Jan 16, 2019

Direct reprogramming of microglia into functional neurons by a single transcription factor, NeuroD1
Published in Neuron

The research group led by Drs. Matsuda, Imamura and Nakashima from the Graduate School of Medical Sciences, Kyushu University succeeded to convert neurons from mouse microglia by expression of a single transcription factor, NeuroD1.

Disruption of neuronal circuits by lesion such as stroke and spinal cord injury impairs neurotransmission and motor function. Reconstruction of disrupted neuronal circuits by provision of new neurons into lesion sites has been tested as a promising strategy to gain functional recovery from these nerve injuries. The research group focused on microglia which converge and accumulate at lesion sites for the clearance of dead cells as immune cells in the central nervous system after nerve injury, while they never differentiate into neurons physiologically. Here, the research group found that NeuroD1, known as an essential transcription factor for neuronal production in developing brain, converts microglia into induced neuronal (iN) cells accompanied by global remodeling of microglial epigenetic signature. Furthermore, iN cells were functionally integrated into brain circuits through synaptic connections with other neurons like endogenous neurons. These findings bring us one step closer to developing therapeutic strategies for nerve injury and disease by reprogramming microglia that accumulate at lesion sites into neurons.

Figure. NeuroD1 initially occupies closed chromatin regions associated with bivalent H3K4me3 and H3K27me3 marks in microglia to induce neuronal gene expression. These regions are resolved to a monovalent H3K4me3 mark at later stages of the reprogramming to establish neuronal identity. The transcriptional repressors Scrt1 and Meis2 are induced as NeuroD1 target genes, resulting in a decrease in the expression of microglial genes. In parallel, the microglial epigenetic signature in promoter and enhancer regions is erased.

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