Identifying an oligodendrocyte enhancer that regulates<i>Olig2</i>expression

Fan, Chuandong; Kim, Dongkyeong; An, Hongjoo; Park, Yungki

doi:10.1093/hmg/ddac249

Cited by 4 publications

(2 citation statements)

References 65 publications

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“…In addition to the promoter region, two regulatory regions are localized in front of the Olig2 gene, approximately −33 and −17 kb upstream of the transcriptional start site and referred to as OLE and 5F7, respectively (Friedli et al, 2010; Oosterveen et al, 2012; Weider et al, 2015). Two additional regulatory regions, named K23 and E1b are present + 9.5 and + 72 kb downstream of the transcriptional start site (Fan et al, 2023; Sun et al, 2006). In contrast to the OLE, 5F7, and E1b enhancers, K23 is active in the neuronal lineage only and thus irrelevant for oligodendroglial expression (Sun et al, 2006).…”

Section: Resultsmentioning

confidence: 99%

“…In addition to the guide RNA‐containing plasmids (see Section on Genome editing), a pCAG‐IRES‐GFP plasmid was generated for retrovirus production that contained the cDNA for T7‐tagged Phf8 between CAG promoter and IRES. Several previously identified regulatory regions in the Olig2 locus (for localization, see Figure 6a) named OLE, 5F7, K23, and E1b (Fan et al, 2023; Friedli et al, 2010; Oosterveen et al, 2012; Sun et al, 2006; Weider et al, 2015) were inserted into the pTATA‐luc reporter plasmid in front of β‐globin minimal promoter and luciferase reporter (Kuhlbrodt, Herbarth, Sock, Hermans‐Borgmeyer, & Wegner, 1998). The Olig2 promoter was placed in front of the luciferase reporter in pGL2‐basic (Promega).…”

Section: Methodsmentioning

confidence: 99%

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Transcription factor Olig2 is a major downstream effector of histone demethylase Phf8 during oligodendroglial development

Kremp,

Aberle,

Sock

et al. 2024

Glia

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The plant homeodomain finger protein Phf8 is a histone demethylase implicated by mutation in mice and humans in neural crest defects and neurodevelopmental disturbances. Considering its widespread expression in cell types of the central nervous system, we set out to determine the role of Phf8 in oligodendroglial cells to clarify whether oligodendroglial defects are a possible contributing factor to Phf8‐dependent neurodevelopmental disorders. Using loss‐ and gain‐of‐function approaches in oligodendroglial cell lines and primary cell cultures, we show that Phf8 promotes the proliferation of rodent oligodendrocyte progenitor cells and impairs their differentiation to oligodendrocytes. Intriguingly, Phf8 has a strong positive impact on Olig2 expression by acting on several regulatory regions of the gene and changing their histone modification profile. Taking the influence of Olig2 levels on oligodendroglial proliferation and differentiation into account, Olig2 likely acts as an important downstream effector of Phf8 in these cells. In line with such an effector function, ectopic Olig2 expression in Phf8‐deficient cells rescues the proliferation defect. Additionally, generation of human oligodendrocytes from induced pluripotent stem cells did not require PHF8 in a system that relies on forced expression of Olig2 during oligodendroglial induction. We conclude that Phf8 may impact nervous system development at least in part through its action in oligodendroglial cells.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Transcription factor Olig2 is a major downstream effector of histone demethylase Phf8 during oligodendroglial development

Kremp,

Aberle,

Sock

et al. 2024

Glia

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OPALIN is an LGI1 receptor promoting oligodendrocyte differentiation

Teng,

Hu,

Zhang

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Leucine-rich glioma-inactivated protein 1 (LGI1), a secretory protein in the brain, plays a critical role in myelination; dysfunction of this protein leads to hypomyelination and white matter abnormalities (WMAs). Here, we hypothesized that LGI1 may regulate myelination through binding to an unidentified receptor on the membrane of oligodendrocytes (OLs). To search for this hypothetic receptor, we analyzed LGI1 binding proteins through LGI1-3 × FLAG affinity chromatography with mouse brain lysates followed by mass spectrometry. An OL-specific membrane protein, the oligodendrocytic myelin paranodal and inner loop protein (OPALIN), was identified. Conditional knockout (cKO) of OPALIN in the OL lineage caused hypomyelination and WMAs, phenocopying LGI1 deficiency in mice. Biochemical analysis revealed the downregulation of Sox10 and Olig2, transcription factors critical for OL differentiation, further confirming the impaired OL maturation in Opalin cKO mice. Moreover, virus-mediated re-expression of OPALIN successfully restored myelination in Opalin cKO mice. In contrast, re-expression of LGI1-unbound OPALIN_K23A/D26A failed to reverse the hypomyelination phenotype. In conclusion, our study demonstrated that OPALIN on the OL membrane serves as an LGI1 receptor, highlighting the importance of the LGI1/OPALIN complex in orchestrating OL differentiation and myelination.

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Uncovering oligodendrocyte enhancers that control Cnp expression

Fan,

An,

Kim

et al. 2023

Human Molecular Genetics

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Oligodendrocytes (OLs) produce myelin sheaths around axons in the central nervous system (CNS). Myelin accelerates the propagation of action potentials along axons and supports the integrity of axons. Impaired myelination has been linked to neurological and neuropsychiatric disorders. As a major component of CNS myelin, 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP) plays an indispensable role in the axon-supportive function of myelin. Notably, this function requires a high-level expression of CNP in OLs, as evidenced by downregulated expression of CNP in mental disorders and animal models. Little is known about how CNP expression is regulated in OLs. Especially, OL enhancers that govern CNP remain elusive. We have recently developed a powerful method that links OL enhancers to target genes in a principled manner. Here, we applied it to Cnp, uncovering two OL enhancers for it (termed Cnp-E1 and Cnp-E2). Epigenome editing analysis revealed that Cnp-E1 and Cnp-E2 are dedicated to Cnp. ATAC-seq and ChIP-seq data show that Cnp-E1 and Cnp-E2 are conserved OL-specific enhancers. Single cell multi-omics data that jointly profile gene expression and chromatin accessibility suggest that Cnp-E2 plays an important role in Cnp expression in the early stage of OL differentiation while Cnp-E1 sustains it in mature OLs.

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Identifying an oligodendrocyte enhancer that regulatesOlig2expression

Cited by 4 publications

References 65 publications

Transcription factor Olig2 is a major downstream effector of histone demethylase Phf8 during oligodendroglial development

Transcription factor Olig2 is a major downstream effector of histone demethylase Phf8 during oligodendroglial development

OPALIN is an LGI1 receptor promoting oligodendrocyte differentiation

Uncovering oligodendrocyte enhancers that control Cnp expression

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