ZNF143 is a transcriptional regulator of nuclear-encoded mitochondrial genes that acts independently of looping and CTCF

Abstract

SummaryGene expression is orchestrated by transcription factors, which function within the context of a three-dimensional genome. Zinc finger protein 143 (ZNF143/ZFP143) is a transcription factor that has been implicated in both gene activation and chromatin looping. To study the direct consequences of ZNF143/ZFP143 loss, we generated a ZNF143/ZFP143 degron line. Our results show that ZNF143/ZFP143 depletion has no effect on chromatin looping. Systematic analysis of ZNF143/ZFP143 occupancy data revealed that a commonly used antibody cross-reacts with CTCF, leading to its incorrect association with chromatin loops. Nevertheless, ZNF143/ZFP143 specifically activates nuclear-encoded mitochondrial genes and its loss leads to severe mitochondrial dysfunction. Using anin vitroembryo model, we find that ZNF143/ZFP143 is an essential regulator of organismal development. Our results establish ZNF143/ZFP143 as a conserved transcriptional regulator of cell proliferation and differentiation by safeguarding mitochondrial activity.HighlightsAcute degradation of ZFP143 leads to rapid and specific loss of gene transcription.Molecular consequences of ZFP143 loss are inconsistent with a role in chromatin looping.ZFP143 is a conserved transcriptional regulator of nuclear-encoded mitochondrial proteins.ZFP143 regulation of mitochondrial homeostasis is critical for multicellular organismal development.Graphical Abstract