Immunofluorescence Stainings and Image Acquisition Paraffinized sections (mouse and human) were prepared for immunofluorescence staining by heating the slides for 15 min at 55°C in an oven, deparaffinized (2 x 100% xylene 5 min each, 2 x 100% ethanol 5 min each, 2 x 95% ethanol 5 min each, 70% ethanol for 5 min) and rinsed in dH2O for 5 min. Antigen retrieval was performed by heating the slides at 95°C for 20 min in HistoVT pH 7.0 (Nacalai USA) for all antibodies used. Specimens were blocked in 5% goat serum PBS-T for 15 min at RT before incubating with primary antibody diluted in 1% goat serum PBS-T overnight at 4°C. For primary antibodies produced in goat, donkey serum was used as the blocking agent. Each slide was rinsed three times in PBS, for 5 min each. Specimens were incubated in fluorochrome-conjugated secondary antibody diluted in 1% goat serum PBS-T for 1 hr at RT in the dark. After rinsing as above, VectorShield with DAPI and coverslip were mounted and slides were allowed to cure overnight at 4°C in the dark before image acquisition. For apoptosis assessment, we used DeadEnd Fluorometric TUNEL (Promega) and performed the staining as recommended by manufacturer. A list of antibodies used can be found in Key Resources Table.Images were acquired using either ApoTome.2 (Zeiss) without structured illumination or LSM780 (Zeiss) and analyzed using ImageJ software unless otherwise stated.

For human samples, analysis of H3K27me3, H3, Insulin and DAPI intensities were automated using customized Cell Profiler pipeline (available upon request).