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ZEB2 locus regulation in differentiating iPSCs

ABSTRACT: The multi-domain transcription factor ZEB2 controls embryonic and adult cell fate decisions and maturation in many stem/progenitor cell types. Defects in these processes in specific cell types underlie Mowat-Wilson syndrome (MOWS), which is caused by ZEB2 haplo-insufficiency. Human ZEB2, like mouse Zeb2, is located on chromosome 2 downstream of an approximately 3.5 Mb-long gene-desert, lacking any protein-coding gene sequence. Using temporal high-resolution Targeted Chromatin Capture (T2C), we show major chromatin structural changes based on mapping in-cis proximities between the ZEB2 gene promoter and this gene desert during neural differentiation of induced pluripotent cells (iPSCs), including at early neuroprogenitor cell (NPC)/rosette state, where ZEB2 mRNA levels increase significantly. Combining T2C with histone-3 acetylation mapping, we identified three novel candidate enhancers about 500 kb upstream of the ZEB2 transcription start site (TSS). Functional luciferase-based assays in heterologous cells and NPCs reveal co-operation between these three enhancers. This study is the first to document in-cis regulatory elements (REs) located in ZEB2’s gene desert. The results further show the usability of T2C for future studies of ZEB2 REs in differentiation and maturation of relevant cell types, and the molecular characterization of identified MOWS patients that lack mutations in ZEB2 protein-coding exons.

ORGANISM(S): Homo sapiens

PROVIDER: GSE147000 | GEO | 2020/08/03

REPOSITORIES: GEO

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