PHF2

PHF2 Full Name

PHD finger protein 2

PHF2 Introduction

PHF2 (PHD finger protein 2) is a JmjC-domain-containing histone demethylase that selectively removes the repressive H3K9me2 mark, an activity that places it among the chromatin-modifying enzymes responsive to oxygen and metabolic state. The protein contains an N-terminal PHD finger that reads H3K4 methylation, a central JmjC catalytic domain, and a C-terminal region that mediates protein–protein interactions. PHF2 is recruited to chromatin through partnerships with PKA-phosphorylated forms of the homeodomain transcription factor HNF-4α and with ARID5B, allowing context-specific demethylation of target genes in hepatocytes and adipocytes.

Figure 1. The structure of PHF2.

H3K9me2 Demethylation at Metabolic and Developmental Genes
PHF2 oxidizes H3K9me2 to H3K9me1 using α-ketoglutarate and Fe(II) as cofactors, a reaction that is intrinsically sensitive to cellular oxygen and to the levels of oncometabolites such as 2-hydroxyglutarate. Demethylation of H3K9me2 by PHF2 at promoters and enhancers of adipocyte differentiation genes relieves heterochromatin-mediated repression, allowing PPARγ and C/EBP family factors to drive adipogenesis. In liver, PHF2 partners with phosphorylated HNF-4α to activate gluconeogenic gene programs under fasting conditions, and in neural progenitors it removes H3K9me2 at neurogenic loci to permit neuronal differentiation.

Obesity, Cancer, and Intellectual Disability
Mice lacking PHF2 become obese on a high-fat diet due to impaired adipocyte turnover and energy expenditure, while tissue-specific overexpression of PHF2 protects against diet-induced weight gain. In cancer, PHF2 acts as a context-dependent tumor suppressor: in clear cell renal cell carcinoma, PHF2 loss cooperates with VHL deficiency to sustain hypoxia-driven gene expression, whereas in diffuse gastric cancer PHF2 mutations are associated with reduced chromatin accessibility and poor prognosis. De novo heterozygous truncating variants in PHF2 have been reported in patients with a neurodevelopmental syndrome featuring intellectual disability, speech delay, and obesity.

Alternate Names for PHF2

PHF2; PHD finger protein 2; GRC5; JHDM1E; CENP-35; lysine-specific demethylase PHF2; centromere protein 35; jumonji C domain-containing histone demethylase 1E;