(A-37) Uncovering chromatin regulator co-dependencies in melanoma through the integration of CRISPR screen and transcriptomics data

Introduction:: Chromatin regulators regulate transcriptional programs responsible for the emergence and survival of diverse cellular states in melanoma  (Wouters et al, 2020). Compensatory mechanisms, driven by redundancy among paralog and non-paralog genes, enable cells to maintain functional chromatin states even in the absence of singleton genes  (Najm et al, 2023). We thus hypothesize that the survival dependency on a regulator is influenced by the expression level of its functional partners. Uncovering these compensatory effects and co-dependencies could lead to novel therapeutic targets in melanoma that might not be evident from individual gene knockout studies.

Materials and Methods:: We conducted a system-wide analysis to integrate mRNA expression and CRISPR/ Cas9 gene dependency datasets of 499 chromatin modifier genes for 41 melanoma cell lines in the Cancer Cell Line Encyclopedia (CCLE). First, we determined whether each gene is expressed at low or high level in a melanoma cell line according to a threshold set based on its low-quantile expression level across all CCLE cell lines. We then applied Independent Samples T-Tests to compare all 499 chromatin regulator gene dependencies between groups of cell lines expressing low or high levels of each of the 499 genes. Significance was defined by pairings that had a mean difference in dependency by +-.2 and a p-value less than .05.

Results, Conclusions, and Discussions:: We identified 104 gene pairs where the expression level of one gene significantly impacted the cell’s survival dependency on another gene. For 47 of these gene pairs, survival dependency on one gene was significantly elevated in cell lines expressing its partner at a low level. Out of these, survival dependency on ARID1A was the most impacted and enhanced by the low expression levels of 8 other chromatin regulator genes, including EP300, KDM5C, KMT2D, MBD1, NFYA, NSD1, NUP153, and CXXC1. On the contrary, 5 7 gene pairs presented the opposite effect, where a gene’s survival dependency was reduced when its partner was lowly expressed. INO80 and BPTF were among the candidates that led to a significant reduction in dependency in multiple gene-pair contexts.

Our analysis provides preliminary evidence in support of the hypothesis that survival dependency on chromatin modifiers in melanoma may be affected by the expression levels of partner regulators. Such interdependent relationships may have a significant impact on the epigenetic plasticity and therapeutic response in melanoma.

Acknowledgements (Optional): :

UVA Biosystems and Computational Biology REU
NSF Award #1950374
NIH Award R35-GM133404

References (Optional): :

Najm et al. (2023). Nature Communications, https://doi.org/10.1038/s41467-023-36150-7
Wouters et al.(2020). Nature Cell Biology, https://doi.org/10.1038/s41556-020-0547-3