Publications

@article{nokey,

title = {Comprehensive transcriptome analysis reveals altered mRNA splicing and post-transcriptional changes in the aged mouse brain},

author = {Nisha Hemandhar Kumar and Verena Kluever and Emanuel Barth and Sebastian Krautwurst and Mattia Furlan and Mattia Pelizzola and Manja Marz and Eugenio F Fornasiero},

doi = {10.1093/nar/gkae172},

year  = {2024},

date = {2024-04-12},

urldate = {2024-04-12},

journal = {Nucleic Acids Research},

volume = {52},

abstract = {A comprehensive understanding of molecular changes during brain aging is essential to mitigate cognitive decline and delay neurodegenerative diseases. The interpretation of mRNA alterations during brain aging is influenced by the health and age of the animal cohorts studied. Here, we carefully consider these factors and provide an in-depth investigation of mRNA splicing and dynamics in the aging mouse brain, combining short- and long-read sequencing technologies with extensive bioinformatic analyses. Our findings encompass a spectrum of age-related changes, including differences in isoform usage, decreased mRNA dynamics and a module showing increased expression of neuronal genes. Notably, our results indicate a reduced abundance of mRNA isoforms leading to nonsense-mediated RNA decay and suggest a regulatory role for RNA-binding proteins, indicating that their regulation may be altered leading to the reshaping of the aged brain transcriptome. Collectively, our study highlights the importance of studying mRNA splicing events during brain aging.},

keywords = {differential expression analysis, RNA / transcriptomics, splicing},

pubstate = {published},

tppubtype = {article}

}

@article{Jordan-Paiz:20,

title = {HIV-1 lethality and loss of Env protein expression induced by single synonymous substitutions in the virus genome intronic splicing silencer},

author = {Ana Jordan-Paiz and Maria Nevot and Kevin Lamkiewicz and Marie Lataretu and Sandra Franco and Manja Marz and Miguel Angel Martinez},

doi = {10.1128/jvi.01108-20},

year  = {2020},

date = {2020-10-14},

urldate = {2020-01-01},

journal = {J Virol},

volume = {94},

number = {21},

publisher = {American Society for Microbiology},

abstract = {Synonymous genome recoding has been widely used to study different aspects of virus biology. Codon usage affects the temporal regulation of viral gene expression. In this study, we performed synonymous codon mutagenesis to investigate whether codon usage affected HIV-1 Env protein expression and virus viability. We replaced the codons AGG, GAG, CCU, ACU, CUC, and GGG of the HIV-1 env gene with the synonymous codons CGU, GAA, CCG, ACG, UUA, and GGA, respectively. We found that recoding the Env protein gp120 coding region (excluding the Rev response element [RRE]) did not significantly affect virus replication capacity, even though we introduced 15 new CpG dinucleotides. In contrast, changing a single codon (AGG to CGU) located in the gp41 coding region (HXB2 env position 2125 to 2127), which was included in the intronic splicing silencer (ISS), completely abolished virus replication and Env expression. Computational analyses of this mutant revealed a severe disruption in the ISS RNA secondary structure. A variant that restored ISS secondary RNA structure also reestablished Env production and virus viability. Interestingly, this codon variant prevented both virus replication and Env translation in a eukaryotic expression system. These findings suggested that disrupting mRNA splicing was not the only means of inhibiting translation. Our findings indicated that synonymous gp120 recoding was not always deleterious to HIV-1 replication. Importantly¸ we found that disrupting an external ISS loop strongly affected HIV-1 replication and Env translation.

},

keywords = {proteins, RNA structure, splicing, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Sieber:19,

title = {The landscape of the alternatively spliced transcriptome remains stable during aging across different species and tissues},

author = {Patricia Sieber and Emanuel Barth and Manja Marz},

doi = {10.1101/541417},

year  = {2019},

date = {2019-02-05},

urldate = {2019-02-05},

journal = {bioRxiv},

pages = {541417},

publisher = {Cold Spring Harbor Laboratory},

abstract = {Aging is characterized by a decline of cellular homeostasis over time, leading to various severe disorders and death. Alternative splicing is an important regulatory level of gene expression and thus takes on a key role in the maintenance of accurate cell and tissue function. Missplicing of certain genes has already been linked to several age-associated diseases, such as progeria, Alzheimer’s disease, Parkinson’s disease and cancer. Nevertheless, many studies focus only on transcriptional variations of single genes or the expression changes of spliceosomal genes, coding for the proteins that aggregate to the spliceosomal machinery. Little is known on the general change of present and switching isoforms in different tissues over time. In this descriptive RNA-Seq study, we report differences and commonalities of isoform usage during aging among different tissues within one species and compare changes of alternative splicing among different, evolutionarily distinct species. Although we identified a multitude of differntially spliced genes among different time points, we observed little to no general changes in the transcriptomic landscape of the investigated samples. Although there is undoubtedly considerable influence of specifically spliced genes on certain age-associated processes, this work shows that alternative splicing remains stable for the majority of genes with aging.},

keywords = {aging, RNA / transcriptomics, splicing},

pubstate = {published},

tppubtype = {article}

}

@article{Barth:16,

title = {The Evolution of COP9 Signalosome in Unicellular and Multicellular Organisms},

author = {Emanuel Barth and Ron Hübler and Aria Baniahmad and Manja Marz},

doi = {10.1093/gbe/evw073},

year  = {2016},

date = {2016-01-01},

urldate = {2016-01-01},

journal = {Genome Biol Evol},

volume = {8},

number = {4},

pages = {1279--1289},

abstract = {The COP9 signalosome (CSN) is a highly conserved protein complex, recently being crystallized for human. In mammals and plants the COP9 complex consists of nine subunits, CSN 1-8 and CSNAP. The CSN regulates the activity of culling ring E3 ubiquitin and plays central roles in pleiotropy, cell cycle, and defense of pathogens. Despite the interesting and essential functions, a thorough analysis of the CSN subunits in evolutionary comparative perspective is missing. Here we compared 61 eukaryotic genomes including plants, animals, and yeasts genomes and show that the most conserved subunits of eukaryotes among the nine subunits are CSN2 and CSN5. This may indicate a strong evolutionary selection for these two subunits. Despite the strong conservation of the protein sequence, the genomic structures of the intron/exon boundaries indicate no conservation at genomic level. This suggests that the gene structure is exposed to a much less selection compared with the protein sequence. We also show the conservation of important active domains, such as PCI (proteasome lid-CSN-initiation factor) and MPN (MPR1/PAD1 amino-terminal). We identified novel exons and alternative splicing variants for all CSN subunits. This indicates another level of complexity of the CSN. Notably, most COP9-subunits were identified in all multicellular and unicellular eukaryotic organisms analyzed, but not in prokaryotes or archaeas. Thus, genes encoding CSN subunits present in all analyzed eukaryotes indicate the invention of the signalosome at the root of eukaryotes. The identification of alternative splice variants indicates possible "mini-complexes" or COP9 complexes with independent subunits containing potentially novel and not yet identified functions.},

keywords = {bacteria, evolution, fungi, splicing},

pubstate = {published},

tppubtype = {article}

}

@article{Linde:15,

title = {Defining the transcriptomic landscape of \textit{Candida glabrata} by RNA-Seq},

author = {Jörg Linde and Seána Duggan and Michael Weber and Fabian Horn and Patricia Sieber and Daniela Hellwig and Konstantin Riege and Manja Marz and Ronny Martin and Reinhard Guthke and Oliver Kurzai},

doi = {10.1093/nar/gku1357},

year  = {2015},

date = {2015-01-13},

urldate = {2015-01-13},

journal = {Nucleic Acids Res},

volume = {43},

number = {3},

pages = {1392--1406},

abstract = {Candida glabrata is the second most common pathogenic Candida species and has emerged as a leading cause of nosocomial fungal infections. Its reduced susceptibility to antifungal drugs and its close relationship to Saccharomyces cerevisiae make it an interesting research focus. Although its genome sequence was published in 2004, little is known about its transcriptional dynamics. Here, we provide a detailed RNA-Seq-based analysis of the transcriptomic landscape of C. glabrata in nutrient-rich media, as well as under nitrosative stress and during pH shift. Using RNA-Seq data together with state-of-the-art gene prediction tools, we refined the annotation of the C. glabrata genome and predicted 49 novel protein-coding genes. Of these novel genes, 14 have homologs in S. cerevisiae and six are shared with other Candida species. We experimentally validated four novel protein-coding genes of which two are differentially regulated during pH shift and interaction with human neutrophils, indicating a potential role in host-pathogen interaction. Furthermore, we identified 58 novel non-protein-coding genes, 38 new introns and condition-specific alternative splicing. Finally, our data suggest different patterns of adaptation to pH shift and nitrosative stress in C. glabrata, Candida albicans and S. cerevisiae and thus further underline a distinct evolution of virulence in yeast.},

keywords = {annotation, fungi, RNA / transcriptomics, splicing},

pubstate = {published},

tppubtype = {article}

}

@article{Qin:14,

title = {Graph-distance distribution of the Boltzmann ensemble of RNA secondary structures},

author = {Jing Qin and Markus Fricke and Manja Marz and Peter F Stadler and Rolf Backofen},

url = {http://www.rna.uni-jena.de/RNAgraphdist.html},

doi = {10.1186/1748-7188-9-19},

year  = {2014},

date = {2014-09-11},

urldate = {2014-09-11},

journal = {Algorithms Mol Biol},

volume = {9},

pages = {19},

abstract = {Large RNA molecules are often composed of multiple functional domains whose spatial arrangement strongly influences their function. Pre-mRNA splicing, for instance, relies on the spatial proximity of the splice junctions that can be separated by very long introns. Similar effects appear in the processing of RNA virus genomes. Albeit a crude measure, the distribution of spatial distances in thermodynamic equilibrium harbors useful information on the shape of the molecule that in turn can give insights into the interplay of its functional domains. Spatial distance can be approximated by the graph-distance in RNA secondary structure. We show here that the equilibrium distribution of graph-distances between a fixed pair of nucleotides can be computed in polynomial time by means of dynamic programming. While a naïve implementation would yield recursions with a very high time complexity of O(n (6) D (5)) for sequence length n and D distinct distance values, it is possible to reduce this to O(n (4)) for practical applications in which predominantly small distances are of of interest. Further reductions, however, seem to be difficult. Therefore, we introduced sampling approaches that are much easier to implement. They are also theoretically favorable for several real-life applications, in particular since these primarily concern long-range interactions in very large RNA molecules. The graph-distance distribution can be computed using a dynamic programming approach. Although a crude approximation of reality, our initial results indicate that the graph-distance can be related to the smFRET data. The additional file and the software of our paper are available from http://www.rna.uni-jena.de/RNAgraphdist.html.},

keywords = {RNA / transcriptomics, RNA structure, software, splicing, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Schwartze:14,

title = {Gene expansion shapes genome architecture in the human pathogen \textit{Lichtheimia corymbifera}: an evolutionary genomics analysis in the ancient terrestrial mucorales (Mucoromycotina)},

author = {Volker U. Schwartze and Sascha Winter and Ekaterina Shelest and Marina Marcet-Houben and Fabian Horn and Stefanie Wehner and Jörg Linde and Vito Valiante and Michael Sammeth and Konstantin Riege and Minou Nowrousian and Kerstin Kaerger and Ilse D. Jacobsen and Manja Marz and Axel A. Brakhage and Toni Gabaldón and Sebastian Böcker and Kerstin Voigt},

doi = {10.1371/journal.pgen.1004496},

year  = {2014},

date = {2014-08-14},

urldate = {2014-08-14},

journal = {PLos Genet},

volume = {10},

pages = {e1004496},

abstract = {Lichtheimia species are the second most important cause of mucormycosis in Europe. To provide broader insights into the molecular basis of the pathogenicity-associated traits of the basal Mucorales, we report the full genome sequence of L. corymbifera and compared it to the genome of Rhizopus oryzae, the most common cause of mucormycosis worldwide. The genome assembly encompasses 33.6 MB and 12,379 protein-coding genes. This study reveals four major differences of the L. corymbifera genome to R. oryzae: (i) the presence of an highly elevated number of gene duplications which are unlike R. oryzae not due to whole genome duplication (WGD), (ii) despite the relatively high incidence of introns, alternative splicing (AS) is not frequently observed for the generation of paralogs and in response to stress, (iii) the content of repetitive elements is strikingly low (<5%), (iv) L. corymbifera is typically haploid. Novel virulence factors were identified which may be involved in the regulation of the adaptation to iron-limitation, e.g. LCor01340.1 encoding a putative siderophore transporter and LCor00410.1 involved in the siderophore metabolism. Genes encoding the transcription factors LCor08192.1 and LCor01236.1, which are similar to GATA type regulators and to calcineurin regulated CRZ1, respectively, indicating an involvement of the calcineurin pathway in the adaption to iron limitation. Genes encoding MADS-box transcription factors are elevated up to 11 copies compared to the 1-4 copies usually found in other fungi. More findings are: (i) lower content of tRNAs, but unique codons in L. corymbifera, (ii) Over 25% of the proteins are apparently specific for L. corymbifera. (iii) L. corymbifera contains only 2/3 of the proteases (known to be essential virulence factors) in comparison to R. oryzae. On the other hand, the number of secreted proteases, however, is roughly twice as high as in R. oryzae.},

keywords = {ancient DNA, assembly, evolution, fungi, RNA / transcriptomics, splicing},

pubstate = {published},

tppubtype = {article}

}

@article{Marz:10,

title = {Temperature-dependent structural variability of RNAs: spliced leader RNAs and their evolutionary history},

author = {Manja Marz and Nathalie Vanzo and Peter F Stadler},

doi = {10.1142/S0219720010004525},

year  = {2010},

date = {2010-09-14},

urldate = {2010-01-01},

journal = {J Bioinform Comput Biol},

volume = {8},

number = {1},

pages = {1--17},

abstract = {The structures attained by RNA molecules depend not only on their sequence but also on environmental parameters such as their temperature. So far, this effect has been largely neglected in bioinformatics studies. Here, we show that structural comparisons can be facilitated and more coherent structural models can be obtained when differences in environmental parameters are taken into account. We re-evaluate the secondary structures of the spliced leader (SL) RNAs from the seven eukaryotic phyla in which SL RNA trans-splicing has been described. Adjusting structure prediction to the natural growth temperatures and considering energetically similar secondary structures, we observe striking similarities among Euglenida, Kinetoplastida, Dinophyceae, Cnidaria, Rotifera, Nematoda, Platyhelminthes, and Tunicata that cannot be explained easily by the independent innovation of SL RNAs in each of these phyla. Supplementary Table is available at http://www.worldscinet.com/jbcb/.},

keywords = {evolution, RNA structure, splicing},

pubstate = {published},

tppubtype = {article}

}

@article{Jones:09,

title = {A survey of nematode SmY RNAs},

author = {Thomas A Jones and Wolfgang Otto and Manja Marz and Sean R Eddy and Peter F Stadler},

doi = {10.4161/rna.6.1.7634},

year  = {2009},

date = {2009-01-01},

urldate = {2009-01-01},

journal = {RNA Biol},

volume = {6},

pages = {5--8},

abstract = {SmY RNAs are a family of approximately 70-90 nt small nuclear RNAs found in nematodes. In C. elegans, SmY RNAs copurify in a small ribonucleoprotein (snRNP) complex related to the SL1 and SL2 snRNPs that are involved in nematode mRNA trans-splicing. Here we describe a comprehensive computational analysis of SmY RNA homologs found in the currently available genome sequences. We identify homologs in all sequenced nematode genomes in class Chromadorea. We are unable to identify homologs in a more distantly related nematode species, Trichinella spiralis (class: Dorylaimia), and in representatives of non-nematode phyla that use trans-splicing. Using comparative RNA sequence analysis, we infer a conserved consensus SmY RNA secondary structure consisting of two stems flanking a consensus Sm protein binding site. A representative seed alignment of the SmY RNA family, annotated with the inferred consensus secondary structure, has been deposited with the Rfam RNA families database.},

keywords = {alignment, ncRNAs, RNA / transcriptomics, RNA structure, splicing},

pubstate = {published},

tppubtype = {article}

}

@article{Marz:08,

title = {Evolution of spliceosomal snRNA genes in metazoan animals},

author = {Manja Marz and Toralf Kirsten and Peter F Stadler},

doi = {10.1007/s00239-008-9149-6},

year  = {2008},

date = {2008-11-22},

urldate = {2008-11-22},

journal = {J Mol Evol},

volume = {67},

pages = {594--607},

abstract = {While studies of the evolutionary histories of protein families are commonplace, little is known on noncoding RNAs beyond microRNAs and some snoRNAs. Here we investigate in detail the evolutionary history of the nine spliceosomal snRNA families (U1, U2, U4, U5, U6, U11, U12, U4atac, and U6atac) across the completely or partially sequenced genomes of metazoan animals. Representatives of the five major spliceosomal snRNAs were found in all genomes. None of the minor splicesomal snRNAs were detected in nematodes or in the shotgun traces of Oikopleura dioica, while in all other animal genomes at most one of them is missing. Although snRNAs are present in multiple copies in most genomes, distinguishable paralogue groups are not stable over long evolutionary times, although they appear independently in several clades. In general, animal snRNA secondary structures are highly conserved, albeit, in particular, U11 and U12 in insects exhibit dramatic variations. An analysis of genomic context of snRNAs reveals that they behave like mobile elements, exhibiting very little syntenic conservation.},

keywords = {evolution, insects, ncRNAs, RNA structure, splicing},

pubstate = {published},

tppubtype = {article}

}