Summary Embryonic stem cells (ESCs) of mice and humans have distinct molecular and biological characteristics, raising the question whether an earlier ‘naive’ state of pluripotency may exist in humans. Here we took a systematic approach to identify small molecules that support self-renewal of naive human ESCs based on maintenance of endogenous OCT4 distal enhancer activity, a molecular signature of ground state pluripotency. Iterative chemical screening identified a combination of five kinase inhibitors that induces and maintains OCT4 distal enhancer activity when applied directly to conventional human ESCs. These inhibitors generate human pluripotent cells in which transcription factors associated with the ground state of pluripotency are highly upregulated and bivalent chromatin domains are depleted. Comparison with previously reported naive human ESCs indicates that our conditions capture a distinct pluripotent state in humans that closely resembles mouse ESCs. This study presents a framework for defining the culture requirements of naive human pluripotent cells.
Global insights into cellular organization and genome function require comprehensive understanding of the interactome networks that mediate genotype-phenotype relationships 1,2 . Here, we present a human "all-by-all" reference interactome map of human binary protein interactions, or "HuRI". With ~53,000 high-quality protein-protein interactions (PPIs), HuRI has approximately four times more such interactions than high-quality curated interactions from smallscale studies. Integrating HuRI with genome 3 , transcriptome 4 , and proteome 5 data enables the study of cellular function within most physiological or pathological cellular contexts. We demonstrate the utility of HuRI in identifying specific subcellular roles of PPIs. Inferred tissuespecific networks reveal general principles for the formation of cellular context-specific functions and elucidate potential molecular mechanisms underlying tissue-specific phenotypes of Mendelian Reprints and permissions information is available at http://www.nature.com/reprints.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
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