Coordinate transcriptional and post-transcriptional repression of pro-differentiation genes maintains intestinal stem cell identity

Abstract

The role of Processing bodies (P-bodies), key sites of post-transcriptional control, in adult stem cells remains poorly understood. Here, we report that adult Drosophila intestinal stem cells, but not surrounding differentiated cells such as absorptive Enterocytes (ECs), harbor P-bodies that contain Drosophila orthologs of mammalian P-body components DDX6, EDC3, EDC4 and LSM14A/B. A targeted RNAi screen in intestinal progenitor cells identified 39 previously known and 64 novel P-body regulators, including Patr-1, a gene necessary for P-body assembly. Loss of Patr-1-dependent P-bodies leads to a loss of stem cells that is associated with inappropriate translation and expression of EC-fate gene nubbin. Transcriptomic analysis of progenitor cells identifies a cadre of such weakly transcribed pro-differentiation transcripts that are elevated after P-body loss. Altogether, this study identifies a coordinated P-body dependent, translational and transcriptional repression program that maintains a defined set of in vivo stem cells in a state primed for differentiation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=198 HEIGHT=200 SRC="FIGDIR/small/175398v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@d57273org.highwire.dtl.DTLVardef@14d057aorg.highwire.dtl.DTLVardef@1a2c4a5org.highwire.dtl.DTLVardef@11c5ba3_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIDrosophila intestinal progenitor cells contain constitutive and ultrastructurally organized P-bodies. C_LIO_LIA P-body regulator Patr-1 is required for intestinal progenitor cell maintenance. C_LIO_LIEnterocyte (EC) genes such as nubbin are weakly transcribed but not translated in intestinal progenitors. C_LIO_LIP-bodies repress EC gene translation to promote stem cell maintenance. C_LI