Hmgb2 improves astrocyte to neuron conversion by increasing the chromatin accessibility of genes associated with neuronal maturation in a proneuronal factor-dependent manner
Abstract Background Direct conversion of reactive glial cells to neurons is a promising avenue for neuronal replacement therapies after brain injury or neurodegeneration. The overexpression of neurogenic fate determinants in glial cells results in conversion to neurons. For repair purposes, the conv...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-04-01
|
| Series: | Genome Biology |
| Online Access: | https://doi.org/10.1186/s13059-025-03556-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850181893873467392 |
|---|---|
| author | Priya Maddhesiya Tjasa Lepko Andrea Steiner-Mezzardi Julia Schneider Veronika Schwarz Juliane Merl-Pham Finja Berger Stefanie M. Hauck Lorenza Ronfani Marco Bianchi Tatiana Simon Anthodesmi Krontira Giacomo Masserdotti Magdalena Götz Jovica Ninkovic |
| author_facet | Priya Maddhesiya Tjasa Lepko Andrea Steiner-Mezzardi Julia Schneider Veronika Schwarz Juliane Merl-Pham Finja Berger Stefanie M. Hauck Lorenza Ronfani Marco Bianchi Tatiana Simon Anthodesmi Krontira Giacomo Masserdotti Magdalena Götz Jovica Ninkovic |
| author_sort | Priya Maddhesiya |
| collection | DOAJ |
| description | Abstract Background Direct conversion of reactive glial cells to neurons is a promising avenue for neuronal replacement therapies after brain injury or neurodegeneration. The overexpression of neurogenic fate determinants in glial cells results in conversion to neurons. For repair purposes, the conversion should ideally be induced in the pathology-induced neuroinflammatory environment. However, very little is known regarding the influence of the injury-induced neuroinflammatory environment and released growth factors on the direct conversion process. Results We establish a new in vitro culture system of postnatal astrocytes without epidermal growth factor that reflects the direct conversion rate in the injured, neuroinflammatory environment in vivo. We demonstrate that the growth factor combination corresponding to the injured environment defines the ability of glia to be directly converted to neurons. Using this culture system, we show that chromatin structural protein high mobility group box 2 (HMGB2) regulates the direct conversion rate downstream of the growth factor combination. We further demonstrate that Hmgb2 cooperates with neurogenic fate determinants, such as Neurog2, in opening chromatin at the loci of genes regulating neuronal maturation and synapse formation. Consequently, early chromatin rearrangements occur during direct fate conversion and are necessary for full fate conversion. Conclusions Our data demonstrate novel growth factor-controlled regulation of gene expression during direct fate conversion. This regulation is crucial for proper maturation of induced neurons and could be targeted to improve the repair process. |
| format | Article |
| id | doaj-art-6f2b7adc98cd42068ade1b38d595dc5f |
| institution | OA Journals |
| issn | 1474-760X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Biology |
| spelling | doaj-art-6f2b7adc98cd42068ade1b38d595dc5f2025-08-20T02:17:47ZengBMCGenome Biology1474-760X2025-04-0126113410.1186/s13059-025-03556-zHmgb2 improves astrocyte to neuron conversion by increasing the chromatin accessibility of genes associated with neuronal maturation in a proneuronal factor-dependent mannerPriya Maddhesiya0Tjasa Lepko1Andrea Steiner-Mezzardi2Julia Schneider3Veronika Schwarz4Juliane Merl-Pham5Finja Berger6Stefanie M. Hauck7Lorenza Ronfani8Marco Bianchi9Tatiana Simon10Anthodesmi Krontira11Giacomo Masserdotti12Magdalena Götz13Jovica Ninkovic14Department of Cell Biology and Anatomy, Biomedical Center Munich (BMC), Medical Faculty, LMUDepartment of Cell Biology and Anatomy, Biomedical Center Munich (BMC), Medical Faculty, LMUInstitute of Stem Cell Research, Helmholtz Zentrum MunichDepartment of Cell Biology and Anatomy, Biomedical Center Munich (BMC), Medical Faculty, LMUDepartment of Cell Biology and Anatomy, Biomedical Center Munich (BMC), Medical Faculty, LMUResearch Unit Protein Science and Metabolomics and Proteomics Core, Helmholtz Centre Munich, German Research Center for Environmental Health, Department of Cell Biology and Anatomy, Biomedical Center Munich (BMC), Medical Faculty, LMUResearch Unit Protein Science and Metabolomics and Proteomics Core, Helmholtz Centre Munich, German Research Center for Environmental Health, School of Medicine, Vita-Salute San Raffaele UniversitySchool of Medicine, Vita-Salute San Raffaele UniversityBiomedical Center Munich (BMC), Institute of Physiological Genomics, LMUInstitute of Stem Cell Research, Helmholtz Zentrum MunichInstitute of Stem Cell Research, Helmholtz Zentrum MunichInstitute of Stem Cell Research, Helmholtz Zentrum MunichDepartment of Cell Biology and Anatomy, Biomedical Center Munich (BMC), Medical Faculty, LMUAbstract Background Direct conversion of reactive glial cells to neurons is a promising avenue for neuronal replacement therapies after brain injury or neurodegeneration. The overexpression of neurogenic fate determinants in glial cells results in conversion to neurons. For repair purposes, the conversion should ideally be induced in the pathology-induced neuroinflammatory environment. However, very little is known regarding the influence of the injury-induced neuroinflammatory environment and released growth factors on the direct conversion process. Results We establish a new in vitro culture system of postnatal astrocytes without epidermal growth factor that reflects the direct conversion rate in the injured, neuroinflammatory environment in vivo. We demonstrate that the growth factor combination corresponding to the injured environment defines the ability of glia to be directly converted to neurons. Using this culture system, we show that chromatin structural protein high mobility group box 2 (HMGB2) regulates the direct conversion rate downstream of the growth factor combination. We further demonstrate that Hmgb2 cooperates with neurogenic fate determinants, such as Neurog2, in opening chromatin at the loci of genes regulating neuronal maturation and synapse formation. Consequently, early chromatin rearrangements occur during direct fate conversion and are necessary for full fate conversion. Conclusions Our data demonstrate novel growth factor-controlled regulation of gene expression during direct fate conversion. This regulation is crucial for proper maturation of induced neurons and could be targeted to improve the repair process.https://doi.org/10.1186/s13059-025-03556-z |
| spellingShingle | Priya Maddhesiya Tjasa Lepko Andrea Steiner-Mezzardi Julia Schneider Veronika Schwarz Juliane Merl-Pham Finja Berger Stefanie M. Hauck Lorenza Ronfani Marco Bianchi Tatiana Simon Anthodesmi Krontira Giacomo Masserdotti Magdalena Götz Jovica Ninkovic Hmgb2 improves astrocyte to neuron conversion by increasing the chromatin accessibility of genes associated with neuronal maturation in a proneuronal factor-dependent manner Genome Biology |
| title | Hmgb2 improves astrocyte to neuron conversion by increasing the chromatin accessibility of genes associated with neuronal maturation in a proneuronal factor-dependent manner |
| title_full | Hmgb2 improves astrocyte to neuron conversion by increasing the chromatin accessibility of genes associated with neuronal maturation in a proneuronal factor-dependent manner |
| title_fullStr | Hmgb2 improves astrocyte to neuron conversion by increasing the chromatin accessibility of genes associated with neuronal maturation in a proneuronal factor-dependent manner |
| title_full_unstemmed | Hmgb2 improves astrocyte to neuron conversion by increasing the chromatin accessibility of genes associated with neuronal maturation in a proneuronal factor-dependent manner |
| title_short | Hmgb2 improves astrocyte to neuron conversion by increasing the chromatin accessibility of genes associated with neuronal maturation in a proneuronal factor-dependent manner |
| title_sort | hmgb2 improves astrocyte to neuron conversion by increasing the chromatin accessibility of genes associated with neuronal maturation in a proneuronal factor dependent manner |
| url | https://doi.org/10.1186/s13059-025-03556-z |
| work_keys_str_mv | AT priyamaddhesiya hmgb2improvesastrocytetoneuronconversionbyincreasingthechromatinaccessibilityofgenesassociatedwithneuronalmaturationinaproneuronalfactordependentmanner AT tjasalepko hmgb2improvesastrocytetoneuronconversionbyincreasingthechromatinaccessibilityofgenesassociatedwithneuronalmaturationinaproneuronalfactordependentmanner AT andreasteinermezzardi hmgb2improvesastrocytetoneuronconversionbyincreasingthechromatinaccessibilityofgenesassociatedwithneuronalmaturationinaproneuronalfactordependentmanner AT juliaschneider hmgb2improvesastrocytetoneuronconversionbyincreasingthechromatinaccessibilityofgenesassociatedwithneuronalmaturationinaproneuronalfactordependentmanner AT veronikaschwarz hmgb2improvesastrocytetoneuronconversionbyincreasingthechromatinaccessibilityofgenesassociatedwithneuronalmaturationinaproneuronalfactordependentmanner AT julianemerlpham hmgb2improvesastrocytetoneuronconversionbyincreasingthechromatinaccessibilityofgenesassociatedwithneuronalmaturationinaproneuronalfactordependentmanner AT finjaberger hmgb2improvesastrocytetoneuronconversionbyincreasingthechromatinaccessibilityofgenesassociatedwithneuronalmaturationinaproneuronalfactordependentmanner AT stefaniemhauck hmgb2improvesastrocytetoneuronconversionbyincreasingthechromatinaccessibilityofgenesassociatedwithneuronalmaturationinaproneuronalfactordependentmanner AT lorenzaronfani hmgb2improvesastrocytetoneuronconversionbyincreasingthechromatinaccessibilityofgenesassociatedwithneuronalmaturationinaproneuronalfactordependentmanner AT marcobianchi hmgb2improvesastrocytetoneuronconversionbyincreasingthechromatinaccessibilityofgenesassociatedwithneuronalmaturationinaproneuronalfactordependentmanner AT tatianasimon hmgb2improvesastrocytetoneuronconversionbyincreasingthechromatinaccessibilityofgenesassociatedwithneuronalmaturationinaproneuronalfactordependentmanner AT anthodesmikrontira hmgb2improvesastrocytetoneuronconversionbyincreasingthechromatinaccessibilityofgenesassociatedwithneuronalmaturationinaproneuronalfactordependentmanner AT giacomomasserdotti hmgb2improvesastrocytetoneuronconversionbyincreasingthechromatinaccessibilityofgenesassociatedwithneuronalmaturationinaproneuronalfactordependentmanner AT magdalenagotz hmgb2improvesastrocytetoneuronconversionbyincreasingthechromatinaccessibilityofgenesassociatedwithneuronalmaturationinaproneuronalfactordependentmanner AT jovicaninkovic hmgb2improvesastrocytetoneuronconversionbyincreasingthechromatinaccessibilityofgenesassociatedwithneuronalmaturationinaproneuronalfactordependentmanner |