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

Date Published: October 10, 2018

Publisher: Public Library of Science

Author(s): Simone Valentin Hansen, Sofie Traynor, Henrik Jørn Ditzel, Morten Frier Gjerstorff, Tudor C Badea.


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.

Partial Text

The zinc finger BED domain-containing protein 1 (ZBED1) is also 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, also called a DNA replication-related element (DRE) [1, 2]. When DREs are located several hundred base pairs upstream of the transcriptional start site, dDREF can function as a traditional transcription factor [3, 4], and it can also function as part of the basal transcriptional machinery together with TBP Related Factor 2 (TRF2) [5]. 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 also 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. Although the function of dDREF is well described, little is known about the functions of ZBED1 in human cells and tissues. We have characterized the cellular expression pattern of ZBED1 in multiple human tissues to illuminate the cellular functions of ZBED1. We focused on a possible association between ZBED1 and cell proliferation since it is well-established that dDREF is important for cell proliferation.




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