A5021760406- CRISPR and Genetic Engineering
- MicroRNA in disease regulation
- Chromosomal and Genetic Variations
- RNA Interference and Gene Delivery
- Pluripotent Stem Cells Research
- RNA Research and Splicing
- Virus-based gene therapy research
- Autophagy in Disease and Therapy
- Genetic Neurodegenerative Diseases
- Circular RNAs in diseases
- Neurogenesis and neuroplasticity mechanisms
- Social and Educational Sciences
- Parkinson's Disease Mechanisms and Treatments
- Nerve injury and regeneration
- Neuroscience and Neural Engineering
- RNA modifications and cancer
- Genomics and Chromatin Dynamics
- Genetics and Neurodevelopmental Disorders
- Neuroinflammation and Neurodegeneration Mechanisms
- Epigenetics and DNA Methylation
- RNA regulation and disease
- Neuroscience and Neuropharmacology Research
- Single-cell and spatial transcriptomics
- 3D Printing in Biomedical Research
- Insect Pheromone Research and Control
Lund University
2016-2025
Wallenberg Wood Science Center
2003-2024
Research Network (United States)
2022-2024
Uppsala University
2022
Institute for Stem Cell Biology and Regenerative Medicine
2014-2019
Karolinska Institutet
2017
Institute of Neurobiology
2011
École Polytechnique Fédérale de Lausanne
2007-2011
Recent reports demonstrate that somatic mouse cells can be directly converted to other mature cell types by using combined expression of defined factors. Here we show the same strategy applied human embryonic and postnatal fibroblasts. By overexpression transcription factors Ascl1, Brn2, Myt1l, fibroblasts were efficiently functional neurons. We also neurons directed toward distinct neurotransmitter phenotypes when appropriate transcriptional cues are provided together with three conversion...
Significance This study shows that neurodegenerative changes induced by α-synuclein in midbrain dopamine neurons vivo can be blocked through activation of the autophagy-lysosome pathway. Using an adeno-associated virus model Parkinson disease to overexpress substantia nigra, we show genetic [transcription factor EB (TFEB) and Beclin-1 overexpression] or pharmacological (rapalog) manipulations enhance autophagy protect nigral from toxicity, but inhibiting exacerbates toxicity. The results...
SummaryThe maintenance of H3K9 and DNA methylation at imprinting control regions (ICRs) during early embryogenesis is key to the regulation imprinted genes. Here, we reveal that ZFP57, its cofactor KAP1, associated effectors bind selectively H3K9me3-bearing, DNA-methylated allele ICRs in ES cells. KAP1 deletion induces a loss heterochromatin marks ICRs, whereas deleting ZFP57 or DNMTs leads ICR demethylation. Accordingly, find with hemimethylated DNA-binding NP95. Finally, identify...
Cellular reprogramming is a new and rapidly emerging field in which somatic cells can be turned into pluripotent stem or other cell types simply by the expression of specific combinations genes. By viral neural fate determinants, it possible to directly reprogram mouse human fibroblasts functional neurons, also known as induced neurons. The resulting are nonproliferating present an alternative for obtaining patient- disease-specific neurons used disease modeling development therapy. In...
New neurons are continuously generated from neural stem cells with astrocyte properties, which reside in close proximity to the ventricle postnatal and adult brain. In this study we found that microRNA-124 (miR-124) dictates neurogenesis mouse subventricular zone. Using a transgenic reporter show miR-124 expression is initiated rapid amplifying progenitors remains expressed resulting neurons. When stably inhibited <i>in vivo</i>, was blocked, leading appearance of ectopic characteristics...
TRIM28 is critical for the silencing of endogenous retroviruses (ERVs) in embryonic stem (ES) cells. Here, we reveal that an essential impact this process protection cellular gene expression early embryos from perturbation by cis -acting activators contained within these retroelements. In TRIM28-depleted ES cells, repressive chromatin marks at ERVs are replaced histone modifications typical active enhancers, stimulating transcription nearby genes, notably those harboring bivalent promoters....
Parkinson's disease (PD) patients experience loss of normal motor function (hypokinesia), but can develop uncontrollable movements known as dyskinesia upon treatment with L-DOPA. Poverty or excess movement in PD has been attributed to overactivity striatal projection neurons forming either the indirect (iSPNs) direct (dSPNs) pathway, respectively. Here, we investigated two pathways' contribution different features using SPN type-specific chemogenetic stimulation rodent models (PD mice) and...
TRIM28 is a corepressor that mediates transcriptional silencing by establishing local heterochromatin. Here, we show deletion of in neural progenitor cells (NPCs) results high-level expression two groups endogenous retroviruses (ERVs): IAP1 and MMERVK10C. We find NPCs use TRIM28-mediated histone modifications to dynamically regulate transcription ERVs, which contrast other somatic cell types using DNA methylation. also derepression ERVs influences dynamics through the activation nearby genes...
Highlights•Stage- and region-specific expression of ERVs during human brain development•TRIM28 binds to induces hetereochromatin in neural progenitor cells•Knockdown TRIM28 hNPCs results the upregulation ERV expression•Protein-coding genes located near upregulated are upregulatedSummaryEndogenous retroviruses (ERVs), which make up 8% genome, have been proposed participate control gene regulatory networks. In this study, we find a region- developmental stage-specific pattern developing brain,...
Abstract Direct conversion of human fibroblasts into mature and functional neurons, termed induced neurons ( iN s), was achieved for the first time 6 years ago. This technology offers a promising shortcut obtaining patient‐ disease‐specific disease modeling, drug screening, other biomedical applications. However, from adult donors do not reprogram as easily fetal donors, no current reprogramming approach is sufficiently efficient to allow use this using patient‐derived material large‐scale...
Human embryonic stem cell (hESC)-derived dopamine neurons are currently moving toward clinical use for Parkinson's disease (PD). However, the timing and extent at which cell-derived functionally integrate into existing host neural circuitry after transplantation remain largely unknown. In this study, we modified rabies virus to trace afferent efferent connectivity of transplanted hESC-derived in a rat model PD report that grafted human an unexpectedly rapid extensive manner. The pattern...
Abstract DNA methylation contributes to the maintenance of genomic integrity in somatic cells, part through silencing transposable elements. In this study, we use CRISPR-Cas9 technology delete DNMT1 , methyltransferase key for maintenance, human neural progenitor cells (hNPCs). We observe that inactivation hNPCs results viable, proliferating despite a global loss CpG-methylation. demethylation leads specific transcriptional activation and chromatin remodeling evolutionarily young,...
Endogenous retroviruses (ERVs) make up a large fraction of mammalian genomes and are thought to contribute human disease, including brain disorders. In the brain, aberrant activation ERVs is potential trigger for an inflammatory response, but mechanistic insight into this phenomenon remains lacking. Using CRISPR/Cas9-based gene disruption epigenetic co-repressor protein Trim28, we found dynamic H3K9me3-dependent regulation in proliferating neural progenitor cells (NPCs), not adult neurons....
The genetic mechanisms underlying the expansion in size and complexity of human brain remain poorly understood. Long interspersed nuclear element-1 (L1) retrotransposons are a source divergent information hominoid genomes, but their importance physiological functions contribution to evolution largely unknown. Using multiomics profiling, we here demonstrate that L1 promoters dynamically active developing adult brain. L1s generate hundreds developmentally regulated cell type-specific...
Mutations in
Abstract Direct gene transfer to the adult brain is dependent on vectors that transduce non‐dividing cells, such as lentiviral vectors. Another aspect of development therapy need for cell‐specific transgene expression. Expression from vesicular stomatitis virus G‐protein (VSV‐G) pseudotyped has been reported be mainly neuron specific in brain. We constructed using neuron‐specific enolase (rNSE) or glial fibrillary acidic protein (hGFAP) promoters and compared them ubiquitous human...
The Krüppel-associated box (KRAB) domain is a transcriptional repression module responsible for the DNA binding-dependent gene silencing activity of hundreds vertebrate zinc finger proteins. We previously exploited KRAB-mediated within context tet repressor-KRAB fusion protein and lentiviral vectors to create method external control. demonstrated that with this system was fully reversible in cell culture as well vivo. Here we reveal that, sharp contrast, results irreversible through promoter...
Many neurodegenerative diseases are characterized by the presence of intracellular protein aggregates, resulting in alterations autophagy. However, consequences impaired autophagy for neuronal function remain poorly understood. In this study, we used cell culture and mouse models huntingtin aggregation as well post-mortem material from patients with Huntington's disease to demonstrate that Argonaute-2 (AGO2) accumulates aggregates is due Accumulation AGO2, a key factor RNA-induced silencing...