Resident adult epithelial stem cells maintain tissue homeostasis by balancing self-renewal and differentiation. The stem cell potential of human epidermal keratinocytes is retained in vitro but lost over time suggesting extrinsic and intrinsic regulation. Transcription factor-controlled regulatory circuitries govern cell identity, are sufficient to induce pluripotency and transdifferentiate cells. We investigate whether transcriptional circuitry also governs phenotypic changes within a given cell type by comparing human primary keratinocytes with intrinsically high versus low stem cell potential. Using integrated chromatin and transcriptional profiling, we implicate IRF2 as antagonistic to stemness and show that it binds and regulates active cis-regulatory elements at interferon response and antigen presentation genes. CRISPR-KD of IRF2 in keratinocytes with low stem cell potential increases self-renewal, migration and epidermis formation. These data demonstrate that transcription factor regulatory circuitries, in addition to maintaining cell identity, control plasticity within cell types and offer potential for therapeutic modulation of cell function.
Summary BET bromodomain inhibitors hold promise as therapeutic agents in diverse indications, but their clinical progression has been challenging and none have received regulatory approval. Early clinical trials in cancer have shown heterogeneous clinical responses, development of resistance, and adverse events. Increased understanding of their mechanism(s) of action and identification of biomarkers are needed to identify appropriate indication(s) and achieve efficacious dosing. Using genome-wide CRISPR-Cas9 screens at different concentrations, we report molecular mechanisms defining cellular responses to BET inhibitors, some of which appear specific to a single compound concentration. We identify multiple transcriptional regulators and mTOR pathway members as key determinants of JQ1 sensitivity and two Ca 2+ /Mn 2+ transporters, ATP2C1 and TMEM165, as key determinants of JQ1 resistance. Our study reveals new molecular mediators of BET bromodomain inhibitor effects, suggests the involvement of manganese, and provides a rich resource for discovery of biomarkers and targets for combination therapies.
Volkszählungen sind ein politisches Ereignis und stellen eine organisatorische Herausforderung dar. Die Organisation der Volkszählung 2010 in Russland war von diversen Schwierigkeiten begleitet, die zwischenzeitlich sogar eine Verschiebung nahe legten. Insgesamt ist die Volkszählung als regulär verlaufen und ihre Grunddaten als verlässliche Datenquelle zu beurteilen.
Volkszählungen sind ein politisches Ereignis und stellen eine organisatorische Herausforderung dar. Die Organisation der Volkszählung 2010 in Russland war von diversen Schwierigkeiten begleitet, die zwischenzeitlich sogar eine Verschiebung nahe legten. Insgesamt ist die Volkszählung als regulär verlaufen und ihre Grunddaten als verlässliche Datenquelle zu beurteilen.
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