Benoit G. Bruneau, PhD
Associate Investigator, Gladstone Institute of Cardiovascular Disease
Email: bbruneau@gladstone.ucsf.edu
Telephone: 415-734-2708
Fax: 415-355-0960

 
Areas of Investigation
The main focus of our lab is to understand how a heart becomes a heart: what cell lineage decisions take place to direct cardiac differentiation, and what morphogenetic and patterning processes occur to assemble all of the heart's components into a functional organ. In both cases, we are primarily interested in regulation by transcription factors and chromatin remodeling. This encompasses both early development and differentiation, as well as postnatal physiology.

The family of genes we study the most are the T-box and Iroquois transcription factors. These transcription factors are involved in important patterning and morphogenetic decisions at various stages of heart development. We have also recently begun a foray into cardiac chromatin remodeling and modification factors, enzymes that unwind DNA or modify histones to turn genes on or off. We are particularly interested in how these factors control cardiac cell lineage decisions. These chromatin remodeling factors may also be key to pushing a stem cell into becoming a heart cell, perhaps opening up new avenues for cardiac regenerative medicine.

Significance

Why study heart development? We believe that primary defects in patterning in early heart development are at the root of congenital heart defects, which affect approximately 1% of live-born children, and we want to understand how these defects occur, to perhaps be able to uncover new and improved diagnostic or even therapeutic options. By manipulating cardiac regulatory genes, we have created mouse models of congenital heart defects commonly found in children, including septal defects (“holes in the heart”) and conduction defects, or arrhythmias. We are now trying to understand the link between a gene
mutation in a transcription factor and specific heart defects, and to examine the pathways that are disrupted. Also, by understanding how cardiac lineage specification occurs, we can better design stem cell-based interventions of cardiac repair, based on the knowledge of what drives an uncommitted cell towards a specific cardiac fate.

Approaches
We mostly utilize conventional mouse transgenic and knockout technology, and we are also using in vivo RNA interference as a tool for rapid phenotypic analysis of genes of interest. We also utilize biochemical and cell culture-based techniques, as well as mouse physiological analyses and 3-dimensional embryo imaging technologies.

Contributions
Our research has taken us into such diverse fields as chromatin remodeling, cardiac electrophysiology, and left-right asymmetry. Some recent findings from our lab have demonstrated a critical role for the Iroquois homeodomain protein Irx5 in regulating the cardiac repolarization gradient, and thereby in preventing arrhythmias. Other work in the lab has uncovered a feed-forward transcriptional network between Tbx5 and Sall4, which is key for fine patterning of heart and limb development. We have also begun to understand the roles played in heart development by a heart-restricted chromatin remodeling complex subunit, Baf60c, which illustrates the novel concept of tissue-specific remodeling complexes.

Some Questions Addressed in Ongoing Studies:

1. What are the roles of chromatin remodeling and modifying complexes in heart development and cardiac lineage determination?
2. How does Baf60c function to activate specific cardiac genes at the level of chromatin?
3. How do Irx proteins regulate cardiac function and development singly and combinatorially in the heart?
4. How do T-box proteins interact with other cardiac transcription factors to regulate cardiac morphogenesis?
5. How are important morphogenetic processes such as cardiac septation regulated at the cellular level?
6. What are the intrinsic determinants of the cardiac conduction system?

Koshiba-Takeuchi K., Takeuchi J.K., Arruda E.P., Kathiriya I.S., Mo R., Hui C.-c., Srivastava D., & Bruneau B.G. (2006) Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heart. Nature Genetics 38:175-183

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