ZNF423 binds EBF2 at EBF2-target gene loci

Stable Identifier
R-HSA-9844375
Type
Reaction [transition]
Species
Homo sapiens
Compartment
ReviewStatus
5/5
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Based on studies in mice, the transcription factor ZNF423 (also known as ZFP423), whose expression is enriched in white compared with brown adipocytes, can form a complex with EBF2 at EBF2 target loci. ZNF423 suppress activation of EBF2 target genes that are part of the thermogenic program in brown and beige adipocytes. The interaction between ZNF423 and EBF2 is essential for the maintenance of the white adipose tissue phenotype (Shao et al. 2016; Shao et al. 2021). The transcriptional repression of EBF2 target genes by ZNF423 involves ZNF423-mediated recruitment of the transcriptional repressor complex NuRD (composed of, at least, core components MTA1 or MTA2 or MTA3, MBD3, the dimer of HDAC1 and HDAC2, RBBP4 and RBBP7, and peripherally associated proteins CHD3 or CHD4 and GATAD2A or GATAD2B) and interference with the recruitment of the transcription factor PPARG to the EBF2 target gene loci.

Based on mouse studies, the following human EBF2 target genes are inferred to be negatively regulated by ZNF423:
CIDEA (Shao et al. 2021: inability of ectopically expressed ZNF423 mutant defective in NuRD binding to repress CIDEA gene transcription in brown adipocytes);
DIO2 (Shao et al. 2016: significant increase in DIO2 mRNA levels upon knockout of ZNF423 gene in white adipocytes; Shao et al. 2021: inability of ectopically expressed ZNF423 mutant defective in NuRD binding to repress DIO2 gene transcription in brown adipocytes);
ELOVL3 (Shao et al. 2016: significant upregulation of ELOVL3 gene transcription by ZNF423 knockout in white adipocytes)
PPARA (Shao et al. 2021: by ChIP qPCR, ZNF423 gene deletion does not interfere with EBF2 binding but promotes PPARG binding to the PPARA gene locus; ZNF423 binds to PPARA gene locus);
PRDM16 (Shao et al. 2016: inhibition of induction of PRDM16 gene transcription by ectopically expressed EBF2 in white adipocytes by co-expression of ZNF423; reduced induction of PRDM16 luciferase reporter gene by EBF2 and the complex of PPARG2:RXRA in the presence of ZNF423; Shao et al. 2021: by ChIP qPCR, ZNF423 gene deletion does not interfere with EBF2 binding but promotes PPARG binding to the PRDM16 gene locus);
UCP1 (Shao et al. 2016: expression of UCP1 gene at both mRNA and protein levels is significantly increased by ZNF423 knockdown or ZNF423 gene knockout in white adipocytes, while expression of UCP1 is repressed by ectopic ZNF423 overexpression in brown and beige adipocytes; Shao et al. 2021: by ChIP qPCR, ZFN423 gene deletion does not interfere with EBF2 binding but promotes PPARG binding to the UCP1 gene locus).

Based on the strength of experimental evidence, UCP1, PPARA, and PRDM16 genes are annotated as members of ZNF423 target gene set, while CIDEA, DIO2, and ELOVL3 genes are annotated as candidate of ZNF423 target gene set.

ZNF423-mediated regulation of EBF2 target genes BLNC1, COX7A1, and PPARGC1A has not been tested.
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