Abstract
Retinoblastoma is an aggressive childhood cancer of the developing retina that initiates by biallelic RB1 gene inactivation. Tumor progression in retinoblastoma is driven by epigenetics, as retinoblastoma genomes are stable, but the mechanism(s) that drive these epigenetic changes remain unknown. Lymphoid-specific helicase (HELLS) protein is an epigenetic modifier directly regulated by the RB/E2F pathway. In this study, we used novel genetically engineered mouse models to investigate the role of HELLS during retinal development and tumorigenesis. Our results indicate that Hells-null retinal progenitor cells divide, undergo cell-fate specification, and give rise to fully laminated retinae with minor bipolar cells defects, but normal retinal function. Despite the apparent nonessential role of HELLS in retinal development, failure to transcriptionally repress Hells during retinal terminal differentiation due to retinoblastoma (RB) family loss significantly contributes to retinal tumorigenesis. Loss of HELLS drastically reduced ectopic division of differentiating cells in Rb1/p107-null retinae, significantly decreased the incidence of retinoblastoma, delayed tumor progression, and increased overall survival. Despite its role in heterochromatin formation, we found no evidence that Hells loss directly affected chromatin accessibility in the retina but functioned as transcriptional co-activator of E2F3, decreasing expression of cell cycle genes. We propose that HELLS is a critical downstream mediator of E2F-dependent ectopic proliferation in RB-null retinae. Together with the nontoxic effect of HELLS loss in the developing retina, our results suggest that HELLS and its downstream pathways could serve as potential therapeutic targets for retinoblastoma.
Highlights
Introduction TheRB pathway can directly regulate genes that control cell cycle exit but can regulate the expression of genes that control cell-fate specification and differentiation through mechanisms, including chromatin remodeling and epigenetic control[1]
Real-time reverse transcriptase PCR (RT-qPCR) analysis of retinal tissue at different developmental stages showed that Hells mRNA is robustly expressed starting at early stages of retinal development (E15.5), reaching its maximal expression around postnatal day 0 (P0) and gradually declining until it reaches its minimal expression after postnatal day 6 (P6), and is maintained at low levels thereafter (Fig. 1b)
The mRNA levels correlate with HELLS protein expression, with high expression of HELLS protein during the proliferative stages of retinal development (E15.5-postnatal day 2 (P2)), followed by a steep decrease that falls under the limits of detection after retinal cell-fate specification has been completed at P6 (Fig. 1c, d)
Summary
RB pathway can directly regulate genes that control cell cycle exit but can regulate the expression of genes that control cell-fate specification and differentiation through mechanisms, including chromatin remodeling and epigenetic control[1]. Genetic ablation of RB is characterized by alterations in ganglion cell, bipolar, and rod photoreceptor terminal differentiation that results in cell death of these retinal. While genetic alterations in the RB1 gene are required for tumor initiation, retinoblastoma tumors have stable genomes, with tumor progression occurring through epigenetic dysregulation of several cancer pathways[6]. HELLS (helicase, lymphoid specific; known as LSH, ICF4, PASG, and SMARCA6), a gene transcriptionally controlled by the RB/E2F pathway[7,8,9], encodes a chromatin remodeling protein thought to be responsible for the epigenetic changes seen in retinoblastoma and required for tumor survival[10].
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