Networks of Histone Demethylases and Their Relevance to the Regulation of Chromatin Structure and Dynamics

Abstract

Regulation of chromatin structure and dynamics is crucial for gene expression, chromosome segregation, DNA replication, and DNA repair, effectively controlling all cellular processes. Such regulation is achieved by a multitude of chromatin modifying enzymes that cause changes in DNA accessibility. Modifications imposed by these enzymes include DNA methylation and various histone modifications. Often, an interplay of multiple mechanisms is necessary to properly regulate chromatin dynamics, leading to a defined functional outcome. Of the various histone modifications, methylation is the most complex and is reversed by the KDM1 and JMJC families of histone demethylases. Collectively, these enzymes can reverse all three histone methylation states, often acting on the same substrates, and yet having different functional outcomes. Thus far, substrates have been identified for 26/32 (80 %) of all known histone demethylases, but functional studies have lagged behind. Analysis of protein–protein interactions has greatly contributed to our understanding of the roles some of these proteins play in the regulation of chromatin structure and dynamics, sometimes explaining genetic associations previously established between aberrant expression of histone demethylases and certain human disorders. Here, we will discuss our current understanding of histone demethylases, emphasizing protein complexes, and their contributions to the function of histone demethylases, their connections to various human disorders and multiple types of cancer.