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PMID: 19597182 Published · ppublish English Journal Article Research Support, N.I.H., Intramural

Cytokine-mediated increases in fetal hemoglobin are associated with globin gene histone modification and transcription factor reprogramming.

Blood ·Vol. 114 ·No. 11 ·2009-09-10 ·Pages 2299-306

Sripichai O, Kiefer CM, Bhanu NV, Tanno T, Noh SJ, Goh SH, Russell JE, Rognerud CL, Ou CN, Oneal PA, Meier ER, Gantt NM, Byrnes C, Lee YT, Dean A, Miller JL

Abstract

Therapeutic regulation of globin genes is a primary goal of translational research aimed toward hemoglobinopathies. Signal transduction was used to identify chromatin modifications and transcription factor expression patterns that are associated with globin gene regulation. Histone modification and transcriptome profiling were performed using adult primary CD34(+) cells cultured with cytokine combinations that produced low versus high levels of gamma-globin mRNA and fetal hemoglobin (HbF). Embryonic, fetal, and adult globin transcript and protein expression patterns were determined for comparison. Chromatin immunoprecipitation assays revealed RNA polymerase II occupancy and histone tail modifications consistent with transcriptional activation only in the high-HbF culture condition. Transcriptome profiling studies demonstrated reproducible changes in expression of nuclear transcription factors associated with high HbF. Among the 13 genes that demonstrated differential transcript levels, 8 demonstrated nuclear protein expression levels that were significantly changed by cytokine signal transduction. Five of the 8 genes are recognized regulators of erythropoiesis or globin genes (MAFF, ID2, HHEX, SOX6, and EGR1). Thus, cytokine-mediated signal transduction in adult erythroid cells causes significant changes in the pattern of globin gene and protein expression that are associated with distinct histone modifications as well as nuclear reprogramming of erythroid transcription factors.

MeSH Terms
Adult Antigens, CD34 Cells, Cultured Cytokines/metabolism Erythroid Cells/cytology,metabolism Fetal Hemoglobin/biosynthesis Gene Expression Profiling Gene Expression Regulation Hemoglobinopathies/metabolism Histones/metabolism Humans Protein Processing, Post-Translational RNA Polymerase II/metabolism Signal Transduction Transcription Factors/metabolism Transcription, Genetic
Chemicals
Antigens, CD34 Cytokines Histones Transcription Factors Fetal Hemoglobin RNA Polymerase II
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Sripichai Orapan
Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Kiefer Christine M
Bhanu Natarajan V
Tanno Toshihiko
Noh Seung-Jae
Goh Sung-Ho
Russell J Eric
Rognerud Cheryl L
Ou Ching-Nan
Oneal Patricia A
Meier Emily R
Gantt Nicole M
Byrnes Colleen
Lee Y Terry
Dean Ann
Miller Jeffery L
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
1528-0020
DOI
10.1182/blood-2009-05-219386
Published
2009-09-10
Epub
2009-00-13
Pages
2299-306
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC2745848
Subset
IM
Grants
NHLBI NIH HHS · R01 HL061399 · United States
NHLBI NIH HHS · R01 HL082754 · United States
Intramural NIH HHS · United States
External Links
PubMed source DOI: 10.1182/blood-2009-05-219386 PMC Full Text View journal details
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