Jumonji and cardiac fate.

C onsiderable information is known about the extracellular signals that drive pluripotent stem cells (PSCs) through a stepwise program to become cardiomyocytes. An article by Ohtani et al in this issue links extrinsic signals to histone demethylation needed to form mesoderm, the first step in cardiogenesis. Extrinsic signals drive the stepwise differentiation of PSCs into cardiomyocytes, and highly efficient protocols exist for producing large numbers of >90% pure cardiomyocytes by judiciously manipulating the timing and concentration of inducing factors that are provided to the cultures. the activities of extrinsic growth factor–like molecules, such as Transforming Growth Factor-β, and Wnt family members and their inhibitors become transduced into changes in the 3-dimensional structure of chromatin that locally influences expression of cardiogenic genes. Moreover, rules are emerging for how epigenetic modifications to histones (acetylation and methylation) and DNA (methylation) influence chromatin structure and transcription, making it possible to predict whether a gene is active, inactive, or poised on the basis of patterns of histone and DNA modifications. 2 Despite these advances, we have only a rudimentary understanding of how extrinsic signals elicit specific chromatin modifications and control cell fate. In this issue, Ohtani et al 4 take a first stab at understanding how functional regulation of histone methylation determines whether PSCs become mesoderm (and hence cardiac). The work focuses on the role of Jumonji d3 (Jmjd3), also known as Kdm6b, a DNA demethylase (DM) that removes repressive marks at H3K27 sites, typically placed by the Polycomb complex. 5 Their finding that genetic deletion of Jmjd3 selectively affects certain mesodermal genes raises the interesting question of how histone DMs recognize particular sites in the genome and dictate cell fate choice. Histone demethylation is regulated genome-wide by lysine-specific demethylase (LSD) and JmjC DMs, which together profoundly influence the transcript profile of cells. 6 There are only 2 LSD family members, whereas ≥18 of 30 JmjC-domain proteins are known to be capable of histone demethylation. 5 All histones can be methylated, but the most common modifications occur on K4, K9, K27, K36, and K79 of histone H3 and on K20 of histone H4. Jmjd3 is selective for H3K27 (the only other DM that can demethylate H3K27 is UTX) and removes methyl groups placed by the Polycomb Repressor Complex 2. 5 Although DMs are selective for the particular methylated residue, on their own they do not recognize the surrounding sequence. Considering that Jmjd3 is also involved …