Hot Off the Press! Graded mesoderm assembly governs cell fate and morphogenesis of the early mammalian

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Published in the Cell journal last month, former lab member and postdoctoral scholar Martin Dominguez along with lab members Jonathon Muncie and Alexis Krup discovered how to longitudinally reconstruct early murine cardiac development at single-cell resolution using four-dimensional whole-embryo light sheet imaging with improved and accessible computational tools. The practicable live embryo imaging approach defines spatial origins and behaviors of cardiac progenitors and identifies their unanticipated morphological transitions. This approach allows tracking the path of an individual cell as the heart develops and revealed unexpected patterns in cell movement that were not captured in previous static images.

“The Most Amazing Thing I’ve Ever Seen:” Heart Development Comes Alive, A Q&A with Gladstone Investigator Benoit Bruneau, delves into this immaculate discovery by his team and the process behind this approach.

Dominguez MH, Krup AL, Muncie JM, Bruneau BG. Graded mesoderm assembly governs cell fate and morphogenesis of the early mammalian heart. Cell. 2023 Feb 2;186(3):479-496.e23. doi: 10.1016/j.cell.2023.01.001.PMID:36736300. https://www.cell.com/cell/fulltext/S0092-8674(23)00001-6

New papers out now! Heterotypic TF interactions, and histone modifications in heart development.

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Two papers from the lab were published earlier this year. One from postdoc Luis Luna-Zurita, in a collaboration with Christoph Muller's lab, explores the interplay between heterotypic transcription factors, TBX5, NKX2-5, and GATA4 (all causative genes in human congenital heart disease) in cardiac differentiation. These interactions are complex, and serve not only to coordinately activate cell type-specific gene expression programs, but also act as locus tethers to prevent partner transcription factors from redistributing to ectopic loci resulting in inappropriate expression of genes that don't belong in a cardiac cell.

The second paper is from graduate student Siang-Yun Ang. This is a deep examination of the role of a histone methyltransferase, KMT2D (aka MLL2) that has been implicated in human congenital heart disease. Using several genetic deletions in the mouse, Yun found that KMT2D is important for activating a set of genes that fall into functional classes that include the excitation-contraction coupling machinery. By genome-wide analysis in embryonic heart, we found that the main role of KMT2D appears to be the addition of a dimethly group to lysine 4 of histone H3.

Together these papers explain unknown features of congenital heart disease-associated genes, and uncover new fundamental aspects of gene regulation.

Luna-Zurita L., Stirnimann C.U., Glatt S., Kaynak B.L., Thomas S., Baudin F., Samee Md.A.H., He D., Small E.M., Mileikovsky M., Nagy A., Holloway A.K., Pollard K.S., Muller C.W., & Bruneau B.G. (2016) Complex interdependence regulates heterotypic transcription factor distribution and coordinates cardiogenesis. *Cell 164:999-1014
Ang S.-Y., Uebersohn A., Spencer C.I., Huang Y., Lee J.-E., Ge K., & Bruneau B.G. (2016) KMT2D regulates specific programs in heart development via histone H3 lysine 4 dimethylation. Development* 143:810-821

Great collaborative paper with Srivastava and Pollard labs on NOTCH1 haploinsufficiency out now!

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Published in Cell last week (http://www.ncbi.nlm.nih.gov/pubmed/25768904), our paper on the transcriptional and epigenomic networks disrtupted in iPS cell models of NOTCH1 haploinsufficiency. This paper explores disease modeling and gene regualtion in endothelial cells derived from human iPS cells, and uncovers new networks regulated by NOTCH1 dosage. This was led by Christina Theodoris, student in the Srivastava lab, in a tight collaboration between Deepak's lab, Katie Pollard's, and our lab.

Theodoris C.V., Li M., White M.P., Liu L., He D., Pollard K.S.(1), Bruneau B.G.(1), Srivastava D (1). (2015) Human disease modeling reveals integrated transcriptional and epigenetic mechanisms of NOTCH1 haploinsufficiency. Cell 160:1072-1086 (1. co-senior authors)

New paper on early cardiac lineages!

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Just out in eLife , our paper on early cardiac lineage specification and patterning changes a lot about how we view the origins of the heart, and how chamber morphogenesis is established. This work incorporates clonal lineage tracing, classic embryology, and inventive dual lineage tracing, to redefine when cardiac precursors are specified and allocated to specific chambers of the heart.

Devine W.P., Wythe J.D., George M., Koshiba-Takeuchi K., & Bruneau B.G. (2014) Early patterning and specification of cardiac progenitors in gastrulating mesoderm. eLife published online 10/08/14  http://dx.doi.org/10.7554/eLife.03848