Biology subjects

Mueller, J.

Publications and source records attributed to Mueller, J..

At least 73 records · Page 4Linked to original sources

bioRxiv2022

Cyclin B3 implements timely vertebrate oocyte arrest for fertilization

To ensure successful offspring ploidy, vertebrate oocytes must halt the cell cycle in meiosis II until sperm entry. Emi2 is essential to keep oocytes arrested until fertilization. Yet, how this arrest is implemented exclusively in meiosis II and not prematurely in meiosis I remained enigmatic. Using mouse and frog oocytes, we show here that cyclin B3, an understudied B- type cyclin, is essential to keep Emi2 levels low in meiosis I. Direct phosphorylation of Emi2 at an evolutionarily highly conserved site by Cdk1/cyclin B3 targets Emi2 for degradation. In contrast, Cdk1/cyclin B1 is inefficient in Emi2 phosphorylation providing a molecular explanation for the requirement of different B-type cyclins for oocyte maturation. Cyclin B3 degradation at exit from meiosis I enables Emi2 accumulation and thus, timely arrest in meiosis II. Our findings illuminate the evolutionarily conserved mechanisms controlling oocyte arrest for fertilization at the correct cell cycle stage, essential for embryo viability.

cell biology↗

bioRxiv2022

Glaucoma and Alzheimer: Neurodegenerative disorders show an adrenergic dysbalance

Glaucoma disease is characterized by an increased intraocular pressure (IOP), glaucomatous alterations of the optic disc and corresponding visual field defects. Even lowering the main risk factor IOP until an individual target level does not prevent this neurodegenerative disorder from proceeding. Several autoimmune mechanisms were discovered, partly showing a functionality. One of these autoimmune phenomena targets the {beta}2 adrenergic receptor ({beta}2-AR; i.e. agonistic autoantibodies; {beta}2-agAAb) and is linked to the elevated IOP and an impaired retinal microcirculation. As neurodegenerative disorder, Alzheimers Disease (AD) is postulated to share a common molecular mechanism with glaucoma. In the present study we investigated autoimmune phenomena targeting the {beta}2-AR in patients with AD. Sera of the patients were analyzed in a rat cardiomyocyte bioassay for the presence of functional autoantibodies against {beta}2-AR. In addition, different species of amyloid beta (A{beta}) monomers were tested (A{beta}1-14, A{beta}10-25, A{beta}10-37 A{beta}1-40, A{beta}1-42, A{beta}28-40, and [Pyr]-A{beta}3-42). Our results demonstrate that none of the short-chain A{beta} (A{beta}1-14, A{beta}10-25, or A{beta}28-40) showed any agonistic or inhibitory effect on {beta}2-AR. Contrary, long-chain [Pyr]-A{beta}3-42, representing a major neurogenic plaque component, exerted an activation that was blocked by the {beta}2-AR antagonist ICI118.551 indicating that the effect was realized via the {beta}2-AR. Moreover, the long chain A{beta}1-40, A{beta}1-42, and A{beta}10-37 yet not the short-chain A{beta} peptides prevented the clenbuterol induced desensitization of the {beta}2-AR. In addition, we identified functional autoantibodies in the sera of AD patients, activating the {beta}2-AR like the {beta}2-agAAb found in patients with glaucoma. As autoimmune mechanisms were reportedly involved in the pathogenesis of glaucoma and Alzheimers Disease, we postulate that overstimulation of the {beta}2-AR pathway can induce an adrenergic overdrive, that may play an important role in the multifactorial interplay of neurodegenerative disorders.

neuroscience↗

bioRxiv2022

Differential UBE2H-CTLH E2-E3 ubiquitylation modules regulate erythroid maturation

The development of haematopoietic stem cells into mature erythrocytes - erythropoiesis - is a controlled process characterized by cellular reorganisation and drastic reshaping of the proteome landscape. Failure of ordered erythropoiesis is associated with anaemias and haematological malignancies. Although the ubiquitin (UB) system is a known crucial post-translational regulator in erythropoiesis, how the erythrocyte is reshaped by the UB system is poorly understood. By measuring the proteomic landscape of in vitro human erythropoiesis models, we found dynamic differential expression of subunits of the CTLH E3 ubiquitin ligase complex that formed distinct maturation stage-dependent assemblies of structurally homologous RANBP9-and RANBP10-CTLH complexes. Moreover, protein abundance of CTLHs cognate E2-conjugating enzyme UBE2H increased during terminal differentiation, which depended on catalytically active CTLH E3 complexes. CRISPR-Cas9 mediated inactivation of all CTLH E3 assemblies by targeting the catalytic subunit MAEA, or UBE2H, triggered spontaneous and accelerated maturation of erythroid progenitor cells including increased heme and haemoglobin synthesis. Thus, the orderly progression of human erythropoiesis is controlled by the assembly of distinct UBE2H-CTLH modules functioning at different developmental stages.

cell biology↗

bioRxiv2022

Machine-learning from Pseudomonas putida transcriptomes reveals its transcriptional regulatory network

Bacterial gene expression is orchestrated by numerous transcription factors (TFs). Elucidating how gene expression is regulated is fundamental to understanding bacterial physiology and engineering it for practical use. In this study, a machine-learning approach was applied to uncover the genome-scale transcriptional regulatory network (TRN) in Pseudomonas putida, an important organism for bioproduction. We performed independent component analysis of a compendium of 321 high-quality gene expression profiles, which were previously published or newly generated in this study. We identified 84 groups of independently modulated genes (iModulons) that explain 75.7% of the total variance in the compendium. With these iModulons, we (i) expand our understanding of the regulatory functions of 39 iModulon associated TFs (e.g., HexR, Zur) by systematic comparison with 1,993 previously reported TF-gene interactions; (ii) outline transcriptional changes after the transition from the exponential growth to stationary phases; (iii) capture group of genes required for utilizing diverse carbon sources and increased stationary response with slower growth rates; (iv) unveil multiple evolutionary strategies of transcriptome reallocation to achieve fast growth rates; and (v) define an osmotic stimulon, which includes the Type VI secretion system, as coordination of multiple iModulon activity changes. Taken together, this study provides the first quantitative genome-scale TRN for P. putida and a basis for a comprehensive understanding of its complex transcriptome changes in a variety of physiological states.

systems biology↗

bioRxiv2021

Partitioning of ribonucleoprotein complexes from the cellular actin cortex

The cell cortex plays a crucial role in cell mechanics, signaling, and development. However, little is known about the influence of the cortical meshwork on the spatial distribution of cytoplasmic biomolecules. Here, we describe a new fluorescence microscopy method to infer the intracellular distribution of labeled biomolecules with sub-resolution accuracy. Unexpectedly, we find that RNA-binding proteins are partially excluded from the cytoplasmic volume adjacent to the plasma membrane that corresponds to the actin cortex. Complementary diffusion measurements of RNA-protein complexes suggest that a rudimentary model based on excluded volume interactions can explain this partitioning effect. Our results suggest the actin cortex meshwork may play a role in regulating the biomolecular content of the volume immediately adjacent to the plasma membrane. TeaserA novel microscopy method reveals exclusion of RNA-protein complexes from the actin cortex due to their large hydrodynamic size.

biophysics↗

bioRxiv2021

The viral vectored vaccine targeting Thymosin β10 controls tumour growth in a murine model of prostate cancer

Direct analysis of MHC-presented antigens by mass spectrometry has been successfully applied for the evaluation of the antigenic landscape of different human tissues and malignancies in the past. In the current study, for the first time this approach has been applied to investigate a murine prostate cancer peptidome for the development of next generation prostate cancer vaccines using the TRansgenic Adenocarcinoma of Mouse Prostate, TRAMP, model. We have performed immunopeptidomic analysis of the normal mouse prostate and mouse prostate adenocarcinoma samples and identified a number of peptides overexpressed on tumour tissue compared to the normal prostate. We selected two of these proteins previously reported to play a role in carcinogenesis, thymosin beta 4 (Thy{beta}4) and thymosin beta 10 (Thy{beta}10), expressed them in the chimpanzee adenovirus (ChAdOx1) and Modified Vaccinia Ankara (MVA) recombinant viral vectors and evaluated these constructs as a candidate prostate cancer vaccine in a murine prostate cancer model. We have found that the vaccine encoding the Thy{beta}10 polypeptide tethered to the MHC class II associated invariant chain, CD74, significantly delayed outgrowth of established tumours in an ectopic TRAMP-C1 mouse model of prostate cancer. The observed tumour-protective efficacy was not associated with Thy{beta}10-specific cellular or antibody responses, suggesting an existence of other mechanisms underlying anti-tumour effect in this model that are yet to be elucidated.

immunology↗

bioRxiv2021

Disentangling effects of climate and land use on biodiversity and ecosystem services - a multi-scale experimental design

O_LIClimate and land-use change are key drivers of environmental degradation in the Anthropocene, but too little is known about their interactive effects on biodiversity and ecosystem services. Long-term data on biodiversity trends are currently lacking. Furthermore, previous ecological studies have rarely considered climate and land use in a joint design, did not achieve variable independence or lost statistical power by not covering the full range of environmental gradients. C_LIO_LIHere, we introduce a multi-scale space-for-time study design to disentangle effects of climate and land use on biodiversity and ecosystem services. The site selection approach coupled extensive GIS-based exploration and correlation heatmaps with a crossed and nested design covering regional, landscape and local scales. Its implementation in Bavaria (Germany) resulted in a set of study plots that maximizes the potential range and independence of environmental variables at different spatial scales. C_LIO_LIStratifying the state of Bavaria into five climate zones and three prevailing land-use types, i.e. near-natural, agriculture and urban, resulted in 60 study regions covering a mean annual temperature gradient of 5.6-9.8 {degrees}C and a spatial extent of 380x360 km. Within these regions, we nested 180 study plots located in contrasting local land-use types, i.e. forests, grasslands, arable land or settlement (local climate gradient 4.5-10 {degrees}C). This approach achieved low correlations between climate and land-use (proportional cover) at the regional and landscape scale with |r [≤]0.33| and |r [≤]0.29|, respectively. Furthermore, using correlation heatmaps for local plot selection reduced potentially confounding relationships between landscape composition and configuration for plots located in forests, arable land and settlements. C_LIO_LIThe suggested design expands upon previous research in covering a significant range of environmental gradients and including a diversity of dominant land-use types at different scales within different climatic contexts. It allows independent assessment of the relative contribution of multi-scale climate and land use on biodiversity and ecosystem services. Understanding potential interdependencies among global change drivers is essential to develop effective restoration and mitigation strategies against biodiversity decline, especially in expectation of future climatic changes. Importantly, this study also provides a baseline for long-term ecological monitoring programs. C_LI

ecology↗

bioRxiv2021

SARS-CoV-2 infection reduces Krüppel-Like Factor 2 in human lung autopsy

Acute respiratory distress syndrome (ARDS) occurred in ~12% of hospitalized COVID-19 patients in a recent New York City cohort. Pulmonary endothelial dysfunction, characterized by increased expression of inflammatory genes and increased monolayer permeability, is a major component of ARDS. Vascular leak results in parenchymal accumulation of leukocytes, protein, and extravascular water, leading to pulmonary edema, ischemia, and activation of coagulation associated with COVID-19. Endothelial inflammation further contributes to uncontrolled cytokine storm in ARDS. We have recently demonstrated that Kruppel-like factor 2 (KLF2), a transcription factor which promotes endothelial quiescence and monolayer integrity, is significantly reduced in experimental models of ARDS. Lung inflammation and high-tidal volume ventilation result in reduced KLF2, leading to pulmonary endothelial dysfunction and acute lung injury. Mechanistically, we found that KLF2 is a potent transcriptional activator of Rap guanine nucleotide exchange factor 3 (RAPGEF3) which orchestrates and maintains vascular integrity. Moreover, KLF2 regulates multiple genome-wide association study (GWAS)-implicated ARDS genes. Whether lung KLF2 is regulated by SARS-CoV-2 infection is unknown. Here we report that endothelial KLF2 is significantly reduced in human lung autopsies from COVID-19 patients, which supports that ARDS due to SARS-CoV-2 is a vascular phenotype possibly attributed to KLF2 down-regulation. We provide additional data demonstrating that KLF2 is down-regulated in SARS-CoV infection in mice.

pathology↗

bioRxiv2020

The secreted hypersensitive response inducing protein 1 from Botrytis cinerea displays non-canonical PAMP-activity

According to their lifestyle, plant pathogens are divided into biotrophic and necrotrophic organisms. While biotrophic pathogens establish a relationship with living host cells, necrotrophic pathogens rapidly kill host cells and feed on the cell debris. To this end, the necrotrophic ascomycete fungus Botrytis cinerea secretes large amounts of phytotoxic proteins and cell wall degrading enzymes. However, the precise role of these proteins during the infection process is unknown. Here we report on the identification and characterization of the previously unknown toxic protein hypersensitive response inducing protein 1 (Hip1), which induces plant cell death. We found the adoption of a folded protein structure to be a prerequisite for Hip1 to exert its necrosis-inducing activity in Nicotiana benthamiana. Localization and the induction of specific plant responses by Hip1 indicate recognition as pathogen-associated molecular pattern at the plant plasma membrane. Our results demonstrate that recognition of Hip1, even in the absence of obvious enzymatic or poreforming activity, induces strong plant defense reactions eventually leading to plant cell death.

plant biology↗

bioRxiv2020

Cellular Protrusions Engage Viral Infection Enhancing EF-C Peptide Nanofibrils

Self-assembling peptide nanofibrils (PNF) have gained increasing attention as versatile molecules in material science and biomedicine. One important application of PNF is to enhance retroviral gene transfer, a technology that has been central to the development of gene therapy. The best-investigated and commercially available PNF is derived from a 12-mer peptide termed EF-C. The mechanism of transduction enhancement depends on the polycationic surface of EF-C PNF, which binds to the negatively charged membranes of viruses and cells thereby overcoming electrostatic repulsion and increasing virion attachment and fusion. Assuming an even distribution of charges at the surfaces of virions and cells would result in an evenly distributed interaction of the virions with the cell surface. However, we here report that PNF do not randomly bind at the cell surface but are actively engaged by cellular protrusions. Chemical suppression of protrusion formation in cell lines and primary CD4+ T cells greatly reduced fibril binding and hence virion binding. Thus, the mechanism of PNF-mediated viral transduction enhancement involves active engagement of virus-loaded fibrils by cellular protrusions.

cell biology↗

bioRxiv2020

Comparative assessment of the effects of bumped kinase inhibitors on early zebrafish embryo development and pregnancy in mice.

Bumped kinase inhibitors (BKIs) are effective against a variety of apicomplexan parasites. Fifteen BKIs with promising in vitro efficacy against Neospora caninum tachyzoites, low cytotoxicity in mammalian cells, and no toxic effects in non-pregnant BALB/c mice, were assessed in pregnant mice. Drugs were emulsified in corn oil and applied by gavage for 5 days. Five BKIs did not affect pregnancy, 5 BKIs exhibited 15-35% of neonatal mortality, and 5 compounds caused strong effects (infertility, abortion, stillbirth and pup mortality). Additionally, the impact of these compounds on zebrafish (Danio rerio) embryo development was assessed by exposing freshly fertilized eggs to 0.2-50M of BKIs and microscopical monitoring of embryo development in a blinded manner during 4 days. We propose an algorithm that includes quantification of malformations and embryo deaths, and established a scoring system that allows to calculate an impact score (Si) that indicates at which concentrations BKIs visibly affect zebrafish embryo development. Comparison of the two models showed that for 9 compounds no clear correlation between Si and pregnancy outcome was visible. However, those 3 BKIs affecting zebrafish embryos only at high concentrations (40M or higher) did not impair mouse pregnancy at all, and those 3 compounds that inhibited zebrafish embryo development already at 0.2M showed detrimental effects in the pregnancy model. Thus, the zebrafish embryo development test has a limited predictive value to foresee pregnancy outcome in BKI-treated mice. We conclude, that maternal health-related factors such as cardiovascular, pharmacokinetic and/or bioavailability properties also contribute to BKI-pregnancy effects.

pathology↗

bioRxiv2020

The Zinc Finger Antiviral Protein restricts SARS-CoV-2

Recent evidence shows that the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is highly sensitive to interferons (IFNs). However, the underlying antiviral effectors remain to be defined. Here, we show that Zinc finger antiviral protein (ZAP) that specifically targets CpG dinucleotides in viral RNA sequences restricts SARS-CoV-2. We demonstrate that ZAP and its cofactors KHNYN and TRIM25 are expressed in human lung cells. Type I, II and III IFNs all strongly inhibited SARS-CoV-2 and further induced ZAP expression. Strikingly, SARS-CoV-2 and its closest relatives from bats show the strongest CpG suppression among all known human and bat coronaviruses, respectively. Nevertheless, knock-down of ZAP significantly increased SARS-CoV-2 production in lung cells, particularly upon treatment with IFN- or IFN-{gamma}. Thus, our results identify ZAP as an effector of the IFN response against SARS-CoV-2, although this pandemic pathogen may be preadapted to the low CpG environment in humans. HighlightsO_LISARS-CoV-2 and its closest bat relatives show strong CpG suppression C_LIO_LIIFN-{beta}, -{gamma} and -{lambda} inhibit SARS-CoV-2 with high efficiency C_LIO_LIZAP restricts SARS-CoV-2 and contributes to the antiviral effect of IFNs C_LI

microbiology↗

bioRxiv2020

Context-dependent functional compensation between Ythdf m6A readers

The N6-methyladenosine (m6A) modification is the most prevalent post-transcriptional mRNA modification, regulating mRNA decay, translation and splicing. It plays a major role during normal development, differentiation, and disease progression. The modification is dynamically regulated by a set of writer, eraser and reader proteins. The YTH-domain family of proteins: Ythdf1, Ythdf2, and Ythdf3, are three homologous m6A binding proteins, which have different cellular functions. However, their sequence similarity and their tendency to bind the same targets suggest that they may have overlapping roles. We systematically knocked out (KO) the Mettl3 writer for each of the Ythdf readers and for the three readers together (triple-KO). We then estimated the effect in-vivo, in mouse gametogenesis and viability, and in-vitro, in mouse embryonic stem cells (mESCs). We show that in gametogenesis, Mettl3-KO severity is increased as the deletion occurs earlier in the process, and Ythdf2 has a dominant role that cannot be compensated by Ythdf1 or Ythdf3, possibly due to differences in readers expression, both in quantity and in spatial location. By knocking out the three readers together and systematically testing offspring genotypes, we have revealed a redundancy in the readers role during early development, a redundancy which is dosage-dependent. Additionally, we show that in mESCs there is compensation between the three readers, since the inability to differentiate and the significant effect on mRNA decay occur only in the triple-KO cells and not in the single KOs. Thus, we suggest a novel model for the Ythdf readers function. There is a dosage-dependent redundancy when all three readers are co-expressed in the same location in the cells.

developmental biology↗

bioRxiv2020

An Algorithm to Build a Multi-genome Reference

1MotivationNew DNA sequencing technologies have enabled the rapid analysis of many thousands of genomes from a single species. At the same time, the conventional approach of mapping sequencing reads against a single reference genome sequence is no longer adequate. However, even where multiple high-quality reference genomes are available, the problem remains how one would integrate results from pairwise analyses. ResultTo overcome the limits imposed by mapping sequence reads against a single reference genome, or serially mapping them against multiple reference genomes, we have developed the MGR method that allows simultaneous comparison against multiple high-quality reference genomes, in order to remove the bias that comes from using only a single-genome reference and to simplify downstream analyses. To this end, we present the MGR algorithm that creates a graph (MGR graph) as a multi-genome reference. To reduce the size and complexity of the multi-genome reference, highly similar orthologous1 and paralogous2 regions are collapsed while more substantial differences are retained. To evaluate the performance of our model, we have developed a genome compression tool, which can be used to estimate the amount of shared information between genomes. Availabilityhttps://github.com/LeilyR/Multi-genome-Reference.git Contactweigel@tue.mpg.de

bioinformatics↗

bioRxiv2020

Loss of Ena/VASP interferes with lamellipodium architecture, motility and integrin-dependent adhesion

Cell migration entails networks and bundles of actin filaments termed lamellipodia and microspikes or filopodia, respectively, as well as focal adhesions, all of which recruit Ena/VASP family members hitherto thought to antagonize efficient cell motility. However, we find these proteins to act as positive regulators of migration in different cell lines. CRISPR/Cas9-mediated loss of Ena/VASP proteins reduced lamellipodial actin assembly and perturbed lamellipodial architecture, as evidenced by changed network geometry as well as reduction of filament length and number that was accompanied by abnormal Arp2/3 complex and heterodimeric capping protein accumulation. Loss of Ena/VASP function also abolished the formation of microspikes normally embedded in lamellipodia, but not of filopodia capable of emanating without lamellipodia. Ena/VASP-deficiency also impaired integrin-mediated adhesion accompanied by reduced traction forces exerted through these structures. Our data thus uncover novel, cellular Ena/VASP functions of these actin polymerases that are fully consistent with their promotion of cell migration.

cell biology↗

bioRxiv2019

Gene-flow from steppe individuals into Cucuteni-Trypillia associated populations indicates long-standing contacts and gradual admixture

The Cucuteni-Trypillia complex (CTC) flourished in eastern Europe for over two millennia (5100 - 2800 BCE) from the end of the Neolithic to the Early Bronze Age. Its vast distribution area encompassed modern-day eastern Romania, Moldova and western/central Ukraine. Due to a lack of existing burials throughout most of this time, only little is known about of the people associated with this complex and their genetic composition. Here, we present genome-wide data generated from the skeletal remains of four females that were excavated from two Late CTC sites in Moldova (3500 - 3100 BCE). All individuals carried a large Neolithic-derived ancestry component and were genetically more closely related to Linear Pottery than to Anatolian farmers. Three of the specimens also showed considerable amounts of steppe-related ancestry, suggesting influx into the CTC gene-pool from people affiliated with, for instance, the Ukraine Mesolithic. The latter scenario is supported by archaeological evidence. Taken together, our results confirm that the steppe component had arrived in eastern Europe farming communities maybe as early as 3500 BCE. In addition, they are in agreement with the hypothesis of ongoing contacts and gradual admixture between incoming steppe and local western populations.

genomics↗

bioRxiv2019

Neolithic genomes reveal a distinct ancient HLA allele pool and population transformation in Europe

The Wartberg culture (WBC, 3,500-2,800 BCE) dates to the Late Neolithic period, a time of important demographic and cultural transformations in western Europe. We perform a genome-wide analysis of 42 individuals who were interred in a WBC collective burial in Niedertiefenbach, Germany (3,300-3,200 cal. BCE). Our results highlight that the Niedertiefenbach population indeed emerged at the beginning of the WBC. This farming community was genetically heterogeneous and carried a surprisingly large hunter-gatherer ancestry component (40%). We detect considerable differences in the human leukocyte antigen gene pool between contemporary Europeans and the Niedertiefenbach individuals whose immune response was primarily geared towards defending viral infections.

evolutionary biology↗

bioRxiv2019

Principles of RNA processing from analysis of enhanced CLIP maps for 150 RNA binding proteins.

A critical step in uncovering rules of RNA processing is to study the in vivo regulatory networks of RNA binding proteins (RBPs). Crosslinking and immunoprecipitation (CLIP) methods enabled mapping RBP targets transcriptome-wide, but methodological differences present challenges to large-scale integrated analysis across datasets. The development of enhanced CLIP (eCLIP) enabled the large-scale mapping of targets for 150 RBPs in K562 and HepG2, creating a unique resource of RBP interactomes profiled with a standardized methodology in the same cell types. Here we describe our analysis of 223 enhanced (eCLIP) datasets characterizing 150 RBPs in K562 and HepG2 cell lines, revealing a range of binding modalities, including highly resolved positioning around splicing signals and mRNA untranslated regions that associate with distinct RBP functions. Quantification of enrichment for repetitive and abundant multi-copy elements reveals 70% of RBPs have enrichment for non-mRNA element classes, enables identification of novel ribosomal RNA processing factors and sites and suggests that association with retrotransposable elements reflects multiple RBP mechanisms of action. Analysis of spliceosomal RBPs indicates that eCLIP resolves AQR association after intronic lariat formation (enabling identification of branch points with single-nucleotide resolution) and provides genome-wide validation for a branch point-based scanning model for 3 splice site recognition. Further, we show that eCLIP peak co-occurrences across RBPs enables the discovery of novel co-interacting RBPs. Finally, we present a protocol for visualization of RBP:RNA complexes in the eCLIP workflow using biotin and standard chemiluminescent visualization reagents, enabling simplified confirmation of ribonucleoprotein enrichment without radioactivity. This work illustrates the value of integrated analysis across eCLIP profiling of RBPs with widely distinct functions to reveal novel RNA biology. Further, our quantification of both mRNA and other element association will enable further research to identify novel roles of RBPs in regulating RNA processing.

genomics↗