Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis
Jaclyn Andricovich, … , Adlen Foudi, Alexandros Tzatsos
Jaclyn Andricovich, … , Adlen Foudi, Alexandros Tzatsos
Published January 25, 2016
Citation Information: J Clin Invest. 2016;126(3):905-920. https://doi.org/10.1172/JCI84014.
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Research Article Hematology

Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis

Abstract

The development of the hematopoietic system is a dynamic process that is controlled by the interplay between transcriptional and epigenetic networks to determine cellular identity. These networks are critical for lineage specification and are frequently dysregulated in leukemias. Here, we identified histone demethylase KDM2B as a critical regulator of definitive hematopoiesis and lineage commitment of murine hematopoietic stem and progenitor cells (HSPCs). RNA sequencing of Kdm2b-null HSPCs and genome-wide ChIP studies in human leukemias revealed that KDM2B cooperates with polycomb and trithorax complexes to regulate differentiation, lineage choice, cytokine signaling, and cell cycle. Furthermore, we demonstrated that KDM2B exhibits a dichotomous role in hematopoietic malignancies. Specifically, we determined that KDM2B maintains lymphoid leukemias, but restrains RAS-driven myeloid transformation. Our study reveals that KDM2B is an important mediator of hematopoietic cell development and has opposing roles in tumor progression that are dependent on cellular context.

Authors

Jaclyn Andricovich, Yan Kai, Weiqun Peng, Adlen Foudi, Alexandros Tzatsos

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Figure 10

KDM2B crosstalks with PcG and TrxG complexes.

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KDM2B crosstalks with PcG and TrxG complexes. (A) Combinatorial binding ...
(A) Combinatorial binding profiles of KDM2B, PcG, and TrxG proteins in K562 cells. Each horizontal line represents the signal for a gene over the TSS. A ± 2 kb window is shown for each gene. Color bar shows average log2 ChIP-seq signal intensity. (B) Venn diagrams showing the overlap of KDM2B-bound genes with components of PRC1/2 (left) and c-MYC/TrxG (right) in K562 cells. (C) Stacked bar graph showing the functional annotation of chromatin occupied (%) by KDM2B, PRC1/2, and TrxG components in K562 cells. (D) IPA of KDM2B-bound genes in the context of PRC1/2 and c-MYC/TrxG. The x axis (log scale) corresponds to the binomial raw P values. (E) Model of KDM2B in hematopoiesis.