ARTICLES https://doi.org/10.1038/s41556-018-0047-x 1 Key Laboratory of Regenerative Biology of the Chinese Academy of Sciences, Joint School of Life Sciences, Guangzhou Medical University and Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. 2 Laboratory of RNA, Chromatin, and Human Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. 3 Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. 4 University of Chinese Academy of Sciences, Beijing, China. 5 Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou, China. 6 Department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan. 7 Laboratory of Metabolism and Cell Fate, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. 8 Institute of Health Sciences, Anhui University, Hefei, China. 9 Department of Medicine, The University of Hong Kong, Hong Kong, China. 10 Department of Biology, Southern University of Science and Technology of China, Shenzhen, China. 11 Guangzhou FitGene Biotechnology Co. Ltd., Guangzhou, China. 12 Drug Discovery Pipeline, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. 13 Hong Kong-Guangdong Joint Laboratory of Stem Cells and Regenerative Medicine, The University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Hong Kong, China. 14 Shenzhen Institutes of Research and Innovation, The University of Hong Kong, Hong Kong, China. 15 School of Life Sciences and Technology, Tongji University, Shanghai, China. 16 These authors contributed equally: Qiang Zhuang, Wenjuan Li and Christina Benda. *e-mail: andrewh@sustc.edu.cn; miguel@gibh.ac.cn S omatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) by enforced expression of defined exogenous fac- tors, originally OCT4, SOX2, KLF4 and c-MYC (OSKM) 1 . At the onset of reprogramming, the exogenous OSKM bind to DNA across the genome and induce successive rounds of chromatin reorganization to allow the activation of the entire pluripotency gene network 2–4 . However, OSKM do not operate in isolation and need co-regulators to modify the local epigenetic environment 5–8 . Despite the growing evidence regarding transcriptional and epi- genetic responses in reprogramming, it remains unclear how OSKM and different transcriptional co-regulators (co-activators and co-repressors) work with or antagonize each other to induce a pluripotent state 9 . In this report, we explored the function of two well-known co- repressors, nuclear receptor co-repressor (NCoR) and silencing mediator of retinoid and thyroid hormone receptor (SMRT) 10,11 , both of which have fundamental roles in preserving cellular identity and tissue homeostasis, in reprogramming. Results NCoR/SMRT co-repressors create a barrier to OSKM repro- gramming. First, we assessed Ncor1 (encoding NCoR) and Ncor2 (encoding SMRT) expression in mouse embryonic fibroblasts (MEFs), embryonic stem cells (ESCs) and OSKM reprogramming by quantitative PCR with reverse transcription (RT–qPCR). Both co-repressors were expressed in all three cell types, with an increase in the levels of Ncor1 during reprogramming and in ESCs com- pared to MEFs (Supplementary Fig. 1a). We then knocked down Ncor1/2 in OG2 MEFs 12–15 transduced with OSKM retroviruses (Supplementary Fig. 1b–d). Knocking down either co-repressor significantly enhanced the number of Oct4–green fluorescent protein-positive (Oct4-GFP + ) colonies in both serum-based and NCoR/SMRT co-repressors cooperate with c-MYC to create an epigenetic barrier to somatic cell reprogramming Qiang Zhuang 1,2,3,5,16 , Wenjuan Li 2,3,4,5,16 , Christina Benda 2,3,5,16 , Zhijian Huang 2,3,5 , Tanveer Ahmed 3,5,6,7 , Ping Liu 2,3,5,8 , Xiangpeng Guo 1,2,3,5 , David P. Ibañez 2,3,4,5 , Zhiwei Luo 2,3,4,5 , Meng Zhang 2,3,4,5 , Mazid Md. Abdul 2,3,4,5 , Zhongzhou Yang 3 , Jiayin Yang 9 , Yinghua Huang 1,3,5,7 , Hui Zhang 3,5,7 , Dehao Huang 2,3,4 , Jianguo Zhou 2,3,5 , Xiaofen Zhong 2,3 , Xihua Zhu 2,3,5 , Xiuling Fu 10 , Wenxia Fan 2,3,5 , Yulin Liu 11 , Yan Xu 2,3,5 , Carl Ward 2,3,5 , Muhammad Jadoon Khan 2,3,5 , Shahzina Kanwal 2,3,5 , Bushra Mirza 6 , Micky D. Tortorella 12 , Hung-Fat Tse 9,13,14 , Jiayu Chen 15 , Baoming Qin 1,3,5,7,13 , Xichen Bao  1,2,3,5 , Shaorong Gao 15 , Andrew P. Hutchins  10 * and Miguel A. Esteban  1,2,3,5,13 * Somatic cell reprogramming by exogenous factors requires cooperation with transcriptional co-activators and co-repressors to effectively remodel the epigenetic environment. How this interplay is regulated remains poorly understood. Here, we demon- strate that NCoR/SMRT co-repressors bind to pluripotency loci to create a barrier to reprogramming with the four Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC), and consequently, suppressing NCoR/SMRT significantly enhances reprogramming efficiency and kinetics. The core epigenetic subunit of the NCoR/SMRT complex, histone deacetylase 3 (HDAC3), contributes to the effects of NCoR/SMRT by inducing histone deacetylation at pluripotency loci. Among the Yamanaka factors, recruitment of NCoR/SMRT–HDAC3 to genomic loci is mostly facilitated by c-MYC. Hence, we describe how c-MYC is beneficial for the early phase of reprogramming but deleterious later. Overall, we uncover a role for NCoR/SMRT co-repressors in reprogramming and propose a dual function for c-MYC in this process. © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. NATURE CELL BIOLOGY | www.nature.com/naturecellbiology