Global H3K4me3 genome mapping reveals alterations of innate immunity signaling and overexpression of JMJD3 in human myelodysplastic syndrome CD34+ cells Academic Article uri icon

Overview

MeSH Major

  • Antigens, CD34
  • Chromosome Mapping
  • Histones
  • Immunity, Innate
  • Jumonji Domain-Containing Histone Demethylases
  • Lysine
  • Myelodysplastic Syndromes

abstract

  • The molecular bases of myelodysplastic syndromes (MDS) are not fully understood. Trimethylated histone 3 lysine 4 (H3K4me3) is present in promoters of actively transcribed genes and has been shown to be involved in hematopoietic differentiation. We performed a genome-wide H3K4me3 CHIP-Seq (chromatin immunoprecipitation coupled with whole genome sequencing) analysis of primary MDS bone marrow (BM) CD34+ cells. This resulted in the identification of 36 genes marked by distinct higher levels of promoter H3K4me3 in MDS. A majority of these genes are involved in nuclear factor (NF)-κB activation and innate immunity signaling. We then analyzed expression of histone demethylases and observed significant overexpression of the JmjC-domain histone demethylase JMJD3 (KDM6b) in MDS CD34+ cells. Furthermore, we demonstrate that JMJD3 has a positive effect on transcription of multiple CHIP-Seq identified genes involved in NF-κB activation. Inhibition of JMJD3 using shRNA in primary BM MDS CD34+ cells resulted in an increased number of erythroid colonies in samples isolated from patients with lower-risk MDS. Taken together, these data indicate the deregulation of H3K4me3 and associated abnormal activation of innate immunity signals have a role in the pathogenesis of MDS and that targeting these signals may have potential therapeutic value in MDS.

publication date

  • November 2013

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4476310

Digital Object Identifier (DOI)

  • 10.1038/leu.2013.91

PubMed ID

  • 23538751

Additional Document Info

start page

  • 2177

end page

  • 86

volume

  • 27

number

  • 11