PRDM2-The Key Research Targets for the Development of Diseases in Various Systems

Abstract

PR/SET domain 2 (PRDM2)/RIZ is a member of the histone/protein methyltransferases (PRDMs) superfamily. Discovered to have the ability to bind retinoblastoma in the mid-1990s, PRDM2 was assumed to play a role in neuronal development. Like other family members characterized by a conserved N-terminal PR structural domain and a classical C2H2 zinc-finger array at the C-terminus, PRDM2 encodes two major protein types, the RIZ1 and RIZ2 isoforms. The two subtypes differ in the presence or absence of the PR domain: the RIZ1 subtype has the PR domain, whereas the RIZ2 subtype lacks it. The PR domain exhibits varying conservation levels across species and shares structural and functional similarities with the catalytic SET domain, defining histone methyltransferases. Functioning as an SET domain, the PR domain possesses protein-binding interfaces and acts as a lysine methyltransferase. The variable number of classic C2H2 zinc fingers at the C-terminus may mediate protein-protein, protein-RNA, or protein-DNA interactions. An imbalance in the RIZ1/RIZ2 mechanism may be an essential cause of malignant tumors, where PR-positive isoforms are usually lost or downregulated. Conversely, PR-negative isoforms are always present at higher levels in cancer cells. RIZ1 isoforms are also important targets for estradiol interaction with hormone receptors. PRDM2 can regulate gene transcription and expression combined with transcription factors and plays a role in the development of several systemic diseases through mRNA expression deletion, code-shift mutation, chromosomal deletion, and missense mutation occurrence. Thus, PRDM2 is a key indicator for disease diagnosis, but it lacks systematic summaries to serve as a reference for study. Therefore, this paper describes the structure and biological function of PRDM2 from the perspective of its role in various systemic diseases. It also organizes and categorizes its latest research progress to provide a systematic theoretical basis for a more in-depth investigation of the molecular mechanism of PRDM2's involvement in disease progression and clinical practice.

Keywords: PRDM2/RIZ; RIZ1; RIZ2; biological function; diseases of various systems; structural.

Figure 1

Structural representation of the PRDM2 protein highlighting functional domains. The three-dimensional structure of PRDM2 was predicted using AlphaFold2. Key functional domains are color-coded: the PR (PRDI-BF1 and RIZ) domain is shown in orange, Rb-binding motifs in blue, and C2H2 zinc finger motifs in red. The protein backbone is rendered in green. The inset provides a zoom-in view of the PR domain, highlighting the structural features underlying its functional importance. The spatial arrangement of these domains suggests potential roles in transcriptional regulation and chromatin interaction. Note: The structural model was obtained from the AlphaFold Protein Structure Database (https://alphafold.ebi.ac.uk/entry/Q13029 (accessed on 14 August 2025)) and visualized using PyMOL 3.1 (Schrödinger, LLC, New York, NY, USA). Domain annotation was performed manually based on UniProt 2025_03 and the literature references.

Figure 2

The role of PRDM2 in cellular metabolic and physiological processes. This figure illustrates the diverse biological functions of PRDM2 across multiple systems. In muscle tissue, PRDM2 maintains quiescence by regulating H3K9 methylation, and its knockdown leads to loss of muscle quiescence. In bone, PRDM2 promotes osteoclast differentiation by upregulating NFATc1 and TRAP expression. In the immune system, PRDM2 (RIZ1 isoform) modulates NF-κB signaling and promotes the expression of inflammatory cytokines IL-6 and TNF-α. In hematopoietic cells, PRDM2 suppresses proliferation through RIZ1-mediated mechanisms. In metabolic regulation, PRDM2 influences obesity-related pathways via AKT3 signaling and H3K9 methylation. Collectively, these findings highlight PRDM2’s pivotal role in transcriptional regulation and cellular homeostasis.

Figure 3

Mechanisms of PRDM2 action in diseases across different systems. The figure illustrates the role of the PRDM2 gene and its mechanisms in diseases across different systems. Promoter methylation affects RIZ1 expression, and its inactivation or mutation is closely associated with the development of various diseases, particularly in the development and progression of tumors, thereby promoting carcinogenesis.