ZNF143 is a transcriptional regulator of nuclear-encoded mitochondrial genes that acts independently of looping and CTCF
Gene expression is orchestrated by transcription factors (TFs), which bind to DNA in a sequence-specific manner, and by spatial genome structure, which constrains and shapes TF activity. Zinc finger protein 143 (ZNF143/ZFP143) is a TF that has been implicated in both gene activation and 3D genome organisation. We have generated an acute ZNF143/ZFP143 depletion system to study its direct consequences on chromatin looping and gene transcription. The effects of ZNF143/ZFP143 depletion are inconsistent with it being a looping factor, which we further confirmed by systematic analysis of previous studies. However, degradation of ZNF143/ZFP143 led to the down-regulation of hundreds of its targets, which were found to be enriched in nuclear-encoded mitochondrial genes. By studying the consequences of ZNF143/ZFP143 loss in monoculture and in an in vitro embryonic development model, we establish ZNF143/ZFP143 as a conserved transcriptional regulator of cell proliferation and differentiation by modulating mitochondrial functions. Overall design: Analysis of chromatin occupancy (ZFP143 and CTCF), nascent RNA, 3D genome structure in ZFP143 transcription factor depletion using the dTAG degron system in mESCs. Analysis of open chromatin and stable RNA in ZFP143 depletion in stem cell-derived differentiation models.