SUMO Safeguards Somatic and Pluripotent Cell Identities by Enforcing Distinct Chromatin States

Understanding general principles that safeguard cellular identity should reveal critical insights into common mechanisms underlying specification of varied cell types. Here, we show that SUMO modification acts to stabilize cell fate in a variety of contexts. Hyposumoylation enhances pluripotency reprogramming in vitro and in vivo, increases lineage transdifferentiation, and facilitates leukemic cell differentiation. Suppressing sumoylation in embryonic stem cells (ESCs) promotes their conversion into 2-cell-embryo-like (2C-like) cells. During reprogramming to pluripotency, SUMO functions on fibroblastic enhancers to retain somatic transcription factors together with Oct4, Sox2, and Klf4, thus impeding somatic enhancer inactivation. In contrast, in ESCs, SUMO functions on heterochromatin to silence the 2C program, maintaining both proper H3K9me3 levels genome-wide and repression of the Dux locus by triggering recruitment of the sumoylated PRC1.6 and Kap/Setdb1 repressive complexes. Together, these studies show that SUMO acts on chromatin as a glue to stabilize key determinants of somatic and pluripotent states. [Display omitted] •SUMO acts on chromatin to maintain cellular identity•SUMO impairs somatic enhancer inactivation early during iPSC reprogramming•Loss of SUMO converts ESCs into a 2C-like state by releasing PRC1.6 from the Dux locus•Loss of SUMO in ESCs leads to genome-wide loss of H3K9me3-dependent heterochromatin SUMO functions as a tether on distinct chromatin types in MEFs and ESCs to stabilize occupancy of protein substrate complexes on key cell-identity genes, thus preserving the somatic and pluripotent states.