Schwartz: Research Summary
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Dr. Schwartz is recognized for defining the regulatory paradigm in which nonmuscle contractile proteins are switched off during muscle differentiation and replaced by muscle specific contractile protein isoforms; thus launching the field of myogenesis in 1981. In the late 1980's Dr. Schwartz identified a highly conserved repeated element shared by the 3 alpha actin genes, later identified as the serum response factor binding site. Over the next 15 years, Schwartz provided the earliest evidence that SRF functioned as the master regulatory platform that directs myogenic gene expression programs through combinatorial interactions with other transcription factors and cofactors. In 1996, SRF was shown to associate with Nkx 2.5 the vertebrate tinman homologue that co-activated cardiac actin gene activity and then a few years later SRF was shown to partner with GATA4-6 factors. The combination of LIM-only proteins CRP1 and CRP2 with SRF and GATA factors were shown as potent cardiovascular differentiation cofactors. Four years ago, Dr. Schwartz presented a gene switch mechanism that facilitated strong repression of SRF-dependent myogenic differentiation genes through phosphorylation of a specific evolutionarily conserved SRF residue in the MADS box, that allowed for activation of immediate early proliferation genes. In addition, Dr. Schwartz and colleagues identified more than 180 direct SRF gene targets that have roles in cellular contractility, movement and mesoderm formation and the newly discovered SM-HAT, a key histone acetyl-transferase that associates with SRF, CRP2 and myocardin directing de novo smooth muscle gene activity.
Conditional knockouts of SRF with Dr. Schwartz' early expressing Nkx2-5Cre completely blocked the appearance of smooth muscle and cardiac actin gene activity and sarcomere formation in the heart; thus, bringing full circle, after 25 years, the absolute proof for SRF obligatory role in muscle differentiation and the gene regulation of myogenic contractile proteins. Finally, in human disease, Dr. Schwartz discovered caspase 3 cleavage of SRF generated a dominant-negative transcription factor responsible for driving depressed contractility in human heart failure and will serve as a new biomarker for human heart failure. SRF is also an important regulator of microRNA expression in the heart involved with silencing inappropriate genes and allowing for cardiomyocyte lineage specification. Schwartz continues to elucidate the chemical basis underlying the specification of cardiac muscle cell differentiation, which will provide opportunities for cell replacement therapy and heart regeneration in the future.