FIGURE

Fig. 7

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ZDB-FIG-101011-52

Publication

Rai et al., 2010 - DNA demethylase activity maintains intestinal cells in an undifferentiated state following loss of APC

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Fig. 7

Lsd1 Represses rdh1l Expression and Intestinal Differentiation, and a Model for Retinoic Acid Regulation of DNA Methylation Dynamics

(A) Whole-mount in situ staining for lsd1 and corest in the intestine (arrows) of apc^mcr and apc^wt embryos (72 hpf).

(B) Fold change in rdh1l expression compared to 28S levels in apc^wt and apc^mcr embryos injected with control/lsd1/corest Mo or treated with pargyline (to inhibit Lsd1 activity). Error bars indicate ± SD. Lsd1 and Corest morpholino knockdown efficiency is shown in Figures S7A and S7B.

(C) Whole-mount in situ staining for fabp2 and irbp in apc^mcr and apc^wt embryos injected with control/lsd1/corest Mo or treated with pargyline (3 mM).

(D and E) Model of APC regulation of intestinal fating via retinoic acid and demethylase. APC promotes RA production by directly negatively regulating CtBP1 levels in a proteasome-dependent fashion. APC also inhibits the transcription of LSD1, CoREST, LEF1, and TLE3. LEF1 binds to the RDH promoter and recruits TLE3 (Groucho2)/CtBP1/LSD1 repressors, which silence RDH expression. Retinoic acid negatively regulates demethylase components by inhibiting Pou5f1 and Cebpβ. Furthermore, regulation of demethylase components by APC is independent of β-catenin. Demethylase promotes the demethylation of key fate regulators (like aldh1a2, hoxa13a, evx1) and proliferative genes (like cyclind1 and pitx2). Fate regulators like aldh1a2 possibly help in maintaining a progenitor cell population.

See also Figure S7.

Expression Data

Genes:	fabp2 kdm1a rbp3 rcor1
Fish:	WT apc^hu745/hu745 apc^hu745/hu745 + MO1-kdm1a apc^hu745/hu745 + MO1-rcor1
Knockdown Reagents:	MO1-kdm1a MO1-rcor1
Anatomical Terms:	intestine retina
Stage:	Protruding-mouth

Expression Detail

Antibody Labeling

Phenotype Data

Fish:	apc^hu745/hu745 apc^hu745/hu745 + MO1-kdm1a apc^hu745/hu745 + MO1-rcor1
Knockdown Reagents:	MO1-kdm1a MO1-rcor1
Observed In:	digestive tract mesoderm development intestine retina retina development in camera-type eye
Stage:	Protruding-mouth

Phenotype Detail

Acknowledgments

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Reprinted from Cell, 142(6), Rai, K., Sarkar, S., Broadbent, T.J., Voas, M., Grossmann, K.F., Nadauld, L.D., Dehghanizadeh, S., Hagos, F.T., Li, Y., Toth, R.K., Chidester, S., Bahr, T.M., Johnson, W.E., Sklow, B., Burt, R., Cairns, B.R., and Jones, D.A., DNA demethylase activity maintains intestinal cells in an undifferentiated state following loss of APC, 930-942, Copyright (2010) with permission from Elsevier. Full text @ Cell