PuSH - Publication Server of Helmholtz Zentrum München: Hmgb2 improves astrocyte to neuron conversion by increasing the chromatin accessibility of genes associated with neuronal maturation in a proneuronal factor-dependent manner.

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Maddhesiya, P. ; Lepko, T. ; Steiner‑Mezzardi, A. ; Schneider, J. ; Schwarz, V. ; Merl-Pham, J. ; Berger, F. ; Hauck, S.M. ; Ronfani, L.* ; Bianchi, M.E.* ; Simon, T.* ; Krontira, A. ; Masserdotti, G. ; Götz, M. ; Ninkovic, J.

Hmgb2 improves astrocyte to neuron conversion by increasing the chromatin accessibility of genes associated with neuronal maturation in a proneuronal factor-dependent manner.

Genome Biol. 26:100 (2025)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Enhanced Neurogenesis; Fate Specification; Reactive Gliosis; Brain Repair; Label-free; Transcription; Fibroblasts; Expression; Mechanisms; Proteins

ISSN (print) / ISBN 1474-760X

e-ISSN 1465-6906

Journal Genome Biology

Quellenangaben Volume: 26, Issue: 1, Article Number: 100

Publisher BioMed Central

Publishing Place Campus, 4 Crinan St, London N1 9xw, England

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Stem Cell Research (ISF)
Research Unit Central Nervous System Regeneration (CNSR)
CF Metabolomics & Proteomics (CF-MPC)

Grants German research foundation (DFG)
Fritz Thyssen Foundation
Research Grant Program: Cellular Dynamics and Regulatory Pathways for Successful Regeneration
ERC Chrono Neurorepair
Graduate School for Systemic Neurosciences GSN-LMU

Projekt DEAL