Biology subjects

Kaasinen, E.

Publications and source records attributed to Kaasinen, E..

8 recordsLinked to original sources

bioRxiv2026

A phosphorylation switch in PAGE4 drives MED12-mutant fibroid pathogenesis

Recurrent somatic mutations in MED12, found in [~]70% of uterine leiomyomas (ULs), define the dominant molecular subtype of these highly prevalent tumors, yet the downstream effector mechanisms remain poorly understood. Using an integrated multi-omics workflow, encompassing discovery-phase DDA proteomics of matched leiomyoma-myometrium pairs, validation-phase DIA proteomics across genetically stratified cohorts (MED12 p.G44D, RAD51B-HMGA2, IRS4/FH subtypes), phosphoproteomics, immunohistochemistry, and AP-MS interactomics, we identify prostate-associated gene 4 (PAGE4) as a central effector of MED12-mutant UL pathogenesis. PAGE4 emerged as one of the most significantly upregulated proteins in MED12-mutant ULs and harbored the highest-occupancy hyperphosphorylation sites (T51, T85) in the tumor phosphoproteome, a pattern confirmed by immunohistochemistry and orthogonal phosphoproteomics. Kinase-substrate enrichment nominated HIPK2 as the primary upstream kinase, with supporting evidence from the broader CMGC family. Subsequent analysis revealed that phosphorylation acts as a molecular switch, fundamentally restructuring the PAGE4 interactome to favor the Mediator complex and RNA Pol II transcriptional machinery. This rewiring was functionally validated by ChIP-seq and luciferase reporter assays, which demonstrated corresponding shifts in transcription factor occupancy and downstream pathway activity. Collectively, these data establish phospho-PAGE4 as a critical mechanistic node downstream of MED12 mutation, expand PAGE4 biology from prostate cancer to female reproductive tumors, and nominate it as a mechanistic biomarker and candidate therapeutic vulnerability in the most prevalent molecular subtype of uterine leiomyomas.

systems biology↗

bioRxiv2024

Recommendations for Bioinformatics in Clinical Practice

Next Generation Sequencing (NGS) is increasingly used in clinical diagnostics, largely driven by the success and robustness of Whole Genome Sequencing (WGS). Whereas updated guidelines exist for how to interpret and report on variants that are identified from NGS using bioinformatics pipelines, there is a need for standardised bioinformatics practices for diagnostics to ensure clinical consensus, accuracy, reproducibility and comparability of the results. This article presents consensus recommendations developed by 13 clinical bioinformatics units taking part in the Nordic Alliance for Clinical Genomics (NACG), by expert bioinformaticians working in clinical production. The recommendations are based on clinical practice and focus on analysis types, test and validation, standardisation and accreditation, as well as core competencies and technical management required for clinical bioinformatics operations. Key recommendations include adopting the hg38 genome build as the reference and a standard set of recommended analyses, including the use of multiple tools for structural variant (SV) calling and in-house data sets for filtering recurrent calls. Clinical bioinformatics production should operate under the ISO 15189 standard, utilising off-grid clinical-grade high-performance computing systems, standardised file formats, and strict code version control. Containerized software containers or environment management systems are needed to ensure reproducibility. Pipelines should be rigorously documented and tested for accuracy and reproducibility, minimally covering unit, integration, and end-to-end testing. Standard truth sets such as GIAB and SEQC2 for germline and somatic variant calling, respectively, should be supplemented by recall testing of previously validated clinical cases. Data integrity must be verified using file hashing, and sample identity should be checked via sample fingerprinting and genetically inferred identification markers such as sex and relatedness. Finally, clinical bioinformatics teams should encompass diverse skills, including software development, data management, quality assurance, and domain expertise in human genetics. These recommendations provide a consensus framework for standardising bioinformatics practices across clinical WGS applications and can serve as a practical guide to facilities that are new to large-scale sequencing-based diagnostics, or as a reference for those who already run high-volume clinical production using NGS.

bioinformatics↗

bioRxiv2021

Sequence determinants of human gene regulatory elements

DNA determines where and when genes are expressed, but the full set of sequence determinants that control gene expression is not known. To obtain a global and unbiased view of the relative importance of different sequence determinants in gene expression, we measured transcriptional activity of DNA sequences that are in aggregate [~]100 times longer than the human genome in three different cell types. We show that enhancers can be classified to three main types: classical enhancers1, closed chromatin enhancers and chromatin-dependent enhancers, which act via different mechanisms and differ in motif content. Transcription factors (TFs) act generally in an additive manner with weak grammar, with classical enhancers increasing expression from promoters by a mechanism that does not involve specific TF-TF interactions. Few TFs are strongly active in a cell, with most activities similar between cell types. Chromatin-dependent enhancers are enriched in forkhead motifs, whereas classical enhancers contain motifs for TFs with strong transactivator domains such as ETS and bZIP; these motifs are also found at transcription start site (TSS)-proximal positions. However, some TFs, such as NRF1 only activate transcription when placed close to the TSS, and others such as YY1 display positional preference with respect to the TSS. TFs can thus be classified into four non-exclusive subtypes based on their transcriptional activity: chromatin opening, enhancing, promoting and TSS determining factors - consistent with the view that the binding motif is the only atomic unit of gene expression.

genomics↗

bioRxiv2018

Retrotransposon insertions can initiate colorectal cancer and are associated with poor survival

Genomic instability pathways in colorectal cancer (CRC) have been extensively studied, but the role of retrotransposition in colorectal carcinogenesis remains poorly understood. Although retrotransposons are usually repressed, they become active in several human cancers, in particular those of the gastrointestinal tract. Here we characterize retrotransposon insertions in 202 colorectal tumor whole genomes and investigate their associations with molecular and clinical characteristics. We found highly variable retrotransposon activity among tumors and identified recurrent insertions in 15 known cancer genes. In approximately 1% of the cases we identified insertions in APC, likely to be tumor-initiating events. Insertions were positively associated with the CpG island methylator phenotype and the genomic fraction of allelic imbalance. Clinically, high number of insertions was independently associated with poor disease-specific survival.

genomics↗

bioRxiv2018

ESR1, WT1, WNT4, ATM and TERT loci are major contributors to uterine leiomyoma predisposition

Uterine leiomyomas (ULs) are benign tumors that are a major burden to womens health. A genome-wide association study on 5,417 UL cases and 331,791 controls was performed, followed by replication of the genomic risk in two cohorts. Effects of the identified risk alleles were evaluated in view of molecular and clinical features.\n\nFive loci displayed a genome-wide significant association; the previously reported TNRC6B, and four novel loci ESR1 (ER), WT1, WNT4, and ATM. The sixth hit TERT is also a conceivable target. The combined polygenic risk contributed by these loci was associated with MED12 mutation-positive tumors. The findings link genes for uterine development and genetic stability to leiomyomagenesis. While the fundamental role of sex hormones in UL aetiology has been clear, this work reveals a connection to estrogen receptor alpha on genetic level and suggests that determinants of UL growth associated with estrogen exposure have an inherited component.

genomics↗

bioRxiv2017

The interaction landscape between transcription factors and the nucleosome

Nucleosomes cover most of the genome and are thought to be displaced by transcription factors (TFs) in regions that direct gene expression. However, the modes of interaction between TFs and nucleosomal DNA remain largely unknown. Here, we use nucleosome consecutive affinity-purification systematic evolution of ligands by exponential enrichment (NCAP-SELEX) to systematically explore interactions between the nucleosome and 220 TFs representing diverse structural families. Consistently with earlier observations, we find that the vast majority of TFs have less access to nucleosomal DNA than to free DNA. The motifs recovered from TFs bound to nucleosomal and free DNA are generally similar; however, steric hindrance and scaffolding by the nucleosome result in specific positioning and orientation of the motifs. Many TFs preferentially bind close to the end of nucleosomal DNA, or to periodic positions at its solvent-exposed side. TFs often also bind nucleosomal DNA in a particular orientation, because the nucleosome breaks the local rotational symmetry of DNA. Some TFs also specifically interact with DNA located at the dyad position where only one DNA gyre is wound, whereas other TFs prefer sites spanning two DNA gyres and bind specifically to each of them. Our work reveals striking differences in TF binding to free and nucleosomal DNA, and uncovers a rich interaction landscape between the TFs and the nucleosome.

systems biology↗

bioRxiv2017

BasePlayer: Versatile Analysis Software For Large-Scale Genomic Variant Discovery

Next-generation sequencing (NGS) is being routinely applied in life sciences and clinical practice, where the interpretation of the resulting massive data has become a critical challenge. Computational workflows, such as the Broad GATK, have been established to take raw sequencing data and produce processed data for downstream analyses. Consequently, results of these computationally demanding workflows, consisting of e.g. sequence alignment and variant calling, are increasingly being provided for customers by sequencing and bioinformatics facilities. However, downstream variant analysis, whole-genome level in particular, has been lacking a multi-purpose tool, which could take advantage of rapidly growing genomic information and integrate genetic variant, sequence, genomic annotation and regulatory (e.g. ENCODE) data interactively and in a visual fashion. Here we introduce a highly efficient and user-friendly software, BasePlayer (http://baseplayer.fi), for biological discovery in large-scale NGS data. BasePlayer enables tightly integrated comparative variant analysis and visualization of thousands of NGS data samples and millions of variants, with numerous applications in disease, regulatory and population genomics. Although BasePlayer has been designed primarily for whole-genome and exome sequencing data, it is well-suited to various study settings, diseases and organisms by supporting standard and upcoming file formats. BasePlayer transforms an ordinary desktop computer into a large-scale genomic research platform, enabling also a non-technical user to perform complex comparative variant analyses, population frequency filtering and genome level annotations under intuitive, scalable and highly-responsive user interface to facilitate everyday genetic research as well as the search of novel discoveries.

bioinformatics↗

bioRxiv2016

Mice deficient of Myc super-enhancer region reveal a differential control mechanism between normal and pathological growth

The gene desert upstream of the Myc oncogene on chromosome 8q24 contains susceptibility loci for several major forms of human cancer, including cancers of breast, prostate, and colon. The region shows high conservation between human and mouse and contains multiple MYC enhancers that are activated in tumor cells. However, the role of this region in normal development has not been addressed. Here we show that a 538 kb deletion of the entire MYC upstream super-enhancer region in mice results in 50 to 80% decrease in MYC expression in multiple tissues. The mice are viable and show no overt phenotype. However, they are resistant to tumorigenesis, and most normal cells isolated from them grow slowly in culture. Consistently, deletion of the 8q24 super-enhancer region perturbs Myc targets only in cultured cells, but not in vivo. These results reveal that only cells whose Myc activity is increased by serum or oncogenic driver mutations depend on the 8q24 super-enhancer region, and indicate that targeting the activity of this element is a promising strategy of cancer chemoprevention and therapy.

cancer biology↗