Biology subjects

Jonsson, M. E.

Publications and source records attributed to Jonsson, M. E..

7 recordsLinked to original sources

bioRxiv2025

Activation of transposable elements is linked to a region- and cell-type-specific interferon response in Parkinson's disease

Parkinsons disease (PD) is a neurodegenerative disorder involving a neuroinflammatory response, the cause of which remains unclear. Transposable elements (TE) have been linked to inflammation, but their potential role in PD remains unexplored. Using bulk- and single-nuclei RNAseq of postmortem brain tissue from four brain regions, we studied TE transcription and its correlation with PD neuroinflammation. Over a thousand TEs, including LINE-1s and ERVs, were expressed in a cell-type and region-specific manner in the human brain. Increased TE expression was found in microglia and neurons in the substantia nigra and putamen of PD brains, but not amygdala or prefrontal cortex, compared to controls. This TE activation correlated with an innate immune response in the same brain regions. The link between an interferon response and TE activation was mechanistically confirmed using human pluripotent stem cell-derived microglia and neurons. Our findings provide insights into TE transcription in the PD brain and suggest TEs may contribute to neuroinflammation and pathological progression in PD. Teaser: Transposable elements are linked to a cell type specific inflammatory state in Parkinsons Disease.

neuroscience↗

bioRxiv2023

Mini-heterochromatin domains constrain the cis-regulatory impact of SVA transposons in human brain development and disease

SVA retrotransposons remain active in humans and contribute to individual genetic variation. Polymorphic SVA alleles harbor gene-regulatory potential and can cause genetic disease. However, how SVA insertions are controlled and functionally impact human disease is unknown. Here, we dissect the epigenetic regulation and influence of SVAs in cellular models of X-linked dystonia-parkinsonism (XDP), a neurodegenerative disorder caused by an SVA insertion at the TAF1 locus. We demonstrate that the KRAB zinc finger protein ZNF91 establishes H3K9me3 and DNA methylation over SVAs, including polymorphic alleles, in human neural progenitor cells. The resulting mini-heterochromatin domains attenuate the cis-regulatory impact of SVAs. This is critical for XDP pathology; removal of local heterochromatin severely aggravates the XDP molecular phenotype, resulting in increased TAF1 intron retention and reduced expression. Our results provide unique mechanistic insights into how human polymorphic transposon insertions are recognized, and their regulatory impact constrained by an innate epigenetic defense system.

neuroscience↗

bioRxiv2023

L1 retrotransposons drive human neuronal transcriptome complexity and functional diversification

The genetic mechanisms underlying the expansion in size and complexity of the human brain remains poorly understood. L1 retrotransposons are a source of divergent genetic information in hominoid genomes, but their importance in physiological functions and their contribution to human brain evolution is largely unknown. Using multi-omic profiling we here demonstrate that L1-promoters are dynamically active in the developing and adult human brain. L1s generate hundreds of developmentally regulated and cell-type specific transcripts, many which are co-opted as chimeric transcripts or regulatory RNAs. One L1-derived lncRNA, LINC01876, is a human-specific transcript expressed exclusively during brain development. CRISPRi-silencing of LINC01876 results in reduced size of cerebral organoids and premature differentiation of neural progenitors, implicating L1s in human-specific developmental processes. In summary, our results demonstrate that L1-derived transcripts provide a previously undescribed layer of primate- and human-specific transcriptome complexity that contributes to the functional diversification of the human brain.

neuroscience↗

bioRxiv2022

Single-cell transcriptomics of resected human traumatic brain injury tissues reveals acute activation of endogenous retroviruses in oligodendrocytes

Traumatic brain injury (TBI) is a leading cause of chronic brain impairment and results in a robust, but poorly understood, neuroinflammatory response that contributes to the long-term pathology. We used snRNA-seq to study transcriptomic changes in different cell populations in human brain tissue obtained acutely after severe, life-threatening TBI. This revealed a unique transcriptional response in oligodendrocyte precursors and mature oligodendrocytes, including the activation of a robust innate immune response, indicating an important role for oligodendroglia in the initiation of neuroinflammation. The activation of an innate immune response correlated with transcriptional upregulation of endogenous retroviruses in oligodendroglia. This observation was causally linked in vitro using human glial progenitors, implicating these ancient viral sequences in human neuroinflammation. In summary, this work provides a unique insight into the initiating events of the neuroinflammatory response in TBI, which has new therapeutic implications.

neuroscience↗

bioRxiv2021

Distinct sub-cellular autophagy impairments occur independently of protein aggregation in induced neurons from patients with Huntington's disease

Huntingtons disease (HD) is a neurodegenerative disorder caused by CAG expansions in the huntingtin (HTT) gene. Modelling HD has remained challenging, as rodent and cellular models poorly recapitulate the disease. To address this, we generated induced neurons (iNs) through direct reprogramming of human skin fibroblasts, which retain age-dependent epigenetic characteristics. HD-iNs displayed profound deficits in autophagy, characterised by reduced transport of late autophagic structures from the neurites to the soma. The neurite-specific alterations in autophagy resulted in shorter, thinner and fewer neurites presented by HD-iNs. CRISPRi-mediated silencing of HTT did not rescue this phenotype but rather resulted in additional autophagy alterations in ctrl-iNs, highlighting the importance of wild type HTT in neuronal autophagy. In summary, our work identifies a distinct subcellular autophagy impairment in aged patient derived HD-neurons and provides a new rational for future development of autophagy activation therapies.

neuroscience↗

bioRxiv2020

A human-specific structural variation at the ZNF558 locus controls a gene regulatory network during forebrain development

The human forebrain has expanded in size and complexity compared to that of chimpanzee despite limited changes in protein-coding genes, suggesting that gene regulation is an important driver of brain evolution. Here we identify a KRAB-ZFP transcription factor, ZNF558, that is expressed in human but not chimpanzee forebrain neural progenitor cells. ZNF558 evolved as a suppressor of LINE-1 transposons but has been co-opted to regulate the mitophagy gene SPATA18, supporting a link between mitochondrial homeostasis and cortical expansion. The unusual on-off switch for ZNF558 expression resides in a downstream variable number tandem repeat (VNTR) that is contracted in humans relative to chimpanzee. Our data reveal the brain-specific co-option of a transposon-controlling KRAB-ZFP and how a human-specific regulatory network is established by a cis-acting structural genome variation. This represents a previously undescribed genetic mechanism in the evolution of the human brain.

genetics↗

bioRxiv2019

Post-transcriptional mechanisms distinguish human and chimp forebrain progenitor cells

The forebrain has expanded in size and complexity during hominoid evolution. The contribution of post-transcriptional control of gene expression to this process is unclear. Using in-depth proteomics in combination with bulk and single-cell RNA sequencing, we analyzed protein and RNA levels of almost 5,000 genes in human and chimpanzee forebrain neural progenitor cells. We found that species differences in protein expression level was often independent of RNA levels, and more frequent than transcriptomic differences. Low-abundant proteins were more likely to show species-specific expression levels, while proteins expressed at a high level appeared to have evolved under stricter constraints. Our study implicates a previously unappreciated broad and important role for post-transcriptional regulatory mechanisms in the evolution of the human forebrain.

neuroscience↗