gene in regions surrounding the cloaca and the rectum between GD 9.5 and 13.5. Sanger sequencing of the complete cohort did not reveal any pathogenic alterations affecting the coding region of WIZ. Conclusions: The present study suggests chromosomal region 19p13.12 as possibly involved in the development of CBE, but further studies are needed to prove a causal relation. The spatiotemporal expression patterns determined for the genes encompassed suggest a role for Wiz in the development of the phenotype. Our mutation screening, however, could not confirm that WIZ mutations are a frequent cause of CBE, although rare mutations might be detectable in larger patient samples. 19p13.12, microduplication, bladder exstrophy-epispadias complex, array-based molecular karyotyping, in situ hybridization analysis, copy number variations, WIZ gene.
    No preview · Article · Mar 2013 · Birth Defects Research Part A Clinical and Molecular Teratology
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    ABSTRACT: Aberrant CpG methylation is a universal epigenetic trait of cancer cell genomes. However, human cancer samples or cell lines preclude the investigation of epigenetic changes occurring early during tumour development. Here, we have used MeDIP-seq to analyse the DNA methylome of APC(Min) adenoma as a model for intestinal cancer initiation, and we present a list of more than 13,000 recurring differentially methylated regions (DMRs) characterizing intestinal adenoma of the mouse. We show that Polycomb Repressive Complex (PRC) targets are strongly enriched among hypermethylated DMRs, and several PRC2 components and DNA methyltransferases were up-regulated in adenoma. We further demonstrate by bisulfite pyrosequencing of purified cell populations that the DMR signature arises de novo in adenoma cells rather than by expansion of a pre-existing pattern in intestinal stem cells or undifferentiated crypt cells. We found that epigenetic silencing of tumour suppressors, which occurs frequently in colon cancer, was rare in adenoma. Quite strikingly, we identified a core set of DMRs, which is conserved between mouse adenoma and human colon cancer, thus possibly revealing a global panel of epigenetically modified genes for intestinal tumours. Our data allow a distinction between early conserved epigenetic alterations occurring in intestinal adenoma and late stochastic events promoting colon cancer progression, and may facilitate the selection of more specific clinical epigenetic biomarkers.
    Full-text · Article · Feb 2013 · PLoS Genetics
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    ABSTRACT: The histone-modifying complexes PRC2 and TrxG/MLL play pivotal roles in determining the activation state of genes controlling pluripotency, lineage commitment, and cell differentiation. Long noncoding RNAs (lncRNAs) can bind to either complex, and some have been shown to act as modulators of PRC2 or TrxG/MLL activity. Here we show that the lateral mesoderm-specific lncRNA Fendrr is essential for proper heart and body wall development in the mouse. Embryos lacking Fendrr displayed upregulation of several transcription factors controlling lateral plate or cardiac mesoderm differentiation, accompanied by a drastic reduction in PRC2 occupancy along with decreased H3K27 trimethylation and/or an increase in H3K4 trimethylation at their promoters. Fendrr binds to both the PRC2 and TrxG/MLL complexes, suggesting that it acts as modulator of chromatin signatures that define gene activity. Thus, we identified an lncRNA that plays an essential role in the regulatory networks controlling the fate of lateral mesoderm derivatives.
    Preview · Article · Jan 2013 · Developmental Cell
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    ABSTRACT: Cellular hierarchies and signals that govern stemness and differentiation of intestinal adenoma cells are not well defined. In this study, we used organotypic culture to investigate the impact of β-catenin and BMP signals in cells that form intestinal adenoma in the mouse. We found that activation of β-catenin signaling by loss of APC or transgenic induction of oncogenic mutant β-catenin (Ctnnb1(mut) ) initiates the conversion of untransformed intestinal cells to tumor cells. These tumor cells display cancer stem cell (CSC) traits such as increased expression of the CSC markers Cd133 and Cd44, a high capacity for self-renewal and unlimited proliferative potential. Subsequent inactivation of transgenic Ctnnb1(mut) results in the reversion of tumor cells to normal intestinal stem cells, which immediately reinstall the cellular hierarchy of the normal intestinal epithelium. Our data demonstrate that oncogenic activation of β-catenin signaling initiates the early steps of intestinal cellular transformation in the absence of irreversible genetic or epigenetic changes. Interestingly, we found that tumor cells in culture and in adenoma produce BMP4, which counteracts CSC-like traits by initiating irreversible cellular differentiation and loss of self-renewal capacity. We conclude that the opposition of stemness-maintaining oncogenic β-catenin signals and autocrine differentiating BMP signals within the adenoma cell provides a rationale for the formation of cellular hierarchies in intestinal adenoma and may serve to limit adenoma growth.
    Full-text · Article · Nov 2012 · International Journal of Cancer

Publication Stats

7k Citations
693.04 Total Impact Points

Institutions

  • 2007-2015
    • Charité Universitätsmedizin Berlin
      • Institute of Medical Genetics and Human Genetics
      Berlín, Berlin, Germany
  • 2004-2015
    • Max Planck Institute for Molecular Genetics
      • Department of Developmental Genetics
      Berlín, Berlin, Germany
  • 2010
    • Freie Universität Berlin
      • Department of Biology, Chemistry, and Pharmacy
      Berlín, Berlin, Germany
  • 1991-2003
    • Max Planck Institute for Developmental Biology
      • Department of Biochemistry
      Tübingen, Baden-Württemberg, Germany
  • 2001
    • Max Planck Institute of Molecular Cell Biology and Genetics
      Dresden, Saxony, Germany
  • 1999-2000
    • Max Planck Institute of Immunobiology and Epigenetics
      • Department of Molecular Embryology
      Freiburg, Baden-Württemberg, Germany
  • 1987-1995
    • MRC National Institute for Medical Research
      Londinium, England, United Kingdom
    • Princeton University
      • Department of Molecular Biology
      Princeton, NJ, United States
    • Cold Spring Harbor Laboratory
      コールド・スプリング・ハーバー, New York, United States
  • 1990
    • University of Wisconsin–Madison
      Madison, Wisconsin, United States
  • 1985-1986
    • European Molecular Biology Laboratory
      Heidelburg, Baden-Württemberg, Germany