Nono, a Bivalent Domain Factor, Regulates Erk Signaling and Mouse Embryonic Stem Cell Pluripotency

• Published in: Cell reports (Cambridge) Vol. 17; no. 4; pp. 997 - 1007
• Main Authors: Ma, Chun, Karwacki-Neisius, Violetta, Tang, Haoran, Li, Wenjing, Shi, Zhennan, Hu, Haolin, Xu, Wenqi, Wang, Zhentian, Kong, Lingchun, Lv, Ruitu, Fan, Zheng, Zhou, Wenhao, Yang, Pengyuan, Wu, Feizhen, Diao, Jianbo, Tan, Li, Shi, Yujiang Geno, Lan, Fei, Shi, Yang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.10.2016; Elsevier
• Subjects: Animals; bivalent domain; Cell Differentiation - genetics; Cell Self Renewal; DNA-Binding Proteins - metabolism; Enzyme Activation; Epigenesis, Genetic; Erk; Gene Expression Profiling; Genome; ground state; Kruppel-Like Transcription Factors - metabolism; MAP Kinase Signaling System; mESC; Mice; Mice, Knockout; Mouse Embryonic Stem Cells - cytology; Mouse Embryonic Stem Cells - metabolism; Nanog Homeobox Protein - metabolism; Neat1; Nono; p54NRB; para-speckle; Phosphorylation; pluripotency; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - metabolism; RNAPII; Transcriptome - genetics; Nono; bivalent domain; mESC; pluripotency; RNAPII; para-speckle; p54NRB; Neat1; ground state; Erk
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.09.078

Nono is a component of the para-speckle, which stores and processes RNA. Mouse embryonic stem cells (mESCs) lack para-speckles, leaving the function of Nono in mESCs unclear. Here, we find that Nono functions as a chromatin regulator cooperating with Erk to regulate mESC pluripotency. We report that Nono loss results in robust self-renewing mESCs with epigenomic and transcriptomic features resembling the 2i (GSK and Erk inhibitors)-induced “ground state.” Erk interacts with and is required for Nono localization to a subset of bivalent genes that have high levels of poised RNA polymerase. Nono loss compromises Erk activation and RNA polymerase poising at its target bivalent genes in undifferentiated mESCs, thus disrupting target gene activation and differentiation. These findings argue that Nono collaborates with Erk signaling to regulate the integrity of bivalent domains and mESC pluripotency. [Display omitted] •Nono loss in mESCs leads to robust self-renewal•Erk interacts with Nono and is required for its chromatin localization•Nono is required for Erk activation and RNAPIIS5P at a subset of bivalent genes•Nono loss compromises mESC differentiation Ma et al. find that Nono KO mESCs have an enhanced capacity to self-renew with features resembling the 2i-induced “ground state.” The authors reveal a role for Nono, along with Erk signaling, in regulating the integrity of bivalent domains and mESC pluripotency.