Rosanna Foti: "Human specific ZNF proteins repress gliogenesis in Huntington’s disease"

Assistant professor, Goldman Lab

Abstract: Huntington’s disease (HD) has been described for several years as a neurological disease with only medium spiny neurons as the most affected cell population. However, a cell-autonomous causal contribution of glial pathology has been recently reported describing a block in the maturation of human glial progenitor cells (GPC) towards myelinating oligodendrocytes.  Oligodendrocytes (OLs) are responsible for the myelination of neuronal axons during development and through adulthood. Deficient myelination, with its attendant disruption of neural transmission, significantly degrade cognition and behavior as well as sensorimotor neurological function. There is emerging evidence that epigenetic regulation plays an important role in oligodendrocyte development by controlling both their gene expression and ability to myelinate axons. Here we present an integrated analysis of chromatin accessibility, DNA methylation and transcriptome of human GPC. Our results show an epigenetic HD signature with the establishment of a repressive chromatin environment around several transcription factors regulating GPC proliferation and maturation such as SOX6 and TCF7L2. Conversely, a small group of genes shows an aberrant exposure of the chromatin to the transcription and an increase in their level of expression.  This cluster of genes include chromatin remodelers and several human specific transcriptional repressors belonging to the family of KRAB-zinc fingers (ZNF). Here we propose a model where HD GPCs present an aberrant epigenetic profile which elicits the expression of human specific KRAB-ZNFs responsible in turn for the repression of developmental glial genes thus far preventing their further maturation towards myelin-producing oligodendrocytes.