Summary An open chromatin largely devoid of heterochromatin is a hallmark of stem cells, from Planarians to Mammals. It remains unknown whether an open chromatin is necessary for the differentiation potential of stem cells, and what are the molecules that maintain open chromatin in stem cells. Here we show that the chromatin remodeling factor Chd1 is required to maintain the open chromatin state of pluripotent mouse Embryonic Stem (ES) cells. Chd1 is a euchromatin protein that associates with the promoters of active genes, and down-regulation of Chd1 leads to accumulation of heterochromatin in ES cells. Chd1-deficient ES cells are no longer pluripotent, because they are incapable of giving rise to primitive endoderm and have a high propensity for neural differentiation. Furthermore, Chd1 is required for efficient reprogramming of fibroblasts to the pluripotent stem cell state. Our results indicate that Chd1 is essential for open chromatin and pluripotency of ES cells, and for somatic cell reprogramming to the pluripotent state. The data suggest that pluripotent stem cells exist in a dynamic state of opposing epigenetic influences of euchromatin and heterochromatin.

Highlights d Drug candidates optimized for ER degradation can weakly activate ER in cancer cells d ''ER degraders'' trigger interaction of ER with DNA at canonical binding sites d Impact on chromatin accessibility distinguishes ER antagonists from weak activators d Dramatic slowing of ER mobility drives ER antagonism, and precedes ER turnover

microRNA-1 (miR-1) is an evolutionarily conserved, striated muscle-enriched miRNA. Most mammalian genomes contain two copies of miR-1, and in mice, deletion of a single locus, miR-1-2, causes incompletely penetrant lethality and subtle cardiac defects. Here, we report that deletion of miR-1-1 resulted in a phenotype similar to that of the miR-1-2 mutant. Compound miR-1 knockout mice died uniformly before weaning due to severe cardiac dysfunction. miR-1-null cardiomyocytes had abnormal sarcomere organization and decreased phosphorylation of the regulatory myosin light chain-2 (MLC2), a critical cytoskeletal regulator. The smooth muscle-restricted inhibitor of MLC2 phosphorylation, Telokin, was ectopically expressed in the myocardium, along with other smooth muscle genes. miR-1 repressed Telokin expression through direct targeting and by repressing its transcriptional regulator, Myocardin. Our results reveal that miR-1 is required for postnatal cardiac function and reinforces the striated muscle phenotype by regulating both transcriptional and effector nodes of the smooth muscle gene expression network.DOI: http://dx.doi.org/10.7554/eLife.01323.001

The cell surface receptor tyrosine kinase HER2/neu enhances tumor metastasis. Recent studies suggest that deregulated microRNA (miRNA) expression promotes invasion and metastasis of cancer cells; we therefore explored the possibility that HER2/neu signaling induces the expression of specific miRNAs involved in this process. We identified a putative oncogenic miRNA, miR-21, whose expression is correlated with HER2/neu up-regulation and is functionally involved in HER2/neu-induced cell invasion. We show that miR-21 is up-regulated via the MAPK (ERK1/2) pathway upon stimulation of HER2/neu signaling in breast cancer cells, and overexpression of other ERK1/2 activators such as RASV12 or ID-1 is sufficient to induce miR-21 up-regulation in HER2/neu-negative breast cancer cells. Furthermore, the metastasis suppressor protein PDCD4 (programmed cell death 4) is down-regulated by miR-21 in breast cancer cells expressing HER2/neu. Our data reveal a mechanism for HER2/neu-induced cancer cell invasion via miRNA deregulation. In addition, our results identify miR-21 as a potential therapeutic target for the prevention of breast cancer invasion and metastasis.The HER2/neu (c-erbB-2) proto-oncogene encodes a transmembrane protein-tyrosine kinase growth factor receptor, p185 HER2 , which is a member of the human epidermal growth factor receptor family. HER2/neu overexpression is found in about 30% of human breast cancers and several other cancer types. HER2/neu overexpression is associated with a poor clinical outcome, including a positive correlation with metastasis (1, 2). The involvement of HER2/neu in metastasis is supported by studies demonstrating that HER2/neu increases the metastatic potential of human and murine cancer cell lines (3) and induces lung metastasis in transgenic animal models (4). Additionally, HER2/neu signaling up-regulates genes that play important roles in cell invasion and metastasis, such as cyclooxygenase-2, CXCR4, and matrix metalloproteinases (5-7). Given the complex signaling network initiated by HER2/neu overexpression in cancer cells, it is likely that HER2/neu regulates additional unidentified players involved in these processes. miRNAs 4 constitute a class of 21 or 22 nucleotides noncoding RNAs that play an important role in development and cellular processes. Aberrant expression of miRNAs is associated with cancer (8), suggesting that some miRNAs can function as tumor suppressor genes or oncogenes. miRNAs may also cooperate with the loss of tumor suppressors or overexpression oncogenes in cancer cells to contribute to a fully malignant phenotype. Up-regulation of several miRNAs in breast cancer cells, such as miR-21 and miR-10b, can increase cell invasion and metastasis (9, 10). HER2/neu signaling activates a variety of transcription factors, such as AP-1, Myc, and NF-B that alter miR-21 and other miRNA transcription (8,11,12). We therefore hypothesize that HER2/neu signaling may induce the expression of specific miRNAs, which contribute to the increased metastatic potential of HER2/neu-over...