HIRA-SETDB1-H3K9me3 axis regulates chromatin architecture in leukemia cells

Journal of Biological Chemistry

27 April 2026 doi.org/10.1016/j.jbc.2026.1130816

Mayur Balkrishna Shirude , Anjali Devarajan , Sai Adarsh Sahu , Ananda Mukherjee , Debasree Dutta

Abstract

Histone cell cycle regulator A (HIRA) confers chromatin accessibility and regulates developmental hematopoiesis. Previously, we showed that HIRA expression is higher in patient samples from chronic myeloid leukemia (CML) compared to samples from healthy individuals. However, the underlying mechanism that connects HIRA with chromatin reorganization and pathogenesis of leukemia associated with abnormal hematopoiesis remains unexplained. We developed a HIRA-knockdown K562 CML cell line model for this study, as this cell line showed a maximal expression of HIRA in the myeloid lineage. A proteome-wide analysis demonstrated the association of HIRA with components of chromatin organization in K562 cells. FRAP and FLIM-FRET microscopy and molecular interaction studies revealed increased chromatin compaction and altered spatial distribution of chromatin towards the nuclear periphery upon downregulation of HIRA in K562 cells. Mechanistically, enhanced chromatin compaction was attributed to increased histone H3K9me3 and HP1α levels mediated by histone methyltransferase SETDB1. The enrichment of histone H3.3 and the reduction in H3K27me3 levels, resulting from the loss of EZH2 recruitment at the SETDB1 and HP1α promoters in HIRA-knockdown cells, led to an increase in their expression. This HIRA-SETDB1-H3K9me3 axis contributed to restricted cell proliferation along with loss in expression of the BCR-ABL fusion protein that causes CML. Thus, loss of HIRA promotes global chromatin condensation and redistribution, thereby regulating the BCR-ABL expression and cell proliferation. Our findings highlight how elevated HIRA expression contributes to the pathogenesis of CML and establish a regulatory axis that could be further explored for therapeutic interventions.