Gore, H. | bioRxiv Science

bioRxiv2021

3'HS1 CTCF binding site in human β-globin locus regulates fetal hemoglobin expression

Mutations in the adult {beta}-globin gene can lead to a variety of hemoglobinopathies, including sickle cell disease and {beta}-thalassemia. An increase in fetal hemoglobin expression throughout adulthood, a condition named Hereditary Persistence of Fetal Hemoglobin (HPFH), has been found to ameliorate hemoglobinopathies. Deletional HPFH occurs through the excision of a significant portion of the 3 end of the {beta}-globin locus, including a CTCF binding site termed 3HS1. Here, we show that the deletion of this CTCF site alone induces fetal hemoglobin expression in both adult CD34+ hematopoietic stem and progenitor cells and HUDEP-2 erythroid progenitor cells. This induction is driven by the ectopic access of a previously postulated distal enhancer located in the OR52A1 gene downstream of the locus, which can also be insulated by the inversion of the 3HS1 CTCF site. This suggests that genetic editing of this binding site can have therapeutic implications to treat hemoglobinopathies.

genomics↗

bioRxiv2020

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 HOXA 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 HOXA genes in normal hematopoiesis and leukemia. Here, we report the interaction between the HOXA cluster with a [~]1.3 Mb upstream DNA methylation Canyon termed "Geneless Canyon" (GLC) in human CD34+/CD38-hematopoietic stem cells (HSCs) and AML cell lines. We show that CRISPR-Cas9 mediated deletion of the whole GLC region reduces the expression of the distal HOXA genes and compromises HSC and leukemia cells self-renewal. This long-range chromatin interaction brings the HOXA cluster in contact with the nuclear pore complex (NPC) at the nuclear periphery, which promotes HOXA 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.

genomics↗