Recruitment of SWI/SNF Complex Is Required for Transcriptional Activation of the SLC11A1 Gene during Macrophage Differentiation of HL-60 Cells

Abstract

The solute carrier family 11 member 1 (SLC11A1) gene is strictly regulated and exclusively expressed in myeloid lineage cells. However, little is known about the transcriptional regulation of the SLC11A1 gene during myeloid development. In this study, we used HL-60 cells as a model to investigate the regulatory elements/factors involved in the transactivation of the SLC11A1 gene during phorbol 12-myristate 13-acetate (PMA)-induced macrophage differentiation of HL-60 cells. Promoter deletion analysis showed that a 7-base AP-1-like element (TGACTCT) was critical for the responsiveness of the SLC11A1 promoter to PMA. Stimulation by PMA induced the binding of ATF-3 and the recruitment of two components of the SWI/SNF complex, BRG1 and ␤-actin, to this element in an ATF-3-dependent manner. RNAi-mediated depletion of ATF-3 or BRG1 markedly decreased SLC11A1 gene expression and its promoter activity induced by PMA. Luciferase reporter experiments demonstrated that ATF-3 cooperated with BRG1 and ␤-actin to activate the SLC11A1 promoter. Furthermore, we showed that PMA can induce the proximal (GT/AC) n repeat sequence to convert to the Z-DNA structure in the SLC11A1 gene promoter, and depletion of BRG1 resulted in a significant decrease of Z-DNA formation. Our results demonstrated that recruitment of the SWI/SNF complex initiated Z-DNA formation and subsequently helped to transactivate the SLC11A1 gene.The solute carrier family 11 member 1 (SLC11A1) gene, also known as Ity/Lsh/BCG or natural resistance-associated macrophage 1 (NRAMP1) gene, is associated with host resistance to infection. In mice, mutations in the Slc11a1 gene, whether naturally occurring or experimentally induced, cause susceptibility to infection with unrelated intracellular pathogens such as Salmonella, Leishmania, and Mycobacteria (1-5). The multiple pleiotropic effects of the SLC11A1 gene on macrophage activation, including regulation of the chemokine KC and cytokines (e.g. TNF␣), as well as induction of nitric oxide (NO) release, MHC class II molecule expression, and oxidative burst (6, 7), display its potential importance in autoimmune and infectious diseases. In humans, polymorphic variants of the SLC11A1 gene are associated with susceptibility to infectious diseases such as tuberculosis, leprosy, and HIV infection, as well as autoimmune diseases such as rheumatoid arthritis, sarcoidosis, diabetes, and Crohn disease (6,8). Furthermore, the polymorphisms of the SLC11A1 gene have been linked with esophageal cancer risk (9).In humans, the SLC11A1 gene is located on chromosome 2q35 and has 15 exons spanning about 14 kb. The gene encodes a transmembrane protein exclusively expressed in the myeloid lineage as follows: monocytes, macrophages, polymorphonuclear neutrophils, and dendritic cells (10, 11). SLC11A1 gene expression is strictly regulated during myeloid development, and SLC11A1 protein expression parallels with its mRNA level (12), suggesting that SLC11A1 expression may be controlled primarily at the level of transcription. The human promyelocy...

Activated Transcription Factor 3 in Association with Histone Deacetylase 6 Negatively Regulates MicroRNA 199a2 Transcription by Chromatin Remodeling and Reduces Endothelin-1 Expression

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Exploring Secrets of Nuclear Actin Involvement in the Regulation of Gene Transcription and Genome Organization

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The alterations in SATB1 and nuclear F-actin expression affect apoptotic response of the MCF-7 cells to geldanamycin

“…It has been shown that actin may translocate into the cell nucleus to function as a transcriptional modulator of gene expression [5,[7][8][9][10][11][12][13][14][15][16]. Our earlier studies have demonstrated not only the translocation of actin into the nucleus but also the involvement of nuclear F-actin in chromatin remodeling during cell death processes [32][33][34][35][36].…”

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