Abstract
Differentiation and lineage specification are controlled by cooperation of growth factor signalling. The involvement of epigenetic regulators in lineage specification remains largely elusive. Here, we show that the histone methyltransferase Mll1 prevents intestinal progenitor cells from differentiation, whereas it is also involved in secretory lineage specification of Paneth and goblet cells. Using conditional mutagenesis in mice and intestinal organoids, we demonstrate that loss of Mll1 renders intestinal progenitor cells permissive for Wnt-driven secretory differentiation. However, Mll1-deficient crypt cells fail to segregate Paneth and goblet cell fates. Mll1 deficiency causes Paneth cell-determined crypt progenitors to exhibit goblet cell features by unleashing Mapk signalling, resulting in increased numbers of mixed Paneth/goblet cells. We show that loss of Mll1 abolishes the pro-proliferative effect of Mapk signalling in intestinal progenitor cells and promotes Mapk-induced goblet cell differentiation. Our data uncover Mll1 and its downstream targets Gata4/6 as a regulatory hub of Wnt and Mapk signalling in the control of lineage specification of intestinal secretory Paneth and goblet cells.
Highlights
The small intestinal epithelium consists of absorptive enterocytes and secretory cells including Paneth cells, mucus-secreting goblet cells, hormone-producing enteroendocrine cells, and tuft cells, which are organized in crypt-villus structures
We observed an increased number of secretory cells in the upper parts of Mll1−/− jejunal crypts, which were doublepositive for the goblet cell marker intestinal trefoil factor (ITF) and the Paneth cell marker lysozyme (Lyz) (Porter et al, 2002) (Fig 1B, quantification on the right)
We report a role of the epigenetic regulator Mll1 in Wnt- and Mapk-driven cell fate specification of secretory progenitors in the intestinal epithelium
Summary
The small intestinal epithelium consists of absorptive enterocytes and secretory cells including Paneth cells, mucus-secreting goblet cells, hormone-producing enteroendocrine cells, and tuft cells, which are organized in crypt-villus structures. Active Wnt signalling is critical for intestinal homeostasis, stem cell maintenance, and the formation of secretory progenitor cells (Pinto et al, 2003; Fevr et al, 2007). The ETS transcription factor Spdef further directs secretory maturation in Paneth and goblet cells and deletion of Spdef in the mouse intestine leads to an accumulation of immature secretory progenitor cells (Gregorieff et al, 2009; Noah, 2010). Persisting high Wnt activity in secretory progenitor cells promotes the differentiation of Paneth cells (van Es et al, 2005). High Wnt activity prevents goblet cell differentiation, as goblet cells are absent in Apc-mutant intestine (Sansom et al, 2004). We have previously shown that Mapk signalling impedes the Wnt-induced maturation of Paneth cells and shifts the differentiation of common Paneth-goblet progenitors towards a goblet cell fate (Heuberger et al, 2014)
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