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C/EBPα creates elite cells for iPSC reprogramming by upregulating Klf4 and increasing the levels of Lsd1 and Brd4. Di Stefano Bruno,Collombet Samuel,Jakobsen Janus Schou,Wierer Michael,Sardina Jose Luis,Lackner Andreas,Stadhouders Ralph,Segura-Morales Carolina,Francesconi Mirko,Limone Francesco,Mann Matthias,Porse Bo,Thieffry Denis,Graf Thomas Nature cell biology Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) is typically inefficient and has been explained by elite-cell and stochastic models. We recently reported that B cells exposed to a pulse of C/EBPα (Bα' cells) behave as elite cells, in that they can be rapidly and efficiently reprogrammed into iPSCs by the Yamanaka factors OSKM. Here we show that C/EBPα post-transcriptionally increases the abundance of several hundred proteins, including Lsd1, Hdac1, Brd4, Med1 and Cdk9, components of chromatin-modifying complexes present at super-enhancers. Lsd1 was found to be required for B cell gene silencing and Brd4 for the activation of the pluripotency program. C/EBPα also promotes chromatin accessibility in pluripotent cells and upregulates Klf4 by binding to two haematopoietic enhancers. Bα' cells share many properties with granulocyte/macrophage progenitors, naturally occurring elite cells that are obligate targets for leukaemic transformation, whose formation strictly requires C/EBPα. 10.1038/ncb3326
Transcriptional pause release is a rate-limiting step for somatic cell reprogramming. Liu Longqi,Xu Yan,He Minghui,Zhang Meng,Cui Fenggong,Lu Leina,Yao Mingze,Tian Weihua,Benda Christina,Zhuang Qiang,Huang Zhijian,Li Wenjuan,Li Xiangchun,Zhao Ping,Fan Wenxia,Luo Zhiwei,Li Yuan,Wu Yasong,Hutchins Andrew P,Wang Dongye,Tse Hung-Fat,Schambach Axel,Frampton Jon,Qin Baoming,Bao Xichen,Yao Hongjie,Zhang Biliang,Sun Hao,Pei Duanqing,Wang Huating,Wang Jun,Esteban Miguel A Cell stem cell Reactivation of the pluripotency network during somatic cell reprogramming by exogenous transcription factors involves chromatin remodeling and the recruitment of RNA polymerase II (Pol II) to target loci. Here, we report that Pol II is engaged at pluripotency promoters in reprogramming but remains paused and inefficiently released. We also show that bromodomain-containing protein 4 (BRD4) stimulates productive transcriptional elongation of pluripotency genes by dissociating the pause release factor P-TEFb from an inactive complex containing HEXIM1. Consequently, BRD4 overexpression enhances reprogramming efficiency and HEXIM1 suppresses it, whereas Brd4 and Hexim1 knockdown do the opposite. We further demonstrate that the reprogramming factor KLF4 helps recruit P-TEFb to pluripotency promoters. Our work thus provides a mechanism for explaining the reactivation of pluripotency genes in reprogramming and unveils an unanticipated role for KLF4 in transcriptional pause release. 10.1016/j.stem.2014.09.018