A5033673376- Gene Regulatory Network Analysis
- Bacterial Genetics and Biotechnology
- Cancer Genomics and Diagnostics
- Single-cell and spatial transcriptomics
- RNA and protein synthesis mechanisms
- Evolution and Genetic Dynamics
- RNA modifications and cancer
- Cell Image Analysis Techniques
- Cancer-related molecular mechanisms research
- Ovarian cancer diagnosis and treatment
- RNA Research and Splicing
- Gene expression and cancer classification
- Epigenetics and DNA Methylation
- Genomics and Chromatin Dynamics
- Health disparities and outcomes
- CRISPR and Genetic Engineering
- Ferroptosis and cancer prognosis
- Molecular Biology Techniques and Applications
- Bioinformatics and Genomic Networks
- Birth, Development, and Health
- Global Health Care Issues
- Cancer-related Molecular Pathways
- Advanced Fluorescence Microscopy Techniques
- Cancer, Lipids, and Metabolism
- Ubiquitin and proteasome pathways
Harvard University
2024-2025
Boston Children's Hospital
2024
University of Helsinki
1999-2024
Tampere University
2009-2019
Signal Processing (United States)
2019
Helsinki Art Museum
2019
Chemotherapy resistance is a critical contributor to cancer mortality and thus an urgent unmet challenge in oncology. To characterize chemotherapy processes high-grade serous ovarian cancer, we prospectively collected tissue samples before after analyzed their transcriptomic profiles at single-cell resolution. After removing patient-specific signals by novel analysis approach, PRIMUS, found consistent increase stress-associated cell state during chemotherapy, which was validated RNA situ...
Ovarian high-grade serous carcinoma (HGSC) is typically diagnosed at an advanced stage, with multiple genetically heterogeneous clones existing in the tumors long before therapeutic intervention. Herein we integrate clonal composition and topology using whole-genome sequencing data from 510 samples of 148 patients HGSC prospective, longitudinal, multiregion DECIDER study. Our results reveal three evolutionary states, which have distinct features genomics, pathways, morphological phenotypes,...
Stochasticity in gene expression affects many cellular processes and is a source of phenotypic diversity between genetically identical individuals. Events elongation, particularly RNA polymerase pausing, are this noise. Since the rate duration pausing sequence-dependent, regulatory mechanism transcriptional dynamics evolvable. The dependency pause propensity on molecules makes response to external stress. Using delayed stochastic model bacterial transcription at single nucleotide level that...
Anduril is an analysis and integration framework that facilitates the design, use, parallelization reproducibility of bioinformatics workflows. has been upgraded to use Scala for pipeline construction, which simplifies software maintenance, design complex pipelines. Additionally, Anduril's repository expanded with multiple components, tutorial pipelines, next-generation sequencing data analysis.Freely available at http://anduril.org.Supplementary are Bioinformatics online.
We present a delayed stochastic model of transcription at the single nucleotide level. The accounts for promoter open complex formation and includes alternative pathways to elongation, namely pausing, arrest, misincorporation editing, pyrophosphorolysis, premature termination. confront dynamics this detailed with single-step multi-delayed measurements expression repressed gene molecule At low rates both models match experiments but, higher two differ significantly, consequences cell-to-cell...
We measured the in vivo production of RNA molecules tagged with MS2d-GFP Escherichia coli, driven by lar promoter, under weak and medium induction. The distributions intervals between consecutive productions RNAs are found to be sub-exponential, process is sub-Poissonian. discuss possible models transcription initiation and, based on our results previous vitro measurements, find that a sequential two-step model at promoter region explains well.
We investigate the hypothesis that, in Escherichia coli, while concentration of RNA polymerases differs different growth conditions, fraction free for transcription remains approximately constant within a certain range these conditions. After establishing this, we apply standard model-fitting procedure to fully characterize vivo kinetics rate-limiting steps initiation Plac/ara-1 promoter from distributions intervals between events cells with polymerase concentrations. find under full...
Transcription kinetics is limited by its initiation steps, which differ between promoters and with intra- extracellular conditions. Regulation of these steps allows tuning both the rate stochasticity RNA production. We used time-lapse, single-RNA microscopy measurements in live Escherichia coli to study how rate-limiting Plac/ara-1 promoter change temperature induction scheme. For this, we compared detailed stochastic models fit empirical data maximum likelihood sense using statistical...
Abstract High-grade serous carcinoma (HGSC) remains the deadliest gynecological cancer, mostly due to widespread metastases in abdominal cavities already at diagnosis. To improve therapy success, understanding metastasis routes and their molecular characteristics is crucial. Herein, we used >400 samples subjected whole-genome bisulfite (WGBS) RNA sequencing from 125 patients with HGSC, enrolled prospective, longitudinal, multi-region, observational DECIDER trial (NCT04846933). These...
Abstract Background In Escherichia coli the mean and cell-to-cell diversity in RNA numbers of different genes vary widely. This is likely due to kinetics transcription initiation, a complex process with multiple rate-limiting steps that affect production. Results We measured vivo production individual molecules under control lar promoter E. . From analysis distributions intervals between events regimes weak medium induction, we find initiation this involves sequential mechanism two main...
Abstract Motivation: Cell division in Escherichia coli is morphologically symmetric. However, as unwanted protein aggregates are segregated to the cell poles and, after divisions, accumulate at older poles, generate asymmetries sister cells’ vitality. Novel single-molecule detection techniques allow observing aging-related processes vivo, over multiple generations, informing on underlying mechanisms. Results: CellAging a tool automatically extract information polar segregation and...
Growing up with one parent is associated economic hardship and health disadvantages, but there limited evidence of its lifetime consequences. We examined whether being born to an unmarried mother socioeconomic position marital history over the lifespan.We analysed data from Helsinki Birth Cohort Study including birth, child welfare clinic school healthcare records people in Helsinki, Finland, between 1934 1944. Using a unique personal identification number, we linked these information on...
A major challenge in analyzing cancer patient transcriptomes is that the tumors are inherently heterogeneous and evolving. We analyzed 214 bulk RNA samples of a longitudinal, prospective ovarian cohort found sample composition changes systematically due to chemotherapy between anatomical sites, preventing direct comparison treatment-naive treated samples.To overcome this, we developed PRISM, latent statistical framework simultaneously extract cell-type-specific whole-transcriptome profiles...
RNA in situ hybridization (RNA-ISH) is a powerful spatial transcriptomics technology to characterize target abundance and localization individual cells. This allows analysis of tumor heterogeneity expression localization, which are not readily obtainable through transcriptomic data analysis. RNA-ISH experiments produce large amounts there need for automated methods. Here we present QuantISH, comprehensive open-source image pipeline that quantifies marker expressions carcinoma, immune,...
Abstract Copy-number alterations (CNAs) are a hallmark of cancer and can regulate cell states via altered gene expression values. Herein, we have developed copy-number impact (CNI) analysis method that quantifies the degree to which value is impacted by CNAs leveraged this at pathway level. Our results show high CNA not necessarily reflected level, our capable detecting genes pathways whose activity strongly influenced CNAs. Furthermore, CNI enables unbiased categorization categories, such...
Summary In E scherichia coli , under optimal conditions, protein aggregates associated with cellular aging are excluded from midcell by the nucleoid. We study functionality of this process sub‐optimal temperatures population and time lapse images individual cells nucleoids within. show that, as temperature decreases, become homogeneously distributed uncorrelated nucleoid size location. present evidence that is due to increased cytoplasm viscosity, which weakens anisotropy in aggregate...
Each patient's cancer consists of multiple cell subpopulations that are inherently heterogeneous and may develop differing phenotypes such as drug sensitivity or resistance. A personalized treatment regimen should therefore target oncoproteins in the populations driving resistance disease progression a given patient to provide maximal therapeutic effect, while avoiding severe co-inhibition non-malignant cells would lead toxic side effects. To address intra- inter-tumoral heterogeneity when...
ABSTRACT Escherichia coli cells employ an asymmetric strategy at division, segregating unwanted substances to older poles, which has been associated with aging in these organisms. The kinetics of this process is still poorly understood. Using the MS2 coat protein fused green fluorescent (GFP) and a reporter construct multiple binding sites, we tracked individual RNA-MS2-GFP complexes E. from time when they were produced. Analyses brightness spots showed that appear midcell region, are...
Little is known about the biological mechanisms that shape distribution of intervals between completion RNA molecules $({T}_{p}^{\text{RNA}})$, and thus transcriptional noise. We characterize numerically analytically how promoter open complex delay $({\ensuremath{\tau}}_{P})$ transcription initiation rate $({k}_{t})$ ${T}_{p}^{\text{RNA}}$. From this, we assess noise mean transcript levels show these can be tuned both independently simultaneously by ${\ensuremath{\tau}}_{P}$ ${k}_{t}$....
Abstract Motivation: Present research on gene expression using live cell imaging and fluorescent proteins or tagged RNA requires accurate automated methods of quantification these molecules from the images. Here, we propose a novel method for classifying pixel intensities spots to numbers. Results: The relies new model intensity distributions RNAs, which estimated parameter values in maximum likelihood sense measurement data, constructed posteriori classifier estimate numbers spots. We...
Single-molecule measurements of live Escherichia coli transcription dynamics suggest that this process ranges from sub- to super-Poissonian, depending on the conditions and promoter. For its accurate quantification, we propose a model accommodates all these settings, statistical methods estimate parameters select relevant components.The new methodology has improved accuracy avoids overestimating rate due finite measurement time, by exploiting unobserved data accounting for effects discrete...
Abstract Motivation : MS2-GFP-tagging of RNA is currently the only method to measure intervals between consecutive transcription events in live cells. For this, new transcripts must be accurately detected from intensity time traces. Results We present a novel for automatically estimating numbers and production temporal data cell fluorescence intensities that reduces uncertainty by exploiting information. also derive robust variant, more resistant outliers caused e.g. RNAs moving out focus....