Georgia Hatzivassiliou

Chromatin Modifier Modulates Gene Expression Modification of chromatin structure is usually thought of as a global, relatively nonspecific way of modulating gene expression. However, Wellen et al. (p. 1076 ; see the Perspective by Rathmell and Newgard ) demonstrate that such regulation helps link growth factor–stimulated increases in metabolism to appropriate changes in gene expression. Adenosine triphosphate (ATP)–citrate lyase (ACL), which converts citrate to acetyl–coenzyme A (CoA) in the mitochondria of mammalian cells during metabolism of glucose, was also found to be present in the nucleus, where it might regulate activity of histone acetyl transferases (HATs) by controlling the availability of acetyl-CoA. Indeed, depletion of ACL from cultured human colon carcinoma cells specifically decreased histone acetylation in the nucleus, but appeared not to affect the overall amount of acetylation of proteins in the cells. Loss of ACL in cultured mouse 3T3-L1 cells diminished the increase in histone acetylation normally associated with hormone-stimulated differentiation of these cells and inhibited the increase in expression of specific genes, such as that encoding the Glut4 glucose transporter. Thus, ACL may help cells link metabolic activity to changes in gene expression.

Bax and Bak play a redundant but essential role in apoptosis initiated by the mitochondrial release of apoptogenic factors. In addition to their presence at the mitochondrial outer membrane, Bax and Bak can also localize to the ER. Agents that initiate ER stress responses can induce conformational changes and oligomerization of Bax on the ER as well as on mitochondria. In wild-type cells, this is associated with caspase 12 cleavage that is abolished in bax-/-bak-/- cells. In bax-/-bak-/- cells, introduction of Bak mutants selectively targeted to either mitochondria or the ER can induce apoptosis. However, ER-targeted, but not mitochondria-targeted, Bak leads to progressive depletion of ER Ca2+ and induces caspase 12 cleavage. In contrast, mitochondria-targeted Bak leads to enhanced caspase 7 and PARP cleavage in comparison with the ER-targeted Bak. These findings demonstrate that in addition to their functions at mitochondria, Bax and Bak also localize to the ER and function to initiate a parallel pathway of caspase activation and apoptosis.