Germanguz, I. | bioRxiv Science

bioRxiv2017

TDG Regulates Cell Cycle Progression In Human Neural Progenitors

As cells divide, they must replicate both their DNA and generate a new set of histone proteins. The newly synthesized daughter strands and histones are unmodified and must therefore be covalently modified to allow for transmission of important epigenetic marks to daughter cells. Human pluripotent stem cells (hPSCs) display a unique cell cycle profile, and control of the cell cycle is known to be critical for their proper differentiation and survival. A major unresolved question is how hPSCs regulate their DNA methylation status through the cell cycle, namely how passive and active demethylation work to maintain a stable genome. TDG, an embryonic essential gene, has been recently implicated as a major enzyme involved in demethylation1. Here we present new data showing that TDG regulates cell cycle related gene expression in human neural progenitors (NPCs) derived from hPSCs and controls their capacity for neural differentiation. These observations suggest that TDG and active demethylation play an important role in hPSC cell cycle regulation and differentiation.

molecular biology↗

bioRxiv2017

Loss of MECP2 leads to telomere dysfunction and neuronal stress

To determine the role for mutations of MECP2 in Rett Syndrome, we generated isogenic lines of human iPSCs (hiPSCs), neural progenitor cells (NPCs), and neurons from patient fibroblasts with and without MECP2 expression in an attempt to recapitulate disease phenotypes in vitro. Molecular profiling uncovered neuronal specific gene expression changes including induction of a Senescence Associated Secretory Phenotype (SASP) program. Patient derived Neurons made without MECP2 show signs of stress, including induction of p53, and senescence. The induction of p53 appeared to affect dendritic branching in Rett neurons, as p53 inhibition restored dendritic complexity. These disease-in-a-dish data suggest that loss of MECP2 can lead to dendritic defects due to an increase in aspects of neuronal aging.

developmental biology↗