| 1. |
- Toskas, Konstantinos, et al.
(author)
-
PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons
- 2022
-
In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 8:34
-
Journal article (peer-reviewed)abstract
- How neurons can maintain cellular identity over an entire life span remains largely unknown. Here, we show that maintenance of identity in differentiated dopaminergic and serotonergic neurons is critically reliant on the Polycomb repressive complex 2 (PRC2). Deletion of the obligate PRC2 component, Eed, in these neurons resulted in global loss of H3K27me3, followed by a gradual activation of genes harboring both H3K27me3 and H3K9me3 modifications. Notably, H3K9me3 was lost at these PRC2 targets before gene activation. Neuronal survival was not compromised; instead, there was a reduction in subtype-specific gene expression and a progressive impairment of dopaminergic and serotonergic neuronal function, leading to behavioral deficits characteristic of Parkinson's disease and anxiety. Single-cell analysis revealed subtype-specific vulnerability to loss of PRC2 repression in dopamine neurons of the substantia nigra. Our study reveals that a PRC2-dependent nonpermissive chromatin state is essential to maintain the subtype identity and function of dopaminergic and serotonergic neurons.
|
|
| 2. |
- Mazzurana, Luca, et al.
(author)
-
Tissue-specific transcriptional imprinting and heterogeneity in human innate lymphoid cells revealed by full-length single-cell RNA-sequencing
- 2021
-
In: Cell Research. - : Springer Science and Business Media LLC. - 1748-7838 .- 1001-0602. ; 31:5, s. 554-568
-
Journal article (peer-reviewed)abstract
- The impact of the microenvironment on innate lymphoid cell (ILC)-mediated immunity in humans remains largely unknown. Here we used full-length Smart-seq2 single-cell RNA-sequencing to unravel tissue-specific transcriptional profiles and heterogeneity of CD127+ ILCs across four human tissues. Correlation analysis identified gene modules characterizing the migratory properties of tonsil and blood ILCs, and signatures of tissue-residency, activation and modified metabolism in colon and lung ILCs. Trajectory analysis revealed potential differentiation pathways from circulating and tissue-resident naïve ILCs to a spectrum of mature ILC subsets. In the lung we identified both CRTH2+ and CRTH2− ILC2 with lung-specific signatures, which could be recapitulated by alarmin-exposure of circulating ILC2. Finally, we describe unique TCR-V(D)J-rearrangement patterns of blood ILC1-like cells, revealing a subset of potentially immature ILCs with TCR-δ rearrangement. Our study provides a useful resource for in-depth understanding of ILC-mediated immunity in humans, with implications for disease.
|
|
| 3. |
- Ohlsson, Mattias, et al.
(author)
-
A novel approach to structure alignment
- 2000
-
Reports (other academic/artistic)abstract
- A novel approach for structure alignment is presented, where the key ingredients are: (1) An error function formulation of the problem simultaneously in terms of binary (Potts) assignment variables and real-valued atomic coordinates. (2) Minimization of the error function by an iterative method, where in each iteration a mean field method is employed for the assignment variables and exact rotation/translation of atomic coordinates is performed, weighted with the corresponding assignment variables. The approach allows for extensive search of all possible alignments, including those involving arbitrary permutations. The algorithm is implemented using a C_alpha representation of the backbone and explored on different protein structure categories using the Protein Data Bank (PDB) and is successfully compared with other algorithms. The approach performs very well with modest CPU consumption and is robust with respect to choice of parameters. It is extremely generic and flexible and can handle additional user-prescribed constraints easily. Furthermore, it allows for a probabilistic interpretation of the results.
|
|
| 4. |
- Johansson, Peter, et al.
(author)
-
SPECLUST: a web tool for clustering of mass spectra
- 2007
-
Reports (other academic/artistic)abstract
- SPECLUST is a web tool for hierarchical clustering of peptide mass spectra obtained from protease-digested proteins. Mass spectra are clustered according to the peptide masses they contain, such that mass spectra containing similar masses are clustered together. Hierarchical clustering of mass spectra with SPECLUST can in particular be useful for MS-screening of large proteomic data sets derived from 2D-gels. SPECLUST can also be used to identify masses shared by mass spectra. Masses present in the majority of the mass spectra in a data set are likely to be contaminants. With SPECLUST, MS/MS can be focused on non-contaminant shared masses in a cluster, facilitating investigations of protein isoforms. Within a cluster, shared and unique masses represent peptides from regions that are similar and different, respectively, between protein isoforms. Taken together, SPECLUST is a versatile tool for analysis of mass spectrometry data. Availability: SPECLUST is freely available at http://bioinfo.thep.lu.se/speclust.html.
|
|
| 5. |
- Autio, Reija, et al.
(author)
-
A method for finding putative causes of gene expression variation
- 2004
-
In: 2nd TICSP Workshop on Computational Systems Biology, WCSB 2004 : Silja Opera, Helsinki-St. Petersburg, June 14 - 16, 2004 - Silja Opera, Helsinki-St. Petersburg, June 14 - 16, 2004. - 1456-2774. - 9521512040 ; 24, s. 29-30
-
Conference paper (other academic/artistic)abstract
- The majority of microarray studies evaluate gene ex- pression differences between various specimens or con- ditions. However, the causes of this variability often re- main unknown. Our aim is to identify underlying causes of these patterns, a process that would eventually enable a mechanistic understanding of the deregulation of gene expression in cancer. The procedure consists of three phases: pre-processing, data integration and statistical analysis. We have applied the strategy to identify genes that are overexpressed due to amplification in breast cancer. The data were obtained from 14 breast cancer cell lines, which were subjected to cDNA microarray based copy number and expression experiments. The re- sult of the analysis was a list that consisted of 92 genes. This set includes several genes that are known to be both overexpressed and amplified in breast cancer. The com- plete study was published in Journal of the Franklin In- stitute 2004, and in this paper we focus on the main issues of the study.
|
|
| 6. |
- Calabrese, Claudia, et al.
(author)
-
Genomic basis for RNA alterations in cancer
- 2020
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 578:7793, s. 129-136
-
Journal article (peer-reviewed)abstract
- Transcript alterations often result from somatic changes in cancer genomes1. Various forms of RNA alterations have been described in cancer, including overexpression2, altered splicing3 and gene fusions4; however, it is difficult to attribute these to underlying genomic changes owing to heterogeneity among patients and tumour types, and the relatively small cohorts of patients for whom samples have been analysed by both transcriptome and whole-genome sequencing. Here we present, to our knowledge, the most comprehensive catalogue of cancer-associated gene alterations to date, obtained by characterizing tumour transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)5. Using matched whole-genome sequencing data, we associated several categories of RNA alterations with germline and somatic DNA alterations, and identified probable genetic mechanisms. Somatic copy-number alterations were the major drivers of variations in total gene and allele-specific expression. We identified 649 associations of somatic single-nucleotide variants with gene expression in cis, of which 68.4% involved associations with flanking non-coding regions of the gene. We found 1,900 splicing alterations associated with somatic mutations, including the formation of exons within introns in proximity to Alu elements. In addition, 82% of gene fusions were associated with structural variants, including 75 of a new class, termed 'bridged' fusions, in which a third genomic location bridges two genes. We observed transcriptomic alteration signatures that differ between cancer types and have associations with variations in DNA mutational signatures. This compendium of RNA alterations in the genomic context provides a rich resource for identifying genes and mechanisms that are functionally implicated in cancer.
|
|
| 7. |
- Filograna, Roberta, et al.
(author)
-
PARKIN is not required to sustain OXPHOS function in adult mammalian tissues
- 2024
-
In: npj Parkinson's Disease. - : Springer Nature. - 2373-8057. ; 10:1
-
Journal article (peer-reviewed)abstract
- Loss-of-function variants in the PRKN gene encoding the ubiquitin E3 ligase PARKIN cause autosomal recessive early-onset Parkinson’s disease (PD). Extensive in vitro and in vivo studies have reported that PARKIN is involved in multiple pathways of mitochondrial quality control, including mitochondrial degradation and biogenesis. However, these findings are surrounded by substantial controversy due to conflicting experimental data. In addition, the existing PARKIN-deficient mouse models have failed to faithfully recapitulate PD phenotypes. Therefore, we have investigated the mitochondrial role of PARKIN during ageing and in response to stress by employing a series of conditional Parkin knockout mice. We report that PARKIN loss does not affect oxidative phosphorylation (OXPHOS) capacity and mitochondrial DNA (mtDNA) levels in the brain, heart, and skeletal muscle of aged mice. We also demonstrate that PARKIN deficiency does not exacerbate the brain defects and the pro-inflammatory phenotype observed in mice carrying high levels of mtDNA mutations. To rule out compensatory mechanisms activated during embryonic development of Parkin-deficient mice, we generated a mouse model where loss of PARKIN was induced in adult dopaminergic (DA) neurons. Surprisingly, also these mice did not show motor impairment or neurodegeneration, and no major transcriptional changes were found in isolated midbrain DA neurons. Finally, we report a patient with compound heterozygous PRKN pathogenic variants that lacks PARKIN and has developed PD. The PARKIN deficiency did not impair OXPHOS activities or induce mitochondrial pathology in skeletal muscle from the patient. Altogether, our results argue that PARKIN is dispensable for OXPHOS function in adult mammalian tissues.
|
|
| 8. |
- Hautaniemi, S, et al.
(author)
-
A strategy for identifying putative causes of gene expression variation in human cancers
- 2004
-
In: Journal of the Franklin Institute. - : Elsevier BV. - 0016-0032. ; 341:1-2, s. 77-88
-
Journal article (peer-reviewed)abstract
- The majority of microarray studies focus on analysis of gene expression differences between various specimens or conditions. However, the causes of this variability from one cancer to another, from one sample to another and from one gene to another often remain unknown. In this study, we present a systematic procedure for finding genes whose expression levels are altered due to an intrinsic or extrinsic explanatory phenomenon. The procedure consists of three stages: preprocessing, data integration and statistical analysis. We tested and verified the utility of this approach in a case study, where expression and copy number levels of 13,824 genes were determined in 14 breast cancer cell lines. The procedure resulted in identification of 92 genes whose expression levels could be explained by the variability of gene copy number. This set includes several genes that are known to be both overexpressed and amplified in breast cancer. Thus, these genes may represent an important set of primary, genetically altered genes that drive cancer progression. (C) 2003 The Franklin Institute.
|
|
| 9. |
- Johansson, Peter, et al.
(author)
-
Classification of genomic and proteomic data using support vector machines
- 2007
-
In: Fundamentals of Data Mining in Genomics and Proteomics. - Boston, MA : Springer US. - 9781402072604 - 9781475778090 - 9780306478154 ; , s. 187-202
-
Book chapter (peer-reviewed)abstract
- Supervised learning methods are used when one wants to construct a classifier. To use such a method, one has to know the correct classification of at least some samples, which are used to train the classifier. Once a classifier has been trained it can be used to predict the class of unknown samples. Supervised learning methods have been used numerous times in genomic applications and we will only provide some examples here. Different subtypes of cancers such as leukemia (Golub et al., 1999) and small round blue cell tumors (Khan et al., 2001) have been predicted based on their gene expression profiles obtained with microarrays. Microarray data has also been used in the construction of classifiers for the prediction of outcome of patients, such as whether a breast tumor is likely to give rise to a distant metastasis (van’t Veer et al., 2002) or whether a medulloblastoma patient is likely to have a favorable clinical outcome (Pomeroy et al., 2002). Proteomic patterns in serum have been used to identify ovarian cancer (Petricoin et al., 2002a) and prostate cancer (Adam et al., 2002); (Petricoin et al., 2002b).
|
|
| 10. |
- Khan, Javed
(creator_code:cre_t)
-
Methods for analyzing high dimensional data for classifying, diagnosing, prognosticating, and/or predicting diseases and other biological states
- 2013
-
Patent (other academic/artistic)abstract
- A method of diagnosing, predicting, or prognosticating about a disease that includes obtaining experimental data, wherein the experimental data is high dimensional data, filtering the data, reducing the dimensionality of the data through use of one or more methods, training a supervised pattern recognition method, ranking individual data points from the data, wherein the ranking is dependent on the outcome of the supervised pattern recognition method, choosing multiple data points from the data, wherein the choice is based on the relative ranking of the individual data points, and using the multiple data points to determine if an unknown set of experimental data indicates a diseased condition, a predilection for a diseased condition, or a prognosis about a diseased condition.
|
|
