Intellectual disability-associated factor Zbtb11 cooperates with NRF-2/GABP to control mitochondrial function

Abstract

Zbtb11 is a conserved transcription factor mutated in families with hereditary intellectual disability.Its precise molecular and cellular functions are currently unknown, precluding our understanding of the aetiology of this disease. Using a combination of functional genomics, genetic and biochemical approaches here we show that Zbtb11 plays essential roles in maintaining the homeostasis of mitochondrial function. Mechanistically, we find Zbtb11 facilitates the recruitment of Nuclear Respiratory Factor 2 (NRF-2) to its target promoters, activating a subset of nuclear genes with roles in the biogenesis of respiratory complex I and the mitoribosome. Genetic inactivation of Zbtb11 resulted in a severe complex I assembly defect, impaired mitochondrial respiration, mitochondrial depolarisation, and ultimately proliferation arrest and cell death. Experimental modelling of the pathogenic human mutations showed these have a destabilising effect on the protein, resulting in reduced Zbtb11 dosage, down-regulation of its target genes, and impaired complex I biogenesis.Our study establishes Zbtb11 as a novel essential mitochondrial regulator, improves our understanding of the transcriptional mechanisms of nuclear control over mitochondria, and provides a rationale for the aetiology of Zbtb11-associated intellectual disability.ETC complexes (I, III and IV) couple substrate oxidation with proton extrusion from the mitochondrial matrix into the intermembrane space, thus creating an electrochemical gradient across the mitochondrial inner membrane which forces protons back into the matrix mainly through complex V (ATP synthase), driving the synthesis of ATP (Schultz & Chan, 2001). While mitochondria are ubiquitous organelles, tissues with high energy demands, such as brain and muscle, are particularly reliant on the activity of the ETC, and these are usually disproportionally affected in mitochondrial diseases. Nevertheless, because the activity of the ETC is also vital for regenerating the cellular pool of redox cofactors that catalyse a number of other metabolic reactions (Birsoy et al, 2015;Sullivan et al, 2015), it is becoming increasingly evident that a functional ETC is essential for all proliferating cells, irrespective of their ATP consumption (Yao et al, 2019).Mitochondria possess their own genome (mtDNA) and transcription machinery, as well as a specialised organellar ribosome (the mitoribosome). While the mtDNA encodes a small number of core subunits of the OXPHOS complexes, the majority of the mitochondrial proteome is encoded in the nuclear genome (nDNA). Mitochondrial biogenesis and function are therefore controlled to a significant extent through transcriptional regulation of nuclear genes. A number or transcription factors have been implicated in the regulation of nuclear-encoded mitochondrial genes, some of which are essential while others have modulatory roles important mainly in specific cell types or in conditions of increased energy demand (Fernandez-Marcos & Auwerx, 2011;Scarpulla et al, 2012).The nuclear re...

The BTB transcription factors ZBTB11 and ZFP131 maintain pluripotency by pausing POL II at pro-differentiation genes

“…Importantly, those include cell fate commitment, morphogenesis, and tissue development (Figure 2E, F, S8B-C). We also detected downregulated mitochondrial and other cellular biosynthetic and metabolic processes genes in Zbtb11Δ and Zfp131Δ ESCs (Figure S8D-F) (Wilson et al , 2019). Thus, Zbtb11 and Zfp131 mutations caused profound transcriptional changes indicative of cell differentiation in the two most common ESC culture conditions.…”

Knockdown of ZBTB11 impedes R‐loop elimination and increases the sensitivity to cisplatin by inhibiting DDX1 transcription in bladder cancer

“…According to data from DepMap (https://depmap.org/portal/gene/ZBTB11?tab=overview), ZBTB11 is a common essential gene and has been reported in a few articles. ZBTB11 gene inactivation leads to impaired mitochondrial respiratory function, resulting in proliferation arrest and cell death 18 . Embryonic stem cells lacking ZBTB11 lost clonal form and exhibited reduced proliferation 37 .…”

“…In our previous study, we screened the CRISPR–Cas9 transcription factor library and found that ZBTB11 is the only protein of the ZBTB family that plays a crucial role in the proliferation of BC cell lines. Recently, ZBTB11 has been associated with intellectual disability‐associated factor and has been reported to regulate neutrophil development and mitochondrial function 17,18 . Previous studies using chromatin immunoprecipitation sequencing have demonstrated that ZBTB11 can specifically recognize and bind to the ‘CGGAA’ motif in the promoter region of downstream genes to regulate transcription 18 .…”

“…Recently, ZBTB11 has been associated with intellectual disability‐associated factor and has been reported to regulate neutrophil development and mitochondrial function 17,18 . Previous studies using chromatin immunoprecipitation sequencing have demonstrated that ZBTB11 can specifically recognize and bind to the ‘CGGAA’ motif in the promoter region of downstream genes to regulate transcription 18 . Inactivation of the ZBTB11 gene results in impaired mitochondrial respiratory function, ultimately leading to proliferation arrest and cell death 18 .…”

“…17,18 Previous studies using chromatin immunoprecipitation sequencing have demonstrated that ZBTB11 can specifically recognize and bind to the 'CGGAA' motif in the promoter region of downstream genes to regulate transcription. 18 Inactivation of the ZBTB11 gene results in impaired mitochondrial respiratory function, ultimately leading to proliferation arrest and cell death. 18 Thus, we speculated that ZBTB11 plays a role in controlling the proliferation of BC cells.…”