{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The human DHRS4 gene cluster comprises three homologous genes—DHRS4, DHRS4L2, and DHRS4L1—that arose through evolutionary gene duplication. Although the prototypical DHRS4 gene encodes an NADP(H)‐dependent short‐chain dehydrogenase/reductase involved in retinoid and 3β‐hydroxysteroid metabolism, the duplicated copy gene, DHRS4L2, appears to have diverged in its regulation rather than in its catalytic function.\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Several studies have demonstrated that the expression of DHRS4L2, along with its genomic neighbors, is tightly controlled by natural antisense transcripts. For instance, the long noncoding RNA AS1DHRS4 mediates local chromatin modifications—including histone deacetylation, demethylation of H3K4, and recruitment of H3K9‐ and H3K27‐specific methyltransferases and DNA methyltransferases—to regulate the transcriptional activity of the entire cluster, thereby discriminately influencing DHRS4L2 expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, an enhancer element located downstream of the DHRS4-AS1 promoter produces an enhancer RNA that facilitates DNA looping and further stimulates the expression of DHRS4-AS1, reinforcing the coordinated regulation of the gene cluster that includes DHRS4L2."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Comprehensive transcript analyses in neuroblastoma and other cell types have revealed that alternative transcription start sites and splicing events in the DHRS4 gene cluster lead to the generation of multiple RNA variants. Notably, DHRS4L2 transcripts often lack exon 1 and show a poor correlation between RNA and protein levels—a discrepancy that has been attributed to epigenetic regulation through promoter CpG island methylation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "and has been further confirmed by methylation studies in neuroblastoma cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Evolutionary analyses indicate that among the duplicated copies, DHRS4L2 is the most recent addition and uniquely exhibits a hypermethylated promoter. This epigenetic modification is thought to contribute to a dose-compensatory mechanism that modulates the expression levels within the cluster."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its regulatory role in metabolic pathways, genetic variation at the DHRS4L2 locus has functional implications in disease. For example, a recessive marker (rs2273946) in DHRS4L2 has been associated with an accelerated age at onset in individuals carrying pathogenic PSEN1 mutations linked to Alzheimer’s disease, suggesting that DHRS4L2 may indirectly influence neurodegenerative processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Moreover, in the context of cancer predisposition, altered expression of DHRS4L2—along with other radiation-sensitive genes—is observed in patients with copy number variations who experience radiation-induced changes to gene expression profiles."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, while DHRS4L2 is positioned within a critical gene cluster important for retinoid and steroid metabolism, its main functional significance lies in its highly regulated expression via antisense RNA–mediated epigenetic mechanisms and CpG methylation. Such regulation appears to be essential for dose compensation following gene duplication and may have broader implications in neurodegenerative diseases and cancer susceptibility.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Qi Li, Zhongjing Su, Xiaoyuan Xu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "AS1DHRS4, a head-to-head natural antisense transcript, silences the DHRS4 gene cluster in cis and trans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1116597109"}], "href": "https://doi.org/10.1073/pnas.1116597109"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22891334"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22891334"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yingying Yang, Zhongjing Su, Xuhong Song, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Enhancer RNA-driven looping enhances the transcription of the long noncoding RNA DHRS4-AS1, a controller of the DHRS4 gene cluster."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep20961"}], "href": "https://doi.org/10.1038/srep20961"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26864944"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26864944"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Zhong-Jing Su, Qiao-Xia Zhang, Ge-Fei Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Bioinformatic analysis of the human DHRS4 gene cluster and a proposed mechanism for its transcriptional regulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Mol Biol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2199-11-43"}], "href": "https://doi.org/10.1186/1471-2199-11-43"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20525226"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20525226"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Qiaoxia Zhang, Yifan Li, Gefei Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Alternative transcription initiation and splicing variants of the DHRS4 gene cluster."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biosci Rep (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BSR20080040"}], "href": "https://doi.org/10.1042/BSR20080040"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18754758"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18754758"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Z Su, G Liu, X Song, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CpG island evolution in the mammalian DHRS4 gene cluster and its role in the regulation of gene transcription."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genet Mol Res (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4238/gmr.15027752"}], "href": "https://doi.org/10.4238/gmr.15027752"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27323117"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27323117"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Jorge I Vélez, Francisco Lopera, Claudia T Silva, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Familial Alzheimer's Disease and Recessive Modifiers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Neurobiol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12035-019-01798-0"}], "href": "https://doi.org/10.1007/s12035-019-01798-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31664702"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31664702"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Galetzka Danuta, Müller Tobias, Dittrich Marcus, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Molecular karyotyping and gene expression analysis in childhood cancer patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Med (Berl) (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00109-020-01937-4"}], "href": "https://doi.org/10.1007/s00109-020-01937-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32577795"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32577795"}]}]}]}