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

Direct conversion of reactive glial cells to neurons is promising avenue for the replacement therapies after brain injury or neurodegeneration. The overexpression of developmental neurogenic fate determinants in glial cells converts them to neurons. For the repair purposes the conversion is confined to the pathology-induced neuroinflammatory environment. However, very little is known about the influence of injury-induced neuroinflammatory environment on the direct conversion process. We established the new in vitro culture system of postnatal astrocytes that reflects the direct conversion rate in the injured, neuroinflammatory environment in vivo. We could show that the growth factor combination corresponding to the injured environment defines the capacity of the glia to be directly converted to neurons. Using this culture, we showed that the chromatin structural protein high mobility group b2 (Hmgb2) regulates the direct conversion rate downstream of the growth factor combination. We could further show that Hmgb2 cooperates with neurogenic fate determinants such as Neurog2 to open the chromatin containing neuronal maturation and synapse formation genes, leading to early chromatin re-arrangements during the direct fate conversion that are necessary for the full fate conversion. Our data demonstrate the novel, environmental cues controlled level of gene regulation during direct fate conversion necessary for the proper maturation of induced neurons that could be targeted to improve the repair process.