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.