ZFP982 confers mouse embryonic stem cell characteristics by regulating expression of Nanog, Zfp42, and Dppa3

Understanding the genetic underpinnings of protein networks conferring stemness is of broad interest for basic and translational research. We used multi-omics analyses to identify and characterize stemness genes, and focused on the zinc finger protein 982 (Zfp982) that regulates stemness through the expression of Nanog, Zfp42, and Dppa3 in mouse embryonic stem cells (mESC). Zfp982 was expressed in stem cells, and bound to chromatin through a GCAGAGKC motif, for example near the stemness genes Nanog, Zfp42, and Dppa3. Nanog and Zfp42 were direct targets of ZFP982 that decreased in expression upon knockdown and increased upon overexpression of Zfp982. We show that ZFP982 expression strongly correlated with stem cell characteristics, both on the transcriptional and morphological levels. Zfp982 expression decreased with progressive differentiation into ecto-, endo- and mesodermal cell lineages, and knockdown of Zfp982 correlated with morphological and transcriptional features of differentiated cells. Zfp982 showed transcriptional overlap with members of the Hippo signaling pathway, one of which was Yap1, the major co-activator of Hippo signaling. Despite the observation that ZFP982 and YAP1 interacted and localized predominantly to the cytoplasm upon differentiation, the localization of YAP1 was not influenced by ZFP982 localization. Together, our study identified ZFP982 as a transcriptional regulator of early stemness genes, and since ZFP982 is under the control of the Hippo pathway, underscored the importance of the context-dependent Hippo signals for stem cell characteristics. ZFP982 is a regulator of the stemness of mouse embryonic stem cells and acts as a transcription factor by activating the expression of stem cell genes including Nanog, Zfp42, and Dppa3. [Display omitted] •Zfp982 is a new mouse stem cell defining marker gene.•Zfp982 is co-expressed with stem cell marker and Yap1 genes in mESC.•ZFP982 binds to DNA and induces expression of master genes of stemness in mESC.•Expression of Zfp982 gene prevents neural differentiation and maintains stem cell characteristics.•ZFP982 and YAP1 interact in mESC and translocate to the cytoplasm upon neural differentiation.