One of the major mechanisms through which eukaryotic cells respond to developmental and environmental signals is by changing their gene expression patterns. This complex and tightly regulated process is largely regulated at the level of RNA polymerase II-mediated transcription. Within this process an important class of transcriptional regulators are the histone acetyltransferases (HATs), proteins that acetylate histones and non-histone substrates. While hyperacetylation of histones is generally associated with active genes, the effect of acetylation of nonhistone proteins varies between substrates resulting in for example alterations in (sub-nuclear) protein localization or protein stability. Given the central role of HATs in transcriptional regulation and other cellular processes, it may not be surprising that genetic alterations in the genes encoding HATs, resulting in aberrant forms of these regulatory proteins, have been linked with various human diseases, including congenital developmental disorders and various forms of cancer, including leukaemia. Here we will review mutations found in genes encoding human HATs and discuss the (putative) functional consequences on the function of these proteins. So far the lessons learned from naturally occurring mutations in humans have proven to be invaluable and recapitulating such genetic alterations in various experimental systems will extend our knowledge even further. This seems particularly relevant given the wide range of diseases in which acetyltransferases have been implicated and may help to open up new therapeutic avenues

Abbreviations: CBP, CREB binding protein; CREB, cAMP response element binding protein; FAT, factor acetyltransferase; HAT, histone acetyltransferase; MLL, mixed lineage leukaemia protein; MORF, MOZ related factor; MOZ, monocytic leukaemia zinc finger protein; PHD, plant homeodomain; RTS, Rubinstein-Taybi syndrome, TIF, transcription intermediary factor