Hsf4

HSF4 stands for heat shock transcription factor 4, a member of the heat shock factor family of transcription factors. It regulates the expression of heat shock proteins and other stress-responsive genes in response to cellular stress, though it has additional roles beyond acute stress responses.

The HSF4 gene encodes multiple isoforms produced by alternative splicing, most notably HSF4a and HSF4b. Like other HSFs, HSF4 contains a conserved DNA-binding domain and oligomerization domains that allow it to trimerize and bind heat shock elements (HSEs) in target gene promoters. The different isoforms vary in their transcriptional activity, with one acting primarily as a repressor and the other as an activator of transcription in certain contexts.

Expression of HSF4 is highest in the lens, and in lens epithelial and differentiating fiber cells it regulates expression of crystallins and other lens-specific genes, contributing to lens transparency and development. HSF4 participates in the lens stress response and may help protect lens cells from protein aggregation and oxidative damage.

Mutations in HSF4 are associated with congenital cataracts in humans, typically inherited in an autosomal dominant pattern, though the phenotypes can vary. These mutations disrupt normal HSF4 function and alter lens gene expression, leading to opacification. Animal models, such as Hsf4 knockout mice, develop lens defects and cataracts, supporting a role for HSF4 in lens development and maintenance.