Activation of the Notch receptor generates the Notch intracellular domain, which translocates to the nucleus and activates transcription of target genes by triggering the replacement of corepressors with coactivators associated with Suppressor of Hairless [Su(H)] at those promoters. In Drosophila, olfactory receptor neurons (ORNs) arise from three asymmetric divisions of the sensory organ precursor cell (see Schmucker and Hassan), which Endo et al. found resulted in the asymmetric segregation of the Notch inhibitor Numb and its adaptor protein Partner of Numb (Pon). Thus, daughter cells derived from the pNa and pNb intermediate cells had high (Naa and Nba cells, respectively) or low (Nab and Nbb cells, respectively) Notch activity because of the relative abundance of Numb and Pon. The transcription factor Hamlet (Ham) was present only in pNa and its daughters Naa and Nab. Analysis of axonal targeting and expression of genes encoding odorant receptors suggested that ham deficiency caused a switch from Nab to Nba identity. In S2 cells with inducible Notch signaling that expressed either Notch alone (S2N cells) or Notch in combination with Ham (S2NHam cells), expression of the Notch target gene E(spl)m3 (enhancer of split m3) was similar in the absence of Notch signaling. When Notch signaling was activated, E(spl)m3 expression increased in S2N cells, an effect that was attenuated in S2NHam cells. Trimethylated histone 3 (H3) K4 (Lys4) and trimethylated H3-K27 (Lys27) mark Notch target genes that are poised for activation and that are refractory to induction, respectively. Ham expression blocked increases in trimethylated H3-K4 that occurred basally and that were induced by Notch signaling; in addition, it increased the abundance of trimethylated H3-K27, an effect that required its direct interaction with the chromatin-modifying enzyme CtBP (C-terminal binding protein). Transcription of E(spl)m3 in S2N cells is associated with low basal H3 density and increased Su(H) occupancy at its Su(H)-binding enhancer after activation of Notch signaling, and in S2NHam cells, this enhancer showed high basal H3 density and reduced Su(H) occupancy. In wild-type ORN clones, the activity of a transcriptional reporter for the Notch target gene E(spl)m8 decreased when the expression of Ham increased, an effect that was lost in ham-deficient clones. Thus, Ham induces chromatin remodeling at the promoters of Notch target genes, thereby changing the transcriptional response to Notch signaling and enabling diversification of cell fates specified by Notch.
K. Endo, M. R. Karim, H. Taniguchi, A. Krejci, E. Kinameri, M. Siebert, K. Ito, S. J. Bray, A. W. Moore, Chromatin modification of Notch targets in olfactory receptor neuron diversification. Nat. Neurosci. 15, 224–233 (2012). [PubMed]
D. Schmucker, B. A. Hassan, Hamlet Notches fate. Nat. Neurosci. 15, 174–176 (2012). [PubMed]