Project description:Mammalian somatic cells can be directly reprogrammed into induced pluripotent stem cells (iPSCs) by introducing defined sets of transcription factors. Somatic cell reprogramming involves epigenomic reconfiguration, conferring iPSCs with characteristics similar to embryonic stem (ES) cells. Human ES cells contain 5-hydroxymethylcytosine (5hmC), which is generated though the oxidation of 5-methylcytosine (5mC) by the TET family of enzymes. Here we show that 5hmC level increases significantly during reprogramming due to the activation of TET1. During this process, dynamic genome-wide 5hmC modification occurs across the genome with more modifications at telomere-proximal regions. Compared with hES cells, we found iPS cells tend to form large-scale (100kb-1.3Mb) aberrant reprogramming hotspots in subtelomeric regions, most of which display incomplete hydroxymethylation. Strikingly, these 5hmC aberrant hotspots largely coincide (>80%) with previously reported aberrant non-CG methylation regions. Our results suggest that 5hmC modification could play important roles during reprogramming to pluripotency, and contribute to the differences between iPSCs and hESCs. we generated comprehensive genome-wide profiles of 5hmC in somatic cells, iPS cell lines derived from a variety of origins, and multiple hES cell lines.
Project description:Mammalian neocortical neurons span one of the most diverse cell type spectra of any tissue. The regulatory strategies that neurons use during progressive development and maturation remain unclear. We present an integrated single-cell epigenomic and transcriptional analysis of individual classes of neurons from both mouse and marmoset neocortex, sampled during both early postmitotic stages of identity acquisition and later stages of neuronal plasticity and circuit integration. We find that in both species, the regulatory strategies controlling early and late stages of pan-neuronal development diverge. Early postmitotic neurons use molecular regulatory programs with broader tissue distribution and greater evolutionary conservation. In contrast, programs that are active during later neuronal maturation implement more brain- and neuron-specific mechanisms showing greater evolutionary divergence. Our work uncovers a temporally-regulated shift in regulatory choices, likely reflecting unique evolutionary constraints on distinct events of neuronal development in the neocortex.
Project description:Mammalian neocortical neurons span one of the most diverse cell type spectra of any tissue. The regulatory strategies that neurons use during progressive development and maturation remain unclear. We present an integrated single-cell epigenomic and transcriptional analysis of individual classes of neurons from both mouse and marmoset neocortex, sampled during both early postmitotic stages of identity acquisition and later stages of neuronal plasticity and circuit integration. We find that in both species, the regulatory strategies controlling early and late stages of pan-neuronal development diverge. Early postmitotic neurons use molecular regulatory programs with broader tissue distribution and greater evolutionary conservation. In contrast, programs that are active during later neuronal maturation implement more brain- and neuron-specific mechanisms showing greater evolutionary divergence. Our work uncovers a temporally-regulated shift in regulatory choices, likely reflecting unique evolutionary constraints on distinct events of neuronal development in the neocortex.
