Biology subjects

Nur Arslantas, E.

Publications and source records attributed to Nur Arslantas, E..

2 recordsLinked to original sources

bioRxiv2025

Feed-forward loops by NR5A2 ensure robust gene activation during pre-implantation development

The pioneer transcription factor NR5A2 plays multiple roles in regulating zygotic genome activation and expression of lineage-determining factor during mouse pre-implantation development. However, how NR5A2 differentially regulates transcriptional networks at distinct developmental stages remains unknown. Here, we demonstrate the dynamics of chromatin binding profiles of NR5A2 from the 2-cell to morula stage, which corresponds to the totipotency-to-pluripotency transition. Our NR5A2 CUT&Tag analysis identifies lineage-determining factor KLF and GATA families as co-regulators for NR5A2 in mouse embryos. We find that KLF5 cooperates with NR5A2 to enhance H3K27ac deposition, and NR5A2 predominantly promotes chromatin accessibility. NR5A2 regulates Xist expression either directly or indirectly through its role in up-regulating GATA factor expression. In vitro assays reveal that NR5A2 co-binds to nucleosomes with KLF5 and GATA6, suggesting that these pioneer transcription factors can simultaneously bind to the chromatin. Our findings highlight the role of NR5A2 in ensuring robust gene activation during pre-implantation development through feed-forward regulatory loops with lineage-determining transcription factors.

developmental biology↗

bioRxiv2023

Nucleosome-bound NR5A2 structure reveals pioneer factor mechanism by minor groove anchor competition

Gene expression during natural and induced reprogramming is controlled by pioneer transcription factors, which bind nucleosomal DNA and initiate gene expression from closed chromatin. How pioneer factors perform this function is poorly understood. Nr5a2 is a pioneer factor that is critical for zygotic genome activation (ZGA) in totipotent embryos, pluripotency in embryonic stem cells and metabolic regulation in adult tissues. To study how Nr5a2 functions as a pioneer factor, we used cryo-electron microscopy to determine a structure of human NR5A2 bound to a nucleosome. The structure shows that the conserved C-terminal extension (CTE) loop of the NR5A2 DNA-binding domain competes with a DNA minor groove anchor of the nucleosome and releases entry-exit site DNA at a [~]50{degrees} angle. Residue aspartic acid 159 of the CTE loop induces the rearrangement by shifting a histone H2A 2 helix towards the nucleosome center. Mutational analysis showed that NR5A2 D159 is largely dispensable for DNA binding but required for stable nucleosome association and persistent DNA unwrapping. These findings suggest that NR5A2 belongs to a previously unknown class of pioneer factors that can use minor groove anchor competition to destabilize nucleosomes and facilitate gene expression changes during reprogramming.

biochemistry↗