Human ZKSCAN3 and Drosophila M1BP are functionally homologous transcription factors in autophagy regulation

Abstract

Autophagy is an essential cellular process that maintains homeostasis by recycling damaged organelles and nutrients during development and cellular stress. ZKSCAN3 is the sole identified master transcriptional repressor of autophagy in human cell lines. How ZKSCAN3 achieves autophagy repression at the mechanistic or organismal level however still remains to be elucidated. Furthermore, Zkscan3 knockout mice display no discernable autophagy-related phenotypes, suggesting that there may be substantial differences in the regulation of autophagy between normal tissues and tumor cell lines. Here, we demonstrate that vertebrate ZKSCAN3 and Drosophila M1BP are functionally homologous transcription factors in autophagy repression. Expression of ZKSCAN3 in Drosophila prevents premature autophagy onset due to loss of M1BP function and conversely, M1BP expression in human cells can prevent starvation-induced autophagy due to loss of nuclear ZKSCAN3 function. In Drosophila ZKSCAN3 binds genome-wide to sequences targeted by M1BP and transcriptionally regulates the majority of M1BP-controlled genes, demonstrating the evolutionary conservation of the transcriptional repression of autophagy. This study thus allows the potential for transitioning the mechanisms, gene targets and plethora metabolic processes controlled by M1BP onto ZKSCAN3 and opens up Drosophila as a tool in studying the function of ZKSCAN3 in autophagy and tumourigenesis.

An RNA-interference screen in Drosophila to identify ZAD-containing C2H2 zinc finger genes that function in female germ cells

“…We also identified a role for M1BP, a transcription factor that associates with thousands of genes in somatic cells ( Li and Gilmour 2013 ; Zouaz et al 2017 ; Barthez et al 2020 ). Similarly, CG30020 is also likely to be transcription factor, as in vitro studies have shown that it binds a unique DNA consensus sequence ( Krystel and Ayyanathan 2013 ).…”

Association of NKAPL rs1635 With Cognitive Function in Early-Onset Schizophrenia

“…Methylation in promoter regions of ZSCAN31 in the brain had an effect on schizophrenia ( Pineda-Cirera et al, 2022 ). ZKSCAN3 plays a role in the transcriptional regulation of autophagy ( Pan et al, 2017 ; Barthez et al, 2020 ; Cho et al, 2021 ). Autophagy is an important cellular process that maintains homeostasis by recycling damaged organelles and nutrients during cell development and stress.…”

“…Autophagy dysfunction in the hippocampus, especially in the CA2 region, may relate to deficits of social communication and interaction in schizophrenia patients ( Yang and Xu, 2020 ). Gene expression pattern of ZNF391 in the brain led to the three biotypes, which performed significantly differently in working memory and demonstrated different gray matter volumes in the right inferior frontal orbital gyrus ( Barthez et al, 2020 ). These data provide clues for further exploring the pathogenesis and cognitive impairment mechanism of schizophrenia.…”

Overexpression of ZNF460 predicts worse survival and promotes metastasis through JAK2/STAT3 signaling pathway in patient with colon cancer

“…In recent years, more and more ZNFs were identified as oncogene and promoted various tumors via enhancing cell proliferation [24], promoting cell migration and invasion [25], suppressing autophagy [26], and epithelial-mesenchymal transition [27]. ZNF460 gene co-expression network analysis established that ZNF460 had a positive correlation with ZNF484, ZNF121, HMBOX1 and a negative correlation with MGAT4B, UCHL3, GTF2IRD1.…”