A temporal in vivo catalog of chromatin accessibility and expression profiles in pineoblastoma reveals a prevalent role for repressor elements

Abstract

Pediatric pineoblastomas (PBs) are rare and aggressive tumors of grade IV histology. Although some oncogenic drivers are characterized, including germline mutations inRB1andDICER1, the role of epigenetic deregulation andcis-regulatory regions in PB pathogenesis and progression is largely unknown. Here, we generated genome-wide gene expression, chromatin accessibility, and H3K27ac profiles covering key time-points of PB initiation and progression from pineal tissues of a mouse model ofCcnd1-driven pineoblastoma. We identified PB-specific enhancers and super-enhancers and found that, in some cases, the accessible genome dynamic precedes the transcriptome, a characteristic that is underexplored in tumor progression. During progression of PB, newly acquired open chromatin regions lacking H3K27ac signal become enriched for repressive state elements and harbor motifs of repressor transcription factors like HINFP, GLI2, and YY1. Copy number variant analysis identified deletion events specific to the tumorigenic stage, affecting among others the histone genes cluster andGas1, the growth arrest specific gene. Gene set enrichment analysis and gene expression signatures positioned the model used here close to human PB samples demonstrating the potential of our findings for exploring new avenues in PB management and therapy. Overall, this study reports the first temporal and in vivocis-regulatory, expression, and accessibility maps in PB.

An imbalance between proliferation and differentiation underlies the development of microRNA-defective pineoblastoma

“…Previous studies have used Rb1 loss, cyclin D1 upregulation, and Dicer1 loss to model the development of pineoblastoma in mice [22][23][24][25][26][27]. To dissect how microRNA loss drives formation of pineoblastoma, we generated mice with loss of microRNAs in the developing pineal gland.…”