Abstract 541: A Hedgehog-signaling Dependent Gene Regulatory Network Directly Delays Second Heart Field Differentiation to Prevent Congenital Heart Disease

The first heart field (FHF) and the second heart field (SHF) comprise the major progenitor pools for the developing vertebrate heart. We investigated the delayed differentiation of the SHF relative to the FHF, a major distinguishing feature of these fields. Single-cell transcriptional profiling of the SHF revealed a differentiation trajectory of SHF progenitors to cardiomyocytes. Hedgehog (Hh) signaling was highly enriched in the progenitor state in signaling pathway analysis, suggesting a possible role in cardiomyocyte differentiation control. Transcriptional profiling of the SHF following removal of active Hh signaling in vivo revealed inappropriate cardiomyocyte gene expression. We observed precocious cardiomyocyte differentiation in the SHF in vivo in Hh mutants, which led to Congenital Heart Disease (CHD). Modeling active Hh signaling in a novel mouse embryonic stem cell (mESC) line through transient expression of the activating Hh transcription factor (TF), GLI1, in cardiac progenitors delayed the onset of cardiomyocyte differentiation. GLI1 directly activated a progenitor-specific gene regulatory network, dominated by repressive TFs, that prevented the acquisition of the cardiomyocyte gene regulatory network. Maintained expression of one GLI1 target TF, FOXF1, repressed the cardiomyocyte differentiation program. FOXF1 binding sites were identified at putative regulatory elements near repressed cardiac genes involved in contraction, electrical impulse propagation and transcriptional regulation. Finally, FOXF1 repressed the activity of these elements in vitro , indicating that FOXF1 can directly repress the activation of genes essential for cardiomyocyte differentiation. Together, these results indicate that a Hh-dependent gene regulatory network including transcriptional repressors directly delays the onset of cardiomyocyte gene expression to delay SHF differentiation. Abrogation of Hh signaling and the resultant premature differentiation of cardiac progenitors provides a molecular mechanism for the ontogeny of some CHD.

Download Full-text

Hedgehog signaling activates a heterochronic gene regulatory network to control differentiation timing across lineages

10.1101/270751 ◽

2018 ◽

Cited By ~ 1

Author(s):

Megan Rowton ◽

Carlos Perez-Cervantes ◽

Ariel Rydeen ◽

Suzy Hur ◽

Jessica Jacobs-Li ◽

...

Keyword(s):

Gene Regulatory Network ◽

Regulatory Network ◽

Hedgehog Signaling ◽

Cardiomyocyte Differentiation ◽

Cardiac Progenitors ◽

Second Heart Field ◽

Heart Field ◽

Gene Regulatory ◽

Hh Signaling

SUMMARYHeterochrony, defined as differences in the timing of developmental processes, impacts organ development, homeostasis, and regeneration. The molecular basis of heterochrony in mammalian tissues is poorly understood. We report that Hedgehog signaling activates a heterochronic pathway that controls differentiation timing in multiple lineages. A differentiation trajectory from second heart field cardiac progenitors to first heart field cardiomyocytes was identified by single-cell transcriptional profiling in mouse embryos. A survey of developmental signaling pathways revealed specific enrichment for Hedgehog signaling targets in cardiac progenitors. Removal of Hh signaling caused loss of progenitor and precocious cardiomyocyte differentiation gene expression in the second heart field in vivo. Introduction of active Hh signaling to mESC-derived progenitors, modelled by transient expression of the Hh-dependent transcription factor GLI1, delayed differentiation in cardiac and neural lineages in vitro. A shared GLI1-dependent network in both cardiac and neural progenitors was enriched with FOX family transcription factors. FOXF1, a GLI1 target, was sufficient to delay onset of the cardiomyocyte differentiation program in progenitors, by epigenetic repression of cardiomyocyte-specific enhancers. Removal of active Hh signaling or Foxf1 expression from second heart field progenitors caused precocious cardiac differentiation in vivo, establishing a mechanism for resultant Congenital Heart Disease. Together, these studies suggest that Hedgehog signaling directly activates a gene regulatory network that functions as a heterochronic switch to control differentiation timing across developmental lineages.

Download Full-text

A Boolean Model of the Cardiac Gene Regulatory Network Determining First and Second Heart Field Identity

PLoS ONE ◽

10.1371/journal.pone.0046798 ◽

2012 ◽

Vol 7 (10) ◽

pp. e46798 ◽

Cited By ~ 36

Author(s):

Franziska Herrmann ◽

Alexander Groß ◽

Dao Zhou ◽

Hans A. Kestler ◽

Michael Kühl

Keyword(s):

Gene Regulatory Network ◽

Regulatory Network ◽

Boolean Model ◽

Second Heart Field ◽

Cardiac Gene ◽

Heart Field ◽

Gene Regulatory

Download Full-text

Faculty Opinions recommendation of Reconstruction of the global neural crest gene regulatory network in vivo.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.736778685.793584536 ◽

2021 ◽

Author(s):

Morris Maduro

Keyword(s):

Neural Crest ◽

Gene Regulatory Network ◽

Regulatory Network ◽

Gene Regulatory

Download Full-text

Towards in vivo computing: Quantitative analysis of an artificial gene regulatory network behaving as a RS flip-flop and simulating the system in silico

2006 1st Bio-Inspired Models of Network, Information and Computing Systems ◽

10.1109/bimnics.2006.361829 ◽

2006 ◽

Author(s):

Sikander Hayat ◽

Kai Ostermann ◽

Lutz Brusch ◽

Wolfgang Pompe ◽

Gerhard Rodel

Keyword(s):

Quantitative Analysis ◽

Gene Regulatory Network ◽

Regulatory Network ◽

In Silico ◽

Flip Flop ◽

Gene Regulatory ◽

Artificial Gene

Download Full-text

Insights Into the Early Gene Regulatory Network Controlling Neural Crest and Placode Fate Choices at the Neural Border

Frontiers in Physiology ◽

10.3389/fphys.2020.608812 ◽

2020 ◽

Vol 11 ◽

Author(s):

Subham Seal ◽

Anne H. Monsoro-Burq

Keyword(s):

Neural Crest ◽

Gene Regulatory Network ◽

Regulatory Network ◽

Cell Types ◽

Model Systems ◽

Early Gene ◽

Secretory Cells ◽

Peripheral Neurons ◽

Gene Regulatory

The neural crest (NC) cells and cranial placodes are two ectoderm-derived innovations in vertebrates that led to the acquisition of a complex head structure required for a predatory lifestyle. They both originate from the neural border (NB), a portion of the ectoderm located between the neural plate (NP), and the lateral non-neural ectoderm. The NC gives rise to a vast array of tissues and cell types such as peripheral neurons and glial cells, melanocytes, secretory cells, and cranial skeletal and connective cells. Together with cells derived from the cranial placodes, which contribute to sensory organs in the head, the NC also forms the cranial sensory ganglia. Multiple in vivo studies in different model systems have uncovered the signaling pathways and genetic factors that govern the positioning, development, and differentiation of these tissues. In this literature review, we give an overview of NC and placode development, focusing on the early gene regulatory network that controls the formation of the NB during early embryonic stages, and later dictates the choice between the NC and placode progenitor fates.

Download Full-text

An Integrative Developmental Genomics and Systems Biology Approach to Identify an In Vivo Sox Trio-Mediated Gene Regulatory Network in Murine Embryos

BioMed Research International ◽

10.1155/2017/8932583 ◽

2017 ◽

Vol 2017 ◽

pp. 1-16 ◽

Cited By ~ 3

Author(s):

Wenqing Jean Lee ◽

Sumantra Chatterjee ◽

Sook Peng Yap ◽

Siew Lan Lim ◽

Xing Xing ◽

...

Keyword(s):

Systems Biology ◽

Gene Regulatory Network ◽

Regulatory Network ◽

Regulatory Networks ◽

Cell Types ◽

Specific Cell ◽

Morpholino Knockdown ◽

Cell Type Specific ◽

Gene Regulatory

Embryogenesis is an intricate process involving multiple genes and pathways. Some of the key transcription factors controlling specific cell types are the Sox trio, namely, Sox5, Sox6, and Sox9, which play crucial roles in organogenesis working in a concerted manner. Much however still needs to be learned about their combinatorial roles during this process. A developmental genomics and systems biology approach offers to complement the reductionist methodology of current developmental biology and provide a more comprehensive and integrated view of the interrelationships of complex regulatory networks that occur during organogenesis. By combining cell type-specific transcriptome analysis and in vivo ChIP-Seq of the Sox trio using mouse embryos, we provide evidence for the direct control of Sox5 and Sox6 by the transcriptional trio in the murine model and by Morpholino knockdown in zebrafish and demonstrate the novel role of Tgfb2, Fbxl18, and Tle3 in formation of Sox5, Sox6, and Sox9 dependent tissues. Concurrently, a complete embryonic gene regulatory network has been generated, identifying a wide repertoire of genes involved and controlled by the Sox trio in the intricate process of normal embryogenesis.

Download Full-text