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Transcriptional Regulation of Histone Demethylase JARID1B/KDM5B by Ikaros Tumor Suppressor in Human Lymphoblastic Leukemia
Author(s) -
Payne Jonathon Lee,
Dovat Elanora,
Song Chunhua,
Ding Yali,
Gowda Chandrika,
Payne Kimberly J,
Dovat Sinisa
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1108.12
Subject(s) - chromatin immunoprecipitation , transcription factor , biology , demethylase , microbiology and biotechnology , chromatin , epigenetics , myeloid leukemia , promoter , repressor , histone , cancer research , gene , gene expression , genetics
IKZF1 encodes the Ikaros DNA‐binding protein that is essential for normal hematopoiesis and acts as a tumor suppressor. Deletion of a single Ikaros allele is associated with the development of high‐risk B‐cell precursor acute lymphoblastic leukemia (B‐ALL) that has a poor prognosis. Despite extensive studies of Ikaros function, the molecular mechanisms by which Ikaros regulates transcription of its target genes and its role in the epigenetic control of gene expression in human leukemia remain unknown. Using chromatin immunoprecipitation followed by deep‐sequencing (ChIP‐seq), we determined that Ikaros binds to the promoter of the histone H3K4 demethylase JARID1B (KDM5B) gene in human leukemia. The objective of our study was to determine the mechanism through which Ikaros regulates transcription of JARID1B in leukemia. Overexpression of Ikaros in B‐ALL cells resulted in transcriptional repression of JARID1B as measured by qRT‐PCR and Western blot. The increase in JARID1B was associated with a global increase in the H3K4me 3 epigenetic mark in leukemia cells. The use of luciferase reporter assays demonstrated that Ikaros co‐transfection directly represses transcription of JARID1B. Knockdown of Ikaros expression in B‐ALL cells with Ikaros shRNA results in increased transcription of JARID1B, as evidenced by qRT‐PCR and Western blot. Together, these experiments suggest that Ikaros regulates global levels of H3K4 tri‐methylation in leukemia by repressing JARID1B transcription. Functional assays showed that Ikaros‐mediated repression of JARID1B requires recruitment of histone deacetylase HDAC1 to the JARID1B promoter, which results in the formation of repressive chromatin. In B‐ALL, the Ikaros protein is phosphorylated by pro‐oncogenic Casein Kinase II (CK2). Functional analysis showed that CK2‐mediated phosphorylation of Ikaros severely impairs its DNA‐binding affinity toward the JARID1B promoter and its function as a transcriptional regulator in high‐risk leukemia. Treatment of leukemia cells with specific CK2 inhibitors restores Ikaros binding to the JARID1B promoter and transcriptional repression of JARID1B. In conclusion, our results demonstrated that CK2, Ikaros, and HDAC1 regulate the global level of H3K4 tri‐methylation in leukemia via transcriptional control of JARID1B expression. These data provide a novel insight into the regulatory network that controls the epigenetic signature in leukemia.