HIRA-SETDB1-H3K9me3 axis regulate chromatin architecture in chronic myeloid leukemia cells

Abstract Histone cell cycle regulator A (HIRA) confers chromatin accessibility and regulates developmental hematopoiesis. But whether HIRA displays similar role in leukemia, a condition caused by abnormalities during hematopoiesis, remain elusive. Here we show that HIRA interact with heterochromatin cluster in Chronic Myeloid Leukemia, K562, cells. FRAP, FLIM-FRET and ATAC-sequencing analysis revealed increased chromatin compaction, altered spatial distribution of chromatin towards nuclear periphery and loss in chromatin accessibility at the promoter and gene bodies upon downregulation of HIRA in K562 cells. Enhanced chromatin compaction was attributed to increased histone H3K9me3 level mediated by histone methyltransferase SETDB1. Incorporation of histone H3.3 within the SETDB1 promoter in HIRA -knockdown cells induced SETDB1 expression. HIRA-SETDB1-H3K9me3 axis regulate the chromatin architecture in CML cells leading to inhibition of proliferation while induction in differentiation. We anticipate that the exploration of this axis would introduce new paradigm in understanding and targeting molecules that could influence CML disease progression.