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Patwary, N.

Publications and source records attributed to Patwary, N..

2 recordsLinked to original sources

Mouse fertilization triggers a conserved transcription program in one-cell embryos

Following fertilization, the new embryo reprograms parental genomes to begin transcription (embryonic genome activation, EGA). EGA is indispensable for development, but its dynamics, profile or when it initiates in vertebrates are unknown. We here characterize the onset of transcription in mouse one-cell embryos. Precise embryo staging eliminated noise to reveal a cascading program of de novo transcription initiating within six hours of fertilization. This immediate EGA (iEGA) utilized canonical promoters, produced spliced transcripts, was distinctive and predominantly driven by the maternal genome. Expression represented pathways not only associated with embryo development but with cancer. In human one-cell embryos, hundreds of genes were up-regulated days earlier than thought, with conservation to mouse iEGA. These findings provide a functional basis for epigenetic analysis in early-stage embryos and illuminate networks governing totipotency and other cell-fate transitions. One Sentence SummaryFertilization instates transcription in mouse and human one-cell embryos far sooner than thought and is programmed.

developmental biology

Interleukin-6 trans-signaling is a candidate mechanism to drive progression of human DCCs during periods of clinical latency

Although thousands of breast cancer cells disseminate and home to bone marrow until primary surgery, usually less than a handful will succeed in establishing manifest metastases months to years later. To identify signals that support survival or outgrowth in patients, we profiled rare bone marrow-derived disseminated cancer cells (DCCs) long before manifestation of metastasis and identified IL6/PI3K-signaling as candidate pathway for DCC activation. Surprisingly, and similar to mammary epithelial cells, DCCs lacked membranous IL6 receptor expression and mechanistic dissection revealed IL6 trans-signaling to regulate a stem-like state of mammary epithelial cells via gp130. Responsiveness to IL6 trans-signals was found to be niche-dependent as bone marrow stromal and endosteal cells down-regulated gp130 in premalignant mammary epithelial cells as opposed to vascular niche cells. PIK3CA activation rendered cells independent from IL6 trans-signaling. Consistent with a bottleneck function of microenvironmental DCC control, we found PIK3CA mutations highly associated with late-stage metastatic cells while being extremely rare in early DCCs. Our data suggest that the initial steps of metastasis formation are often not cancer cell-autonomous, but also depend on microenvironmental signals.

cancer biology