Three-dimensional regulation of HOXA cluster genes by a cis -element in hematopoietic stem cell and leukemia

Proper gene regulation is crucial for cellular differentiation, and dysregulation of key genes can lead to diseased states such as cancer. The HOX transcription factors play such a role during hematopoiesis, and aberrant expression of certain genes is found in certain acute myeloid leukemias (AMLs). While studies have shown that these genes are targeted by a variety of mutant proteins including mutant NPM1, MLL fusions, and NUP98 fusions, little is known about how long-range 3D chromatin interactions regulate the genes in normal hematopoiesis and leukemia. Here, we report the interaction between the cluster with a ∼1.3 Mb upstream DNA methylation Canyon termed “” () in human CD34+/CD38-hematopoietic stem cells (HSCs) and AML cell lines. We show that CRISPR-Cas9 mediated deletion of the whole region reduces the expression of the distal genes and compromises HSC and leukemia cells self-renewal. This long-range chromatin interaction brings the cluster in contact with the nuclear pore complex (NPC) at the nuclear periphery, which promotes gene expression and maintains HSC and leukemia cell self-renewal. These findings reveal how long-range 3D chromatin organization regulates key transcription factor genes in both normal and diseased hematopoietic cells.