Machine learning classification of cell-specific cardiac enhancers uncovers developmental subnetworks regulating progenitor cell division and cell fate specification.
The Drosophila heart is composed of two distinct cell types, the contractile cardial cells (CCs) and the surrounding non-muscle pericardial cells (PCs), development of which is regulated by a network of conserved signaling molecules and transcription factors (TFs). Here, we used machine learning with array-based chromatin immunoprecipitation (ChIP) data and TF sequence motifs to computationally classify cell type-specific cardiac enhancers. Extensive testing of predicted enhancers at single-cell resolution revealed the added value of ChIP data for modeling cell type-specific activities. Furthermore, clustering the top-scoring classifier sequence features identified novel cardiac and cell type-specific regulatory motifs. For example, we found that the Myb motif learned by the classifier is crucial for CC activity, and the Myb TF acts in concert with two forkhead domain TFs and Polo kinase to regulate cardiac progenitor cell divisions. In addition, differential motif enrichment and cis-trans genetic studies revealed that the Notch signaling pathway TF Suppressor of Hairless [Su(H)] discriminates PC from CC enhancer activities. Collectively, these studies elucidate molecular pathways used in the regulatory decisions for proliferation and differentiation of cardiac progenitor cells, implicate Su(H) in regulating cell fate decisions of these progenitors, and document the utility of enhancer modeling in uncovering developmental regulatory subnetworks.
Laboratory of Developmental Systems Biology, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Shaad M
SM
Ahmad
Brian W
BW
Busser
Di
D
Huang
Elizabeth J
EJ
Cozart
Sébastien
S
Michaud
Xianmin
X
Zhu
Neal
N
Jeffries
Anton
A
Aboukhalil
Martha L
ML
Bulyk
Ivan
I
Ovcharenko
Alan M
AM
Michelson
D000818:Animals; D001185:Artificial Intelligence; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D002965:Classification / Q000379:methods; D004330:Drosophila / Q000166:cytology / Q000254:growth & development*; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D006321:Heart / Q000254:growth & development*; D016296:Mutagenesis; D032386:Myoblasts, Cardiac / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D014157:Transcription Factors
Cell division; Drosophila; Gene regulation; Machine learning; Organogenesis; Progenitor specification; Transcription factors