PT  - JOURNAL ARTICLE
AU  - Megan Rowton
AU  - Andrew D. Hoffmann
AU  - Jeffrey D. Steimle
AU  - Xinan Holly Yang
AU  - Alexander Guzzetta
AU  - Sonja Lazarevic
AU  - Chul Kim
AU  - Nikita Deng
AU  - Emery Lu
AU  - Jessica Jacobs-Li
AU  - Shuhan Yu
AU  - Erika Hanson
AU  - Carlos Perez-Cervantes
AU  - Sunny Sun-Kin Chan
AU  - Kohta Ikegami
AU  - Daniel J. Garry
AU  - Michael Kyba
AU  - Ivan P. Moskowitz
TI  - Hedgehog signaling controls progenitor differentiation timing during heart development
AID  - 10.1101/270751
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 270751
4099  - http://biorxiv.org/content/early/2018/02/23/270751.short
4100  - http://biorxiv.org/content/early/2018/02/23/270751.full
AB  - A balance between progenitor cell maintenance and differentiation is tightly regulated during embryonic development1–3 and adult tissue homeostasis4–8. Hedgehog (Hh) signaling is known to function within the progenitor cell populations of several developing9 and regenerative10 organs, and in cancers with resident progenitor subpopulations11–12. Here we provide evidence that Hh signaling dictates differentiation timing by promoting progenitor status and inhibiting differentiation during mammalian heart morphogenesis. Removal of active Hh signaling from cardiac progenitors in vivo caused increased cardiomyocyte differentiation gene expression, precocious differentiation, and Congenital Heart Disease (CHD). Modeling active Hh signaling through expression of the activating Hh transcription factor (TF), GLI1, in cardiac progenitors enabled the maintenance of a progenitor-specific regulatory network and delayed onset of the cardiomyocyte differentiation program. Progenitor-specific, but not differentiated cardiomyocyte-specific, accessible chromatin regions were enriched for GLI binding motifs. Furthermore, GLI1 expression promoted a global shift of chromatin accessibility towards progenitor-like, and away from cardiomyocyte-like, profiles at distal regulatory elements. The shift from active to repressive GLI TF abundance comprised a molecular switch that determined the activity patterns of progenitor-specific regulatory elements in vitro and in vivo. Thus, Hh signaling modulates a GLI switch at progenitor enhancers to activate progenitor gene expression and inhibit premature differentiation, thereby determining cardiac progenitor differentiation timing. This provides a novel molecular paradigm for progenitor maintenance by signal-dependent TFs with implications for organ development, regenerative potential, and cancer.