The focus of the Louma G. Laboratory of Epigenetic Research is to uncover fundamental truths regarding the role of epigenetics in health and disease and use those insights to develop novel therapeutic options for individuals with rare untreatable disorders.
1. Kabuki syndrome research: Our group has published more than 20 peer-reviewed papers in the last 10 years that focus on Kabuki syndrome, including clinical guidelines, a DNA methylation episignature, and several potential therapeutic strategies. We are grateful for continued support by the Louma G. Foundation which allows us to continue our push towards a deeper mechanistic understanding of Kabuki syndrome and towards bringing therapeutic strategies to the clinic. Our major collaborators on studying Kabuki syndrome are Jacqui Harris MD and Jill Fahrner MD PhD.
Links:
All things Kabuki
Professor at the UI Faculty of Medicine awarded research grant of ISK 260 million
2. The EDDA-MD project focuses on understanding the role of the epigenetic machinery on neuronal development. In previous work, we have shown that intellectual disability is a unifying phenotype among the Mendelian disorders of the Epigenetic Machinery. Furthermore, a subset of EM factors show strong co-expression with one another and those that are co-expressed tend to be more intolerant to variation. Here, thanks to the Rannís Grant of Excellence, we are systematically knocking out EM factors in a murine neurodevelopmental model to try to understand how these disorders cause intellectual disability. This project is part of concerted work with long-time collaborator Kasper Daniel Hansen.
Links:
The Epigenetic Machinery
Role of Epigenetics in Disease Determined through Analysis of Machinery Disruption
3. Understanding the basis of Wiedemann-Steiner and Pilarowski-Bjornsson syndromes: Our group first described Pilarowski-Bjornsson syndrome in 2017 and has been investigating it since. Wiedemann-Steiner syndrome is caused by mutations in KMT2A, a factor highly similar to KMT2D (the root cause of Kabuki syndrome). We have recently found that the critical domain in Wiedemann-Steiner is the CXXC-domain, unlike in Kabuki syndrome, in which the key domain is the SET domain.
Links:
WSS Foundation - First Grant Awarded
Pilarowski-Bjornsson syndrome; Pilbos
4. The role of epigenetics in the mild hypothermia response: Our group has recently uncovered a novel epigenetic regulator of the mild hypothermia response (SMYD5). This is the first mammalian example of how temperature stimuli are integrated into genetic circuits. For this project we are collaborating with Akhilesh Pandey, Valborg Guðmundsdóttir and Mike Beer.
Link:
SMYD5 is a novel epigenetic gatekeeper of the mild hypothermia response
A novel epigenetic gatekeeper of the mild hypothermia response (2024). We have discovered that SMYD5 is an epigenetic regulator of the SP1-CIRBP mild hypothermia response. This is an elegant example of how an environmental stimulus is integrated into the genetic circuit.
Overlapping epigenetic abnormalities among multiple Mendelian Disorders of the Epigenetic Machinery. In two publications (eLIFE, 2021 and Genome Research, 2024) we show overlapping epigenetic abnormalities in multiple MDEM. The defects are cell-type specific, making it difficult to develop blood-based biomarkers of neurological disruption in these disorders. Remarkably, in Kabuki syndrome, the abnormality in neurons occurs at aging-related loci.
That ITGB7 and other integrins cause immune deficiency in Kabuki syndrome (2020, 2024). ITGB7 is the most strongly validated KMT2D-target gene discovered to date and in this work we show defects of multiple related integrins.
A method to predict loss of function intolerance (2020). We have shown that CpG content can be used to predict loss of function intolerance in very small genes.
The first mouse model of Kabuki syndrome (2014). We characterized the first mouse model of Kabuki syndrome (Kmt2d+/βGeo mice) and demonstrated that these mice have many features seen in patients (growth retardation, skeletal abnormalities, learning problems). This model also revealed novel features, such as an ongoing defect of adult neurogenesis (see Bjornsson et al. Science TM, 2014).
Proof-of-principle studies demonstrating that Kabuki syndrome may be a treatable cause of intellectual disability (2014, 2017, 2021). We have shown that hippocampal memory defects and defects of adult neurogenesis improve upon treatment with agents that favor chromatin opening and thereby counter the defect (TAK-418, AR-42, ketogenic diet, BHB injection; see Bjornsson et al. Science TM, 2014; Benjamin, 2017, PNAS; Zhang et al. Molecular Therapy, Methods and Clinical Development, 2021).
Novel insights into the basis of Kabuki syndrome (2019). We have observed precocious differentiation in neurons and mesenchymal cells in mouse models of Kabuki syndrome (See Fahrner and Carosso in JCI Insight, 2019).
DNA methylation as a biomarker in Kabuki syndrome (2017). We recently showed that DNA methylation patterns are abnormal in Kabuki syndrome. These changes may be used in the future as a diagnostic biomarker (see Sobreira et al. EJHG, 2017).
The description of the novel Bjornsson-Pilarowski syndrome (2018). We recently found mutations in the chromatin remodeler CHD1 in patients with autism and speech apraxia (see Pilarowski et al. JMG, 2017).
Insights into causes of haploinsufficiency of the Mendelian disorders of the epigenetic Machinery (2015, 2018). In a recent review article, we noted that even though epigenetic writers, erasers and remodelers are enzymes, these predominantly cause disease when one copy is lost (haploinsufficiency), which is exceedingly rare for enzymes. We extended this observation to the entire subset of epigenetic machinery components (almost 300) and found that haploinsufficiency is mainly seen in a subset of epigenetic machinery components that show extensive co-expression in the GTEX dataset. It is possible that this co-expression phenotype plays a role in the haploinsufficiency of these factors (see Bjornsson et al. Genome Research, 2015; Boukas et al. Genome Research, 2019).
Insights into germline DNA methylation through studies of a mutational biomarker (Bjornsson et al. Gene, 2004; Sigurdsson M et al. Gene, 2012; Sigurdsson M et al. Genome Research, 2009; Sigurdsson M et al. BMC genetics, 2012).
Demonstration that DNA methylation changes over time in humans (Bjornsson et al. JAMA, 2008). This shows that even in healthy people epigenetic patterns change over time.
Demonstration that allele-specific expression abnormalities are common in humans (Bjornsson et al. Genome Research, 2008).
Demonstration that loss of imprinting in Wilms tumors is specific (Bjornsson et al. JNCI 2007). This paper shows that rest of imprinted genes are normal when you have disruption of imprinting of a specific locus.
Hans Tómas Björnsson MD PhD is Professor of Translational Medicine and Pediatrics at the University of Iceland, Chief of the Department of Genetics and Molecular Biology, Landspitali University Hospital and Associate Professor of Genetics and Pediatrics (Part time) at the Johns Hopkins University, USA. Dr. Bjornsson joined the faculty at the University of Iceland in 2018, after being primary faculty member at the McKusick-Nathans Institute of Genetic Medicine and the Department of Pediatrics from 2012.
His research has focused on how genetics, environment, age and therapeutics modify epigenetics and subsequently disease states. Dr. Bjornsson has received numerous awards for both clinical care and scientific work, including the William K. Bowes Jr. Award in Medical Genetics (2014), the Outstanding Achievement Award in Medical Sciences – Arni Kristinsson and Thorður Hardarson Foundation (2021) and Kabuki syndrome foundation award for exceptional contribution to Kabuki syndrome (2023).
