{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSFPQ is a multifunctional nucleic acid–binding protein that plays a central role in transcriptional regulation. It integrates into distinct protein complexes to modulate gene expression in a context‐dependent manner. For example, in the regulation of circadian rhythms, SFPQ associates with PERIOD complexes to recruit transcriptional inhibitory machinery (via SIN3A and histone deacetylases), thereby repressing Per1 transcription."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In steroid‐responsive cells such as Sertoli cells, SFPQ is part of DBHS protein complexes that coactivate androgen receptor–mediated transcription."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In hepatocytes and other cell types, SFPQ is also found in multiprotein assemblies regulating genes such as RBP4 and even proto‐oncogenes, functioning as either a coactivator or repressor. In tumor models, changes in SFPQ activity (and its modulation by interacting noncoding RNAs) have been linked to altered cell proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Moreover, in the context of neovascularization, SFPQ partners with factors like Hakai to repress IGF-1–induced VEGF gene activation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", and similar interactions extend to its role with HELZ2 during adipocyte differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in transcription, SFPQ is a key regulator of posttranscriptional RNA processing. It contributes to pre-mRNA splicing decisions and orchestrates mRNA fate via its RNA-binding capacity, as illustrated by its involvement in axonal mRNA assembly and transport in sensory neurons."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " SFPQ modulates alternative splicing events that are critical for neuronal gene expression; disruption of these processes has been implicated in neurodegenerative conditions such as ALS, where aberrant intron retention and nuclear loss of SFPQ are observed."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Its interaction with other splicing regulators—including binding partners like NONO—and with specific long noncoding RNAs (for example, Morrbid lncRNA that influences NRAS isoform generation via coupling to the nonsense-mediated decay pathway) further underlines its importance in fine-tuning the transcriptome."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Moreover, SFPQ assists in the efficient transcriptional elongation of exceptionally long neuronal genes by facilitating critical interactions (such as those between CDK9 and the elongation complex)."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSFPQ’s versatility extends to its involvement in neuronal development and cellular homeostasis. In developing brain systems, a reduction or functional perturbation of SFPQ leads to increased cell death and abnormalities in neuronal differentiation, as shown in zebrafish mutants and in developing murine cerebral cortex."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " In hippocampal neurons, learning triggers the upregulation of SFPQ (along with other splicing factors), underscoring its role in long-term memory formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " SFPQ also interacts with signaling mediators; for instance, it binds to PKCα in the nucleus"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "and couples with JNK in neuronal granules to promote neurite outgrowth."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " In the immune system, a partial knockdown of SFPQ in thymocytes results in decreased stability of histone mRNAs and increased apoptosis, demonstrating its role in cell survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " Additionally, SFPQ is found within transcriptional complexes operating in dopaminergic neurons"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "and modulates miRNA-mediated gene silencing in both the nucleoplasm and cytoplasm."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, the studies summarized here illustrate that SFPQ acts as an integrative regulator at the nexus of transcription, splicing, mRNA stability, and signal-dependent gene expression. Its roles in diverse biological processes—from circadian rhythm regulation and control of proliferative signals to neuronal differentiation, long-term memory formation, and cellular homeostasis—highlight its importance as a multifunctional factor whose dysregulation may contribute to a variety of human diseases.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hao A Duong, Maria S Robles, Darko Knutti, et al. 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