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Antisense lncRNA transcription mediates DNA demethylation to drive stochastic Protocadherin α promoter choice

ABSTRACT: Antisense lncRNA transcription mediates DNA demethylation to drive stochastic Protocadherin α promoter choice

PROVIDER: PRJNA476330 | ENA |

REPOSITORIES: ENA

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Antisense lncRNA transcription mediates DNA demethylation to drive stochastic Protocadherin α promoter choice

Project description:Stochastic activation of clustered Protocadherin (Pcdh) α, β, and γ genes generates a cell-surface identity code in individual neurons that functions in neural circuit assembly. Here, we show that Pcdhα gene choice involves the activation of an antisense promoter located in the first exon of each Pcdhα alternate gene. Transcription of an antisense long noncoding RNA (lncRNA) from this antisense promoter extends through the sense promoter, leading to DNA demethylation of the CTCF binding sites proximal to each promoter. Demethylation-dependent CTCF binding to both promoters facilitates cohesin-mediated DNA looping with a distal enhancer (HS5-1), locking in the transcriptional state of the chosen Pcdhα gene. Uncoupling DNA demethylation from antisense transcription by Tet3 overexpression in mouse olfactory neurons promotes CTCF binding to all Pcdhα promoters, resulting in proximity-biased DNA looping of the HS5-1 enhancer. Thus, antisense transcription-mediated promoter demethylation functions as a mechanism for distance-independent enhancer/promoter DNA looping to ensure stochastic Pcdhα promoter choice.

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Antisense lncRNA Transcription Mediates DNA Demethylation to Drive Stochastic Protocadherin α Promoter Choice.

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Systematic Functional Characterization of Antisense eRNA of Protocadherin alpha HS5-1 Enhancer

Project description:Enhancers generate bidirectional noncoding enhancer RNAs (eRNA) that may regulate gene expression. At present, the eRNA function remains enigmatic. Here, we report a 5’ capped antisense eRNA PEARL (Pcdh eRNA associated with R-loop formation) that is transcribed from the protocadherin (Pcdh) alpha HS5-1 enhancer region. Through loss- and gain-of-function experiments with CRISPR/Cas9 DNA-fragment editing, CRISPRi, and CRISPRa as well as locked nucleic acid strategies, in conjunction with ChIRP, MeDIP, DRIP, QHR-4C, and HiChIP experiments, we find that PEARL regulates Pcdh alpha gene expression by forming local RNA-DNA duplexes (R-loops) in situ within the HS5-1 enhancer region to promote long-distance chromatin interactions between distal enhancer and target promoter. In particular, increased levels of eRNA PEARL via perturbing transcription elongation factor SPT6 leads to strengthened local three-dimensional chromatin organization within the Pcdh superTAD. These findings have important implications regarding molecular mechanisms by which the HS5-1 enhancer regulates stochastic Pcdh alpha promoter choice in single cells in the brain.

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WAPL functions as a rheostat of Protocadherin isoform diversity that controls neural wiring

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