HSF4 regulates lens fiber cell differentiation by activating p53 and its downstream regulators

Abstract

Cataract refers to opacities of the lens that impede the passage of light. Mutations in heat shock transcription factor 4 (HSF4) have been associated with cataract; however, the mechanisms regarding how mutations in HSF4 cause cataract are still obscure. In this study, we generated an hsf4 knockout zebrafish model using TALEN technology. The mutant zebrafish developed an early-onset cataract with multiple developmental defects in lens. The epithelial cells of the lens were overproliferated, resulting in the overabundance of lens fiber cells in hsf4null zebrafish lens. Consequently, the arrangement of the lens fiber cells became more disordered and irregular with age. More importantly, the terminal differentiation of the lens fiber cell was interrupted as the organelles cannot be cleaved in due time. In the cultured human lens epithelial cells, HSF4 could stabilize and retain p53 in the nucleus to activate its target genes such as fas cell surface death receptor (Fas) and Bcl-2-associated X apoptosis regulator (Bax). In the hsf4null fish, both p53 and activated-caspase3 were significantly decreased. Combined with the finding that the denucleation defect could be partially rescued through microinjection of p53, fas and bax mRNA into the mutant embryos, we directly proved that HSF4 promotes lens fiber cell differentiation by activating p53 and its downstream regulators. The data we presented suggest that apoptosis-related genes are involved in the lens fiber cell differentiation. Our finding that HSF4 functions in the upstream to activate these genes highlighted the new regulatory modes of HSF4 in the terminal differentiation of lens fiber cell.

Transcriptome Differences Suggest Novel Mechanisms for Intrauterine Growth Restriction Mediated Dysfunction in Small Intestine of Neonatal Piglets

“…HSF4 is a member of the heat shock transcription factor family that contains conserved DNA binding and trimerization domains (Morimoto, 1993;Nakai et al, 1997). Recent studies showed that HSF4 is expressed in many tissues and is required for mammalian cellular proliferation and differentiation (Min et al, 2004;Mitsuaki et al, 2004;Gao et al, 2017). Notably, Jin et al (2012) observed HSF4 is positively involved in tumorigenesis that is induced following disruption of the p53 gene.…”

HSP4 triggers epithelial‐mesenchymal transition and promotes motility capacities of hepatocellular carcinoma cells via activating AKT

“…shRNA transfection was conducted according to the previous studies 14,21 . Briefly, HCC cells were seeded in a 6‐well plate.…”

“…Heat shock transcription factors (HSFs) play an important role in regulating heat shock proteins expression, and HSFs have been reported to be a critical regulator of many vital physiological processes such as proteotoxic stresses protection and inflammation 12‐14 . Heat shock factor 4, which contains conserved DNA binding and trimerization domains, is a vital member of HSFs.…”

Proteasome subunitPSMC3variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress

“…(Cvekl and Zhang, 2017) Pathogenic variations or knockdown of genes implicated in human cataract and/or deafness in zebrafish have been shown to recapitulate similar phenotypes. (Gao et al, 2017;Mishra et al, 2018;Yousaf et al, 2018;Takamiya et al, 2016;Busch-Nentwich, 2004) Using two strategies (morpholino and CRISPR/Cas9) the fish developed a cataract and ear phenotype that could be rescued. We did not observe other obvious anomalies.…”