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      Histone demethylase LSD1-mediated repression of GATA-2 is critical for erythroid differentiation

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          Abstract

          Background

          The transcription factor GATA-2 is predominantly expressed in hematopoietic stem and progenitor cells and counteracts the erythroid-specific transcription factor GATA-1, to modulate the proliferation and differentiation of hematopoietic cells. During hematopoietic cell differentiation, GATA-2 exhibits dynamic expression patterns, which are regulated by multiple transcription factors.

          Methods

          Stable LSD1-knockdown cell lines were established by growing murine erythroleukemia (MEL) or mouse embryonic stem cells together with virus particles, in the presence of Polybrene ® at 4 μg/mL, for 24–48 hours followed by puromycin selection (1 μg/mL) for 2 weeks. Real-time polymerase chain reaction (PCR)-based quantitative chromatin immunoprecipitation (ChIP) analysis was used to test whether the TAL1 transcription factor is bound to 1S promoter in the GATA-2 locus or whether LSD1 colocalizes with TAL1 at the 1S promoter. The sequential ChIP assay was utilized to confirm the role of LSD1 in the regulation of H3K4me2 at the GATA-2 locus during erythroid differentiation. Western blot analysis was employed to detect the protein expression. The alamarBlue ® assay was used to examine the proliferation of the cells, and the absorbance was monitored at optical density (OD) 570 nm and OD 600 nm.

          Results

          In this study, we showed that LSD1 regulates the expression of GATA-2 during erythroid differentiation. Knockdown of LSD1 results in increased GATA-2 expression and inhibits the differentiation of MEL and embryonic stem cells. Furthermore, we demonstrated that LSD1 binds to the 1S promoter of the GATA-2 locus and suppresses GATA-2 expression, via histone demethylation.

          Conclusion

          Our data revealed that LSD1 mediates erythroid differentiation, via epigenetic modification of the GATA-2 locus.

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          Most cited references 39

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          Multivalent engagement of chromatin modifications by linked binding modules.

          Various chemical modifications on histones and regions of associated DNA play crucial roles in genome management by binding specific factors that, in turn, serve to alter the structural properties of chromatin. These so-called effector proteins have typically been studied with the biochemist's paring knife--the capacity to recognize specific chromatin modifications has been mapped to an increasing number of domains that frequently appear in the nuclear subset of the proteome, often present in large, multisubunit complexes that bristle with modification-dependent binding potential. We propose that multivalent interactions on a single histone tail and beyond may have a significant, if not dominant, role in chromatin transactions.
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            An early haematopoietic defect in mice lacking the transcription factor GATA-2.

            Blood cell development relies on the expansion and maintenance of haematopoietic stem and progenitor cells in the embryo. By gene targeting in mouse embryonic stem cells, we demonstrate that the transcription factor GATA-2 plays a critical role in haematopoiesis, particularly of an adult type. We propose that GATA-2 regulates genes controlling growth factor responsiveness or the proliferative capacity of early haematopoietic cells.
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              • Record: found
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              • Article: not found

              Regulation of histone methylation by demethylimination and demethylation.

              Histone methylation has important roles in regulating transcription, genome integrity and epigenetic inheritance. Historically, methylated histone arginine and lysine residues have been considered static modifications because of the low levels of methyl-group turnover in chromatin. The recent identification of enzymes that antagonize or remove histone methylation has changed this view and now the dynamic nature of these modifications is being appreciated. Here, we examine the enzymatic and structural basis for the mechanisms that these enzymes use to counteract histone methylation and provide insights into their substrate specificity and biological function.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                19 June 2015
                : 9
                : 3153-3162
                Affiliations
                [1 ]School of Life Sciences, Jilin University, Changchun, People’s Republic of China
                [2 ]Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, Jilin University, Changchun, People’s Republic of China
                [3 ]National Engineering Laboratory of AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, People’s Republic of China
                Author notes
                Correspondence: Xin Hu, School of Life Sciences, Jilin University, 2699 Qianjin Road, Changchun 130012, People’s Republic of China, Tel +86 186 4311 9899, Fax +86 431 8451 5118, Email huxinjilin@ 123456yeah.net
                Article
                dddt-9-3153
                10.2147/DDDT.S81911
                4482369
                26124638
                © 2015 Guo et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                gata factor switching, lsd1, histone demethylation

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