Targeting chromatin in fungal pathogens as a novel therapeutic strategy: histone modification gets infectious.

In the early 1950s, at the time of the discovery of the double helix of DNA, the central dogma emerged that genetic information is propagated as DNA and translated into RNA to produce proteins exerting biological functions. However, it has since become clear that histone proteins, which associate with DNA to form the chromatin of eukaryotic cells, can modulate this unidirectional information flow. For instance, posttranslational modifications of histones regulate gene-expression programs of numerous cellular processes ranging from cancer biology as well as infectious diseases. In eukaryotes, DNA is packaged around nucleosomes to form chromatin. A nucleosome unit consists of an octamer of histone proteins, whose protruding tails are subject to reversible chemical modifications, including methylation, acetylation, phosphorylation, ADP ribosylation, sumoylation or ubiquitination [1]. Many modifications influence chromatin condensation and transcription rates. Conserved enzymes write, read and erase such epigenetic histone marks, whose combinatorial effects have formed the rationale for the ‘histone code’ hypothesis [2]. Interestingly enough, certain histone modifications are heritable for generations and are the under lying cause of epigenetic phenomena seemingly violating Mendel’s laws of inheritance. On the other hand, histone modifications can have nonepigenetic functions, and there is accumulating evidence that they do not form a code but rather modulate biological processes in a context-dependent manner by acting as components of a dedicated chromatin signaling pathways that control gene regulation in physiology and pathology [3]. Here, we discuss how genetic and chemical inhibition of histonemodifying enzymes such as histone deacetylases (HDACs) or histone acetyltransferases (HATs) can pave the way for novel therapeutic strategies to combat infectious diseases caused by human fungal pathogens.