Biology subjects

Tammimies, K.

Publications and source records attributed to Tammimies, K..

11 recordsLinked to original sources

bioRxiv2026

Transcriptomic-guided compound prioritization and proteomics validation for HNRNPU deficiency identify signalling correction

Heterogeneous nuclear ribonucleoprotein U (HNRNPU) deficiency is a rare genetic cause of neurodevelopmental disorders (NDDs) lacking targeted therapies. Here, we developed a transcriptomic-guided compound prioritization pipeline using Connectivity Map (CMap) analysis on multi-model transcriptomic signatures from HNRNPU-deficient human cells and mouse models. Ten compounds were selected through manual curation and functionally screened in patient-derived HNRNPU-deficient neuroepithelial stem (NES) cells with earlier observed cellular phenotypes. Two of the compounds, AS601245 and Lenalidomide, significantly reduced the elevated neural progenitor population during differentiation, and their combination further decreased primary cilia incidence, indicating partial rescue of the patient-specific cellular phenotypes. To understand the mechanisms underlying the partial rescue, we employed proteome integral solubility alteration (PISA) and expression proteomics. PISA assay identified TMEM150C and GSK3A as proximal targets of combined treatment. Additionally, we observed reversal of multiple biological pathways including downregulation of Wnt signalling and upregulation of mitochondrial pathways and transmembrane proteins. Altogether, we established a computational-experimental pipeline for transcriptomic-guided drug repurposing for a monogenic NDD, and demonstrated that the network-level modulation partially rescues the delayed neural differentiation in HNRNPU-deficient neural cells.

molecular biology↗

bioRxiv2025

Molecular interactome of HNRNPU reveals regulatory networks in neuronal differentiation and DNA methylation

HNRNPU is an RNA-binding protein with diverse roles in transcriptional and post-transcriptional regulation. Pathogenic genetic variants of HNRNPU cause a severe neurodevelopmental disorder (NDD), but the underlying molecular mechanisms are unclear. Here, we comprehensively investigate the HNRNPU molecular interactome by integrating protein-protein interaction (PPI) mapping, RNA target identification, and genome-wide DNA methylation profiling in human neuroepithelial stem cells and differentiating neural cells. We identified extensive HNRNPU-centered networks, including a strong association with the mammalian SWI/SNF chromatin-remodelling complex, and uncovered a previously unrecognized role in translation. We present evidence that HNRNPU associates with mRNAs encoding proteins important for neuronal development, including several linked to NDDs. Silencing HNRNPU reprogrammed methylation dynamics at regulatory regions, particularly at active and bivalent promoters of neurodevelopmental transcription factors. Integrative analysis across PPI, RNA, and methylome datasets identified 19 converging genes at all three molecular levels, including NDD genes within the SWI/SNF complex and RNA-processing machinery such as SYNCRIP. Together, these data showcase HNRNPU as a central coordinator of RNA metabolism and epigenetic remodelling during neural differentiation, linking RNA-binding, chromatin organization, and DNA methylation to the pathogenesis of HNRNPU-related NDDs.

molecular biology↗

bioRxiv2022

Circular RNAs arising from synaptic host genes are modulated by SFPQ RNA-binding protein and increased during human neuronal differentiation

BackgroundCircular RNAs (circRNAs) are emerging as a key component of the complex neural transcriptome implicated in brain development. However, the specific expression patterns and functions of circRNAs in human neuronal differentiation have not been explored. ResultsUsing total RNA sequencing analysis, we identified expressed circRNAs during the differentiation of human neuroepithelial stem (NES) cells into developing neurons and discovered that many circRNAs originated from host genes associated with synaptic function. Interestingly, when assessing population data, exons giving rise to circRNAs in our dataset had a higher frequency of genetic variants. Additionally, screening for RNA-binding protein sites identified enrichment of Splicing Factor Proline and Glutamine Rich (SFPQ) motifs in increased circRNAs, several of which were reduced by SFPQ knockdown and enriched in SFPQ ribonucleoprotein complexes. ConclusionsOur study provides an in-depth characterisation of circRNAs in a human neuronal differentiation model and highlights SFPQ as both a regulator and binding partner of circRNAs elevated during neuronal maturation.

neuroscience↗

bioRxiv2022

Deficiency of Heterogeneous Nuclear Ribonucleoprotein U leads to delayed neurogenesis

Genetic variants affecting Heterogeneous Nuclear Ribonucleoprotein U (HNRNPU) have been identified in several neurodevelopmental disorders (NDDs). HNRNPU is widely expressed in the human brain and shows the highest postnatal expression in the cerebellum. Recent studies have investigated the role of HNRNPU in cerebral cortical development, but the effects of HNRNPU deficiency on cerebellar development remain unknown. Here, we describe the molecular and cellular outcomes of HNRNPU locus deficiency during in vitro neural differentiation of patient-derived and isogenic neuroepithelial stem cells with a hindbrain profile. We demonstrate that HNRNPU deficiency leads to chromatin remodeling of A/B compartments, and transcriptional rewiring, partly by impacting exon inclusion during mRNA processing. Genomic regions affected by the chromatin restructuring and host genes of exon usage differences show a strong enrichment for genes implicated in epilepsies, intellectual disability, and autism. Lastly, we show that at the cellular level. HNRNPU downregulation leads to altered neurogenesis and an increased fraction of neural progenitors in the maturing neuronal population. We conclude that, HNRNPU locus is involved in delayed commitment of neural progenitors to neuronal maturation in cell types with hindbrain profile.

neuroscience↗

bioRxiv2022

Transcriptomic and functional mapping of autism associated environmental factors in developing human neurons

Research continues to identify genetic variation, environmental exposures, and their mixtures underlying different diseases and conditions. There is a need for screening methods to understand the molecular outcomes of such factors. Here, we investigate a highly efficient and multiplexable, fractional factorial experimental design (FFED) to study six environmental factors and four human induced pluripotent stem cell line derived differentiating human neural progenitors. We showcase the FFED coupled with RNA-sequencing to identify the effects of low-grade exposures to these environmental factors and analyse the results in the context of autism spectrum disorder (ASD). We performed this after five-day exposures on differentiating human neural progenitors accompanied by a layered analytical approach and detected several convergent and divergent, gene and pathway level responses. We revealed significant upregulation of pathways related to synaptic function and lipid metabolism following lead and fluoxetine exposure, respectively. The lipid changes were validated using mass spectrometry- based metabolomics after fluoxetine exposure. Our study demonstrates that the FFED can be used for multiplexed transcriptomic analyses to detect relevant pathway-level changes in human neural development caused by low-grade environmental risk factors. Future studies will require multiple cell lines with different genetic backgrounds for characterising the effects of environmental exposures in ASD.

neuroscience↗

bioRxiv2021

Infants' attention to eyes is an independent, heritable trait predicting later verbal competence

From birth, infants orient preferentially to faces, and when looking at the face, they attend primarily to eyes and mouth - two areas that convey different types of information. Here, in a sample of 535 5-month-old infant twins, we assessed eye (relative to mouth) preference in early infancy. Eye preference was independent from all other concurrent traits measured, and had a moderate-to-high contribution from genetic influences (A = .57; 95% CI: .45, .66). Preference for eyes over mouth at 5 months predicted higher parent ratings of verbal competence in toddlerhood, but did not predict autistic traits. These results suggest that variation in eye looking reflects a type of biological niche picking emerging before infants can select their environments by other means (crawling or walking).

developmental biology↗

bioRxiv2021

Babytwins Study Sweden (BATSS): A multi-method infant twin study of genetic and environmental factors influencing infant brain and behavioral development

Twin studies can help us understand the relative contributions of genes and environment to phenotypic trait variation including attentional and brain activation measures. In terms of applying methodologies like electroencephalography (EEG) and eye tracking, which are key methods in developmental neuroscience, infant twin studies are almost non-existent. Here we describe the Babytwins Study Sweden (BATSS), a multi-method longitudinal twin study of 177 MZ and 134 DZ twin pairs (i.e. 622 individual infants) covering the 5 - 36 month time period. The study includes EEG, eye tracking and genetics, together with more traditional measures based on in-person testing, direct observation and questionnaires. The results show that interest in participation in research among twin parents is high, despite the comprehensive protocol. DNA analysis from saliva samples was possible in virtually all participants, allowing for both zygosity confirmation and polygenic score analyses. Combining a longitudinal twin design with advanced technologies in developmental cognitive neuroscience and genomics, BATSS represents a new approach in infancy research, which we hope to have impact across multiple disciplines in the coming years.

neuroscience↗

bioRxiv2019

Presynaptic dysfunction in CASK-related neurodevelopmental disorders

CASK-related disorders are a genetically defined group of neurodevelopmental syndromes. There is limited information about the effects of CASK mutations in human neurons. Therefore, we sought to delineate CASK mutation consequences and neuronal level effects using induced pluripotent stem cell-derived neurons from two mutation carriers; one male diagnosed with ASD and a female with MICPCH. We show a reduction of the CASK protein in maturing neurons from the mutation carriers, which leads to significant downregulation of gene sets involved in presynaptic development and CASK protein interactors. Furthermore, CASK-deficient neurons showed decreased inhibitory presynapse size as indicated by VGAT staining, which may alter the excitatory-inhibitory (E/I) balance in developing neural circuitries. Using in vivo magnetic resonance spectroscopy quantification of GABA in the male mutation carrier, we further highlight the possibility to validate in vitro cellular data in brain. Our data shows that future pharmacological and clinical studies on targeting presynapses and E/I imbalance could lead to specific treatments for CASK-related disorders. HighlightsModelling of CASK-related disorders using iPSC-derived human neuronal cells CASK mutations cause dysregulation of its protein interactor partners Reduced CASK levels primarily affect inhibitory presynapse development In vitro GABAergic phenotype predicts in vivo neurotransmitter levels

genetics↗

bioRxiv2018

Association Between Rare Copy Number Variation and Response to Social Skills Training in Autism Spectrum Disorder

Challenges in social communication and interaction are core symptoms in autism spectrum disorder (ASD) for which social skills group training (SSGT) is a commonly used intervention. SSGT has shown modest but heterogeneous effects in clinical trials, and therefore identification of effect moderators could enable more precise intervention decisions. One of the major genetic risk factors in ASD are rare copy number variation (CNV). However, limited information exists whether rare CNVs profiles can be used to aid in intervention decisions. Therefore, we conducted the first study to date analyzing rare CNVs as genetic moderators in the outcome of SSGT in ASD. For this, we analyzed rare genic CNV carrier status of 207 children of which 105 received SSGT and 102 standard care as part of a recent randomized clinical trial for 12-weeks SSGT. We used mixed linear models to assess the association of being a CNV carrier, grouped by the effect and size of the CNVs and the primary response to SSGT, the parent-report Social Responsiveness Scale (SRS) measured at post-intervention and 3-months follow-up. Additionally, we analyzed the secondary outcome assessments included parent-rated adaptive behaviors (ABAS-II) and trainer-rated clinical global impression (CGI). We show that being a carrier of any size rare genic CNV did not impact on the SSGT outcome. However, when stratifying the groups by size of the CNVs, we identified that carriers of large CNVs (>500 kb) showed inferior SRS outcomes at post-intervention ({beta} = 15.35, 95% CI 2.86-27.84, P=0.017) and follow-up ({beta} = 14.19, 95% CI 1.68-26.70, P=0.028). Similar results were shown for the parent-rated secondary outcome. In contrast, the carriers of small CNVs had better outcome at post-intervention ({beta} = -1.20, 95 % CI - 2.0 - -0.4 P = 0.003) but not at follow-up for the trainer-rated secondary outcome CGI. These results remained when we tested the specificity of the effect by including the standard care group and adjusting for IQ levels. While our study suggests that being a carrier of any size rare genic CNV did not impact the outcome, it provides preliminary evidence that carriers of high-risk CNVs might not benefit on SSGT as much as non-carriers. Our results indicate that genetic information eventually might help guide personalized intervention planning in ASD. We additionally highlight that more research is needed to understand the intervention needs of autistic individuals with specified molecular alterations.

genetics↗

bioRxiv2017

Copy number variation and neurodevelopmental problems in females and males in the general population

ObjectiveNeurodevelopmental problems (NPs) are childhood phenotypes that are more common in males. Conversely, anxiety and depression (which are frequently comorbid with NPs) are more common in females. Rare copy number variants (CNVs) have been implicated in clinically-defined NPs. Here, we aimed to characterise the relationship between rare CNVs with NPs and anxiety/depression in a population sample of twin children. Additionally, we examined whether sex-specific CNV effects underlie the sex bias of these disorders.\n\nMethodWe analysed a sample of N=12,982 children, of whom 5.3% had narrowly-defined NPs (clinically-diagnosed), 20.9% had broadly-defined NPs (based on validated screening measures, but no diagnosis) and 3.0% had clinically-diagnosed anxiety or depression. Rare (<1% frequency) CNVs were categorised by size (medium: 100-500kb or large: >500kb), type (duplication or deletion) and putative relevance to NPs (affecting previously implicated loci or evolutionarily-constrained genes). We tested for associations between the different CNV categories with NPs and anxiety/depression, followed by examination of sex-specific effects.\n\nResultsMedium deletions (OR(CI)=1.18(1.05-1.33),p=0.0053) and large duplications (OR(CI)=1.45(1.19-1.75),p=0.00017) were associated with broadly-defined NPs. Large deletions (OR(CI)=1.85(1.14-3.01),p=0.013) were associated with narrowly-defined NPs. The effect sizes increased for large NP-relevant CNVs (broadly-defined: OR(CI)=1.60(1.06-2.42),p=0.025; narrowly-defined: OR(CI)=3.64(2.16-6.13),p=1.2E-6). No sex differences in CNV burden were found in individuals with NPs (p>0.05). In individuals diagnosed with anxiety or depression, females were more likely to have large CNVs (OR(CI)=3.75(1.45-9.68),p=0.0064).\n\nConclusionRare CNVs are significantly associated with both narrowly- and broadly-defined NPs in a general population sample of children. Our results also suggest that large, rare CNVs may show sex-specific phenotypic effects.

genetics↗

bioRxiv2017

Copy Number Variation Analysis of 100 Twin Pairs Enriched for Neurodevelopmental Disorders

Hundreds of penetrant risk loci have been identified across different neurodevelopmental disorders (NDDs), and these often involve rare (<1% frequency) copy number variations (CNVs), which can involve one or more genes. Monozygotic (MZ) twin pairs are long thought to share 100% of their genomic information. However, genetic differences in the form of postzygotic somatic variants have been reported recently both in typically developing (TD) and in clinically discordant MZ pairs. Here, we sought to investigate the contribution of CNVs in 100 twin pairs enriched for NDD phenotypes with a particular focus on MZ pairs discordant for autism spectrum disorder (ASD) using the PsychChip array. In our collection, no postzygotic de novo CNVs were found in 55 MZ twin pairs, including the 13 pairs discordant for ASD. When analyzing the burden of rare CNVs among pairs concordant and discordant for ASD/NDD in comparison with typically developed (TD) pairs, no differences were found. However, we did detect a higher rate of CNVs overlapping genes involved in disorders of the nervous system in MZ pairs discordant and concordant for ASD in comparison with TD pairs (p=0.02). Our results are in concordance with earlier findings that postzygotic de novo CNV events are typically rare in genomic DNA derived from saliva or blood and, in the majority of MZ twins, do not explain the discordance of NDDs. Still, studies investigating postzygotic variation in MZ discordant twins using DNA from different tissues and single cells and higher resolution genomics are needed in the future.

genetics↗