PHF2, also known as plant homeodomain finger protein 2, is a histone demethylase that plays crucial roles in various biological processes. It specifically demethylates histone 3 lysine 9 dimethyl (H3K9me2), thereby regulating gene expression. PHF2 is involved in multiple pathways, including lipid metabolism, cancer metastasis, myogenesis, DNA replication, neural development, memory consolidation, and DNA repair [1-9].

In hepatocellular carcinoma, palmitoylation of PHF2 by ZDHHC23 enhances its ubiquitin-dependent degradation, disrupting the PHF2/SREBP1c axis which regulates lipid metabolism [1]. In lung cancer, AMPK phosphorylates PHF2 at S655, enhancing its demethylation activity, reducing H3K9me2, and inhibiting cancer metastasis [2]. In myogenesis, Phf2 knockout in C2C12 myoblasts impairs the expression of genes related to skeletal muscle fiber formation and muscle cell development [3]. In neural stem cells, PHF2 loss impairs DNA replication and weakens topologically-associated domains (TADs) due to reduced RAD21 occupancy [4]. In neural progenitors, PHF2 depletion increases transcription of heterochromatic repeats, decreases H3K9me3 levels, and disrupts heterochromatin stability [5]. In the mouse hippocampus, transgenic overexpression of PHF2 enhances memory formation, while its silencing impairs it [6]. In DNA repair, PHF2 knockdown leads to impaired homologous recombination due to defective resection of double-strand breaks [7]. In neural progenitors, PHF2 depletion induces DNA damage and cell cycle arrest [8]. In cancer, PHF2 acts as a tumor suppressor in association with p53, ensuring p53-mediated cell death in response to chemotherapy [9].

In conclusion, PHF2 is essential for regulating various biological functions such as lipid metabolism, cancer-related processes, myogenesis, neural development, memory, and DNA repair. Gene knockout models of PHF2 in different cell types and organisms have significantly contributed to understanding its role in these processes and associated diseases, providing insights into potential therapeutic targets for conditions like cancer, neurodegenerative diseases, and muscle-related disorders.