Human DREF/ZBED1 is a nuclear protein widely expressed in multiple cell types derived from all three primary germ layers

Simone Valentin Hansen,Sofie Traynor,Morten Frier Gjerstorff,Henrik Jørn Ditzel

doi:10.1371/journal.pone.0205461

Abstract

Drosophila DNA replication-related element binding factor (DREF) is a transcription regulatory factor that binds the promoters of many genes involved in replication and cell proliferation and is required for normal cell cycle progression. Human DREF/zinc finger BED domain-containing protein 1 (ZBED1), an orthologue of Drosophila DREF, also has DNA binding activity, but its cellular functions remain largely uncharacterized. Herein, we show that ZBED1 is a chromatin-associated nuclear protein with a wide expression profile in human tissues from all three primary germ layers. For instance, ZBED1 was expressed in mesodermal-derived epithelial cells of the reproductive system and urinary tract, in endodermal-derived epithelial cells throughout the gastrointestinal tract, and in epidermal epithelium from the ectoderm. ZBED1 was also expressed in connective tissue and smooth muscle cells of multiple organs. To investigate whether ZBED1 is implicated in cell proliferation, similar to Drosophila DREF, we compared the tissue distribution of ZBED1 to that of the proliferation marker Ki-67. ZBED1 and Ki-67 were co-expressed in many epithelial tissues, but ZBED1 expression extended widely beyond that of Ki-67-positive cells. In other tissues, ZBED1 expression was more restricted than Ki-67 expression. These results suggest that ZBED1 is not a cell proliferation-associated factor such as Drosophila DREF, and our study adds to the cumulative understanding of the functions of ZBED1 in human cells and tissues.

Highlights

The zinc finger BED domain-containing protein 1 (ZBED1) is known as DNA replication-related element binding factor (DREF) and was first discovered in Drosophila
ZBED1 expression in human tissues transcriptional machinery together with TBP Related Factor 2 (TRF2) [5]. Drosophila DREF (dDREF) is involved in chromatin organization and epigenetic regulation through activation of the transcription of key subunits of the BRM chromatin-remodelling complex [6], by direct association with the XNP/dATRX chromatin remodelling complex [7], by interacting with the Mi-2 chromatin remodelling protein [8] and by antagonizing the boundary element-associated factor (BEAF) [9]. dDREF activates the transcription of the Drosophila histone methyltransferase, nuclear receptor-binding SET domain protein (NSD) [10] and may play a role in telomere maintenance [8]
ZBED1 is the human orthologue of the Drosophila transcription factor dDREF

Summary

Introduction

The zinc finger BED domain-containing protein 1 (ZBED1) is known as DNA replication-related element binding factor (DREF) and was first discovered in Drosophila. Drosophila DREF (dDREF) contains a BED zinc finger domain at the N-terminal of the protein, which has DNA binding activity and is responsible for binding to the consensus sequence 5’-TATCGATA, called a DNA replication-related element (DRE) [1, 2]. DDREF is instrumental for cell proliferation in enhancing the expression of several genes important for DNA replication and cell cycle progression, including replication factor C 1 (rcf1) [11], S-Phase Kinase Associated Protein 1-related A (skpA) [12], E2F [13], cyclin A [14], DNA polymerase α and proliferating cell nuclear antigen (PCNA) [2, 3, 15]. Gene knockdown demonstrated that dDREF is required for cells to efficiently progress through the late G1 and S phase of cell cycle, further demonstrating its importance in cell proliferation [3]. dDREF regulates the transcription of several genes involved in replication and transcription of mitochrondrial DNA [8], and is involved in control of protein synthesis by positive regulation of genes required for ribosome biogenesis [8]

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