PRC1 Fine-tunes Gene Repression and Activation to Safeguard Skin Development and Stem Cell Specification Independently of PRC2

Idan Cohen ¹ Dejian Zhao ² Carmit Bar ¹ Victor Julian Valdes ¹ Katherine Dauber-Decker ¹ Minh Nguyen ¹ Manabu Nakayama ³ Michael Rendl ¹ Wendy Bickmore ⁴ Haruhiko Koseki ⁵ Deyou Zheng ² Elena Ezhkova ¹

¹Black Family Stem Cell Institute, Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, USA
²Department of Genetics, Albert Einstein College of Medicine, USA
³Department of Frontier Research and Development, Kazusa DNA Research Institute, Japan
⁴MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, UK
⁵Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences (RIKEN-IMS), Japan

Polycomb-repressive complex 1 (PRC1) and PRC2 are critical chromatin regulators of gene expression. Here, we show that despite extensive genomic co-binding, PRC1 is essential for epidermal tissue development, whereas PRC2 is dispensable. Loss of PRC1 resulted in impaired stem cell specification, arrested epidermal development, and blistering skin reminiscent of human skin fragility syndromes. Epigenetic and transcriptional profiling demonstrated that, despite well-established repressor function, PRC1 binds to both silent and active genes in epidermal stem cells. Molecular dissection demonstrated that PRC1 functions with PRC2 to silence/dampen expression of non-epidermal lineage genes. In striking contrast, Non-canonical PRC1 complexes also bind to and promote the expression of genes critical for skin development and stem cell formation. Together, our findings highlight PRC1`s diverse roles in executing a precise developmental program, and demonstrate a functional link between PRC1-mediated epigenetic regulation and skin diseases.