Marian Kies Memorial Award for 2007
Dr. Siming Shen
Dr.
Siming Shen
Dr.
Siming Shen
Dr. Siming Shen was the recipient of the 2007 Marian Kies Award. During her graduate work she addressed the molecular mechanisms involved in oligodendrocyte progenitor differentiation, with an emphasis on the post-translational modification of nucleosomal histones, the basic unit of chromatin. Oligodendrocytes are the cells responsible for insulating (myelinating) axons and allow fast and accurate nerve conduction in the central nervous system. Therefore, understanding how they are generated is essential for normal brain development, and for the design of therapeutic strategies of demyelinating diseases. The major finding of her research was that deacetylation of lysine residues in nucleosomal histones (mediated by histone deacetylases, i.e. HDACs) is essential for the initiation of oligodendrocyte differentiation. Pharmacological inhibition of HDAC during the first weeks of post-natal brain development, impaired progenitor differentiation, and suggested a critical role for histone deacetylation during developmental myelination, that it was followed by repressive histone methylation. The levels of global histone deacetylation and histone methylation were developmentally regulated, since a progressive decline could be detected in aging animals. The direct result of this “epigenetic memory loss” was the up-regulation of transcriptional inhibitors for oligodendrocyte differentiation, including Hes5, Sox2 and Id4. Finally, she defined the role of HDAC activity for remyelination in experimental models of demyelination. Histone deacetylation results in gene repression. In contrast to neurons and astrocytes, the initial stage of oligodendrocyte differentiation is HDAC activity dependent, which makes a unique “deacetylate to differentiate” phenomenon for oligodendrocytes. Her research suggests that the decision of a progenitor to become a mature oligodendrocyte requires the repression of “differentiation inhibitors”, which is dependent on HDAC activity. Pictured above are Dr. Shen with her PhD advisor, Dr. Patrizia Casaccia-Bonefil.