Metabolic Oxidoreductases: Central Regulators of the Epigenetic Landscapes in Stemness

JMJD (Jumonji C domain-containing) histone demethylases are a large family of α-KG-dependent dioxygenases that remove methyl groups from histone lysine residues. They play critical roles in regulating chromatin structure and gene expression, which are essential for stem cell self-renewal, differentiation, and disease progression. Each JMJD isoform exhibits substrate specificity, targeting specific histone lysine residues (e.g., H3K4, H3K9, H3K27, H3K36) and methylation states (mono-, di-, or trimethyl). This precise control allows for dynamic regulation of both activating and repressive histone codes during cell state transitions. For example, JMJD3 (KDM6B) is crucial for H3K27me3 demethylation, facilitating the activation of developmental genes and driving differentiation, while KDM5 family members remove H3K4me2/3 marks to repress transcription.

N6-methyladenosine (m6A) is a prevalent internal modification in various RNAs, dynamically regulated by methyltransferases and demethylases like ALKBH5 and FTO. These α-KG-dependent dioxygenases are crucial for mRNA stability, splicing, translation, and decay, thereby influencing gene expression and cellular processes. ALKBH5 primarily demethylates m6A in single-stranded RNA, supporting stem cell self-renewal and preventing differentiation by stabilizing key transcripts. FTO, while also demethylating m6A, has broader substrate specificity, including hm6A and f6A, and affects neurogenesis, osteogenic differentiation, and the stability of transposable elements. Both enzymes are vital for embryonic development, and their dysregulation is linked to developmental defects and various cancers, highlighting their importance in epitranscriptomic regulation for maintaining stemness.

Comparison of ALKBH5 and FTO in RNA Epigenetics

Beyond their catalytic roles, some oxidoreductases function as non-enzymatic scaffold proteins that recruit chromatin-modifying complexes. CTBP (C-terminal binding protein), a NADH-dependent dehydrogenase, assembles into tetramers in response to NAD(H) levels, acting as a platform to gather DNA-binding transcription factors and epigenetic regulators like HDACs and LSD1. This scaffolding function is critical for transcriptional repression in embryonic stem cells (ESCs), priming genes for differentiation. Similarly, NPAC/GLYR1, another NADH-dependent dehydrogenase, lacks catalytic activity but binds H3K36me3 and recruits splicing factors and epigenetic enzymes (like LSD2) to regulate alternative splicing and transcriptional elongation. These non-enzymatic roles demonstrate how metabolic signals, specifically redox state, can directly reorganize chromatin regulatory machinery, providing a unique layer of metabolic-epigenetic coupling in stem cell biology.