Aim: Human induced pluripotent stem cells (iPSCs) are inefficiently derived from somatic cells by overexpression of defined transcription factors. Overexpression of H2A histone variant macroH2A1.1, but not macroH2A1.2, leads to increased iPSC reprogramming by unclear mechanisms. Materials & methods: Cleavage under targets and tagmentation (CUT&Tag) allows robust epigenomic profiling of a low cell number. We performed an integrative CUT&Tag-RNA-Seq analysis of macroH2A1-dependent orchestration of iPSCs reprogramming using human endothelial cells. Results: We demonstrate wider genome occupancy, predicted transcription factors binding, and gene expression regulated by macroH2A1.1 during reprogramming, compared to macroH2A1.2. MacroH2A1.1, previously associated with neurodegenerative pathologies, specifically activated ectoderm/neural processes. Conclusion: CUT&Tag and RNA-Seq data integration is a powerful tool to investigate the epigenetic mechanisms occurring during cell reprogramming.

Bioinformatics Unit Fondazione IRCCS Casa Sollievo della Sofferenza 71013 San Giovanni Rotondo Italy

Department of Biomedical and Biotechnological Sciences University of Catania 95123 Catania Italy

Department of Histology and Embryology Faculty of Medicine Masaryk University 62500 Brno Czech Republic

Department of Translational Stem Cell Biology Research Institute Medical University of Varna 9002 Varna Bulgaria

Faculty of Health Liverpool John Moores University L2 2ER Liverpool UK

Institute of Experimental Biology Faculty of Science Masaryk University 62500 Brno Czech Republic

International Clinical Research Center St Anne's University Hospital 65691 Brno Czech Republic

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