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The Core Regulatory Circuitry (CRC) is a set of genes that define cell state and identity by encoding transcription factors. In certain cancers, we have shown CRC to be selective dependencies. We are now elucidating the critical CRC circuitry CTRC in acute myelogenous leukemia (AML). We have shown that BET inhibitors trigger CRC transcriptional collapse in AML cell lines. We have integrated multiple sources of epigenomics data including ChIPSeq, HiC seq, HiChIP, DNase, Degron, WGS, RNAseq and PerturbSeq, to uncover patterns of co-binding that might explain selective AML dependencies. We will present a data integration pipeline and show early results on CRC co-occupancy mapping in AML cell lines. Additionally, we discuss the lessons learned in quality control and bias correction that may prove useful for deep epigenomics analysis.


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