RT Journal
A1 Idriss, Salam
A1 Hallal, Mohammad
A1 El-Kurdi, Abdullah
A1 Zalzali, Hasan
A1 El-Rassi, Inaam
A1 Ehli, Erik A.
A1 Davis, Christel M.
A1 Chung, Philip E.D.
A1 Gendoo, Deena M.A.
A1 Zacksenhaus, Eldad
A1 Saab, Raya
A1 Khoueiry, Pierre
T1 A temporal in vivo catalog of chromatin accessibility and expression profiles in pineoblastoma reveals a prevalent role for repressor elements
JF Genome Research 
JO Genome Research 
YR 2023 
FD February 01 
VO 33 
IS 2 
SP 269 
OP 282 
DO 10.1101/gr.277037.122 
UL http://genome.cshlp.org/content/33/2/269.abstract 
AB Pediatric pineoblastomas (PBs) are rare and aggressive tumors of grade IV histology. Although some oncogenic drivers are characterized, including germline mutations in RB1 and DICER1, the role of epigenetic deregulation and cis-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 of CCND1-driven PB. We identified PB-specific enhancers and super-enhancers, and found that in some cases, the accessible genome dynamics precede transcriptomic changes, 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 gene cluster and Gas1, the growth arrest specific gene. Gene set enrichment analysis and gene expression signatures positioned the model used here close to human PB samples, showing the potential of our findings for exploring new avenues in PB management and therapy. Overall, this study reports the first temporal and in vivo cis-regulatory, expression, and accessibility maps in PB.