The study investigates the epigenomic reprogramming process in human induced pluripotent stem cells (iPSCs) by profiling DNA methylation patterns at single-base resolution. The researchers compared the methylomes of iPSCs with those of embryonic stem (ES) cells and somatic cells, finding significant variability in the reprogramming process. Key findings include: 1. **Global Similarity and Variability**: While the methylomes of ES cells and iPSCs are globally similar, each iPSC line shows significant variability, including somatic memory and aberrant reprogramming of DNA methylation. 2. **Somatic Memory and Aberrant Reprogramming**: iPSCs share megabase-scale differentially methylated regions (DMRs) near centromeres and telomeres, with incomplete reprogramming of non-CG methylation and differences in CG methylation and histone modifications. 3. **Differentiation and Transmission of DMRs**: Differentiation of iPSCs into trophoblast cells revealed that errors in reprogramming CG methylation are transmitted at a high frequency, indicating a signature of incomplete reprogramming that persists after differentiation. 4. **Megabase-Scale Non-CG Methylation Diffs**: Large regions of non-CG methylation (non-CG mega-DMRs) are repeatedly resistant to reprogramming, associated with altered histone modifications and transcriptional activity, suggesting distinct molecular properties of these chromosomal regions. 5. **Conclusions**: The study highlights the fundamental differences between iPSCs and ES cells, emphasizing the need for further research to understand the full range of epigenomic variability and identify factors enabling complete reprogramming. The research provides insights into the epigenomic reprogramming process and the challenges in achieving complete reprogramming of somatic cells to an ES-cell-like state.The study investigates the epigenomic reprogramming process in human induced pluripotent stem cells (iPSCs) by profiling DNA methylation patterns at single-base resolution. The researchers compared the methylomes of iPSCs with those of embryonic stem (ES) cells and somatic cells, finding significant variability in the reprogramming process. Key findings include: 1. **Global Similarity and Variability**: While the methylomes of ES cells and iPSCs are globally similar, each iPSC line shows significant variability, including somatic memory and aberrant reprogramming of DNA methylation. 2. **Somatic Memory and Aberrant Reprogramming**: iPSCs share megabase-scale differentially methylated regions (DMRs) near centromeres and telomeres, with incomplete reprogramming of non-CG methylation and differences in CG methylation and histone modifications. 3. **Differentiation and Transmission of DMRs**: Differentiation of iPSCs into trophoblast cells revealed that errors in reprogramming CG methylation are transmitted at a high frequency, indicating a signature of incomplete reprogramming that persists after differentiation. 4. **Megabase-Scale Non-CG Methylation Diffs**: Large regions of non-CG methylation (non-CG mega-DMRs) are repeatedly resistant to reprogramming, associated with altered histone modifications and transcriptional activity, suggesting distinct molecular properties of these chromosomal regions. 5. **Conclusions**: The study highlights the fundamental differences between iPSCs and ES cells, emphasizing the need for further research to understand the full range of epigenomic variability and identify factors enabling complete reprogramming. The research provides insights into the epigenomic reprogramming process and the challenges in achieving complete reprogramming of somatic cells to an ES-cell-like state.