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A bioinformatics approach to uncover the role of the epigenetic machinery in neurodevelopment
(University of Iceland, School of Health Sciences, Faculty of Medicine, 2025-09-19) okay, kaan; Hans Tómas Björnsson, Kasper Daniel Hansen; Læknadeild (HÍ); Faculty of Medicine (UI); Heilbrigðisvísindasvið (HÍ); School of Health Sciences (UI)
The epigenetic machinery (EM) comprises molecular components, such as enzymes and protein complexes, that place, remove, or read epigenetic marks on histone tails and DNA, or remodel the chromatin, thereby regulating gene accessibility and expression. Pathogenic variants in these EM genes cause the Mendelian Disorders of the Epigenetic Machinery (MDEMs), a group of rare disorders with unifying phenotypes, including intellectual disability (ID) and growth dysregulation. However, the underlying mechanisms behind these overlapping phenotypes have not been extensively studied. One unifying feature is that many of these disorders have distinct DNA methylation (DNAm) abnormalities in blood samples; however, the relevance of this in disease-associated cell types, such as neurons, remains unclear. Furthermore, despite clinical reports of tumor risk in certain MDEMs, the underlying molecular basis of cancer susceptibility in patients with MDEMs is poorly understood. To address these gaps, this thesis pursues three aims: First, identifying functionally important EM domains using large-scale pathogenic missense variant (PMV) enrichment analysis; second, investigating shared DNAm and transcriptional abnormalities across multiple EM gene knockouts (KOs) in hippocampal murine neuronal progenitor cells (mNPCs). Through haplotype-resolved methylation profiling, imprinting control region (ICR) analysis, and gene expression integration, this aim uncovers convergent disruptions underlying MDEM pathogenesis; third, characterizing mutational signatures in hippocampal mNPCs after EM gene disruption to evaluate potential impairments in DNA damage response (DDR). Together, these aims integrate genomic, epigenomic, transcriptomic, and mutational analyses to advance our understanding of EM gene function and its role in the pathogenesis of MDEMs. Chapter I presents a domain-centric analysis of EM genes based on PMV enrichment, identifying functionally important domains and their roles in Rubinstein-Taybi (RSTS) and Menke-Hennekam (MKHK) syndromes. Among 21 EM genes, 71.4% exhibited significant PMV enrichment in a single, most often the epigenetically canonical, domain. Notably, enrichment in non-epigenetic domains in a subset of EM genes suggests alternative functions and suggests that some of these may need to be reclassified. Syndrome-specific domain enrichment was observed from PMVs in RSTS and MKHK: RSTS variants clustered in the enzymatic HAT domain, while MKHK variants enriched non-enzymatic domains, with structural modeling implicating defects in SUMOylation and phosphorylation. These insights refine the link between protein domain disruption and disease phenotype, offering a framework for mechanistically informed diagnostics and future therapeutic targeting in MDEM. vii Chapter II investigates the effects of EM gene loss on DNAm and gene expression using an mNPC model derived from F1 off-springs of B6 and FVB mouse strains. KO of 46 EM genes, paired with long-read whole-genome sequencing (WGS), haplotype phasing, and RNA-seq, revealed multi-omic disruptions during early neuronal development. While most KOs induced subtle DNAm changes, promoter methylation analysis identified an EM gene cluster enriched for proteins interacting with DNAm writers or erasers, implicating indirect regulation of DNAm via protein-protein interactions (PPIs). Transcriptomic profiling revealed convergent expression changes in Dnmt1- and Kmt2a-KOs, both showing premature differentiation phenotypes. No DNAm abnormality was shared between these two EM-KOs detected, which suggests transcriptional dysregulation, rather than methylation dysregulation, plays a critical role in the premature differentiation observed here. However, it is not clear whether this is a primary or secondary effect. Haplotype-resolved methylomes revealed thousands of haplotype-specific differentially methylated regions (DMRs), associated with cis regulating methylation quantitative trait loci (cis-mQTLs). Abnormal methylation in imprinting control regions (ICRs) was observed in a subset of EM-KOs, suggesting EM involvement in ICR regulation. Collectively, these results demonstrate that EM gene disruption can result in epigenetic and transcriptional convergence, offering mechanistic insight into MDEM pathogenesis. Chapter III explores the relationship between EM gene loss and DDR in MDEMs, using the same mNPC dataset used in Chapter II. Although no overall significant increase in somatic variant load was observed in EM-KOs compared to controls, B6 controls showed significantly higher variant loads than FVB, likely due to differences in genetic background. A higher somatic variant load than expected by chance was observed in Asxl3, Crebbp, Kmt2d, Kmt2e, Lbr, Tdrd3, and Msl3-KOs, implicating putative roles of these genes in DDR. Among these, Kmt2e, Msl3, and Tdrd3 may represent novel candidates playing a role in the DNA damage response. Mutational signature analysis revealed shared enrichment of two trinucleotide signatures, SBS30 (base excision repair, BER) and SBS44 (mismatch repair, MMR), between multiple EM-KOs, suggesting shared DNA repair impairments. Together, these findings indicate that specific EM gene disruptions may compromise genome integrity and elevate cancer risk in a subset of MDEMs. Collectively, these chapters integrate domain-centric, multi-omic, and mutational analyses to elucidate the diverse, context-dependent functions of EM genes in neurodevelopmental and associated disorders.
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Ég fíla íslensku! Islandčina ma fakt baví! : Kennsluhefti fyrir byrjendur. Jazyková príručka pre začiatočníkov.
(Rannsóknarstofa í máltileinkun - RÍM, 2025) Bédi, Branislav
Kennslubók þessi er fyrir alla þá sem hafa áhuga á að kynnast íslenskri tungu á fjölbreyttan hátt. Bókin byggir á hugmyndum um kennslufræði um tilfinningar (e. sensory pedagogy) og er tvímælt. Áherslan er lögð á lestur og tal á A0–A1 stigi samkvæmt Evrópska tungumálarammanum og þar af leiðandi hentar einnig bókin til sjálfsnáms fyrir byrjendur. Bókin inniheldur þýðingu texta úr íslensku yfir á slóvakísku og er því einkum ætluð slóvakísku mælandi nemendum.
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Málfregnir 34 : Vefrit Íslenskrar málnefndar
(2024-11-14) Thorbergsdottir, Agusta
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Málfregnir 33, 2. tölublað, 21. árgangur : Vefrit Íslenskrar málnefndar
(Íslensk málnefnd, 2023-12-18) Thorbergsdottir, Agusta
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Lesson plans for a project aiming for developing virtue literacy in visual arts classes
(2023-12-05) Waage, Ingimar Ólafsson; The Department of Arts Education
Appendix with lesson plans for an article in the Journal of Moral Education Ingimar Ólafsson Waage: Cultivating virtue literacy in visual arts classes: Reflection on a fine-arts intervention aimed at moral education in a lower-secondary school in Iceland https://doi.org/10.1080/03057240.2023.2290977