<i>PAUPAR</i>and PAX6 sequentially regulate human embryonic stem cell cortical differentiation

Xu, Yanxin; Xi, Jiajie; Wang, Guiying; Guo, Zhenming; Sun, Qiaoyi; Lu, Chenqi; Ma, Li; Wu, Yukang; Jia, Wenwen; Zhu, Shifeng; Guo, Xudong; Bian, Shan

doi:10.1093/nar/gkab030

Cited by 22 publications

(19 citation statements)

References 40 publications

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“…Overexpression of SOX1 could rescue the neuronal differentiation impairment caused by SOX1‐OT V1 inhibition. Our previous study showed that SOX1 could be regulated by PAX6 through PAX6 directly binding to the SOX1 gene region (Xu et al , 2021). In this study, we found that inhibition of SOX1‐OT V1 did not affect the expression of PAX6 but reduced the expression level of SOX1, suggesting that SOX1‐OT V1 functions as a novel regulator of SOX1 in a PAX6‐independent manner.…”

Section: Discussionmentioning

confidence: 99%

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LncRNA SOX1‐OT V1 acts as a decoy of HDAC10 to promote SOX1‐dependent hESC neuronal differentiation

Guo

et al. 2021

EMBO Reports

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Long noncoding RNAs (lncRNAs) are abundantly expressed in the nervous system, but their regulatory roles in neuronal differentiation are poorly understood. Using a human embryonic stem cell (hESC)‐based 2D neural differentiation approach and a 3D cerebral organoid system, we show that SOX1‐OT variant 1 (SOX1‐OT V1), a SOX1 overlapping noncoding RNA, plays essential roles in both dorsal cortical neuron differentiation and ventral GABAergic neuron differentiation by facilitating SOX1 expression. SOX1‐OT V1 physically interacts with HDAC10 through its 5' region, acts as a decoy to block HDAC10 binding to the SOX1 promoter, and thus maintains histone acetylation levels at the SOX1 promoter. SOX1 in turn activates ASCL1 expression and promotes neuronal differentiation. Taken together, we identify a SOX1‐OT V1/HDAC10‐SOX1‐ASCL1 axis, which promotes neurogenesis, highlighting a role for lncRNAs in hESC neuronal differentiation.

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Section: Discussionmentioning

confidence: 99%

“…Knockdown of Pnky can enhance neuronal differentiation (Ramos et al , 2015). LncRNA PAUPAR can interact with its adjacent transcription factor PAX6 and regulate hESC cortical differentiation (Xu et al , 2021). These studies suggested that lncRNAs play key regulatory roles in neural differentiation.…”

Section: Introductionmentioning

confidence: 99%

LncRNA SOX1‐OT V1 acts as a decoy of HDAC10 to promote SOX1‐dependent hESC neuronal differentiation

Guo

et al. 2021

EMBO Reports

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“…For example, the human-specific LncRNA, SMILR , was investigated in organ cultures of human saphenous vein grafts to define its role in mediating smooth muscle cell proliferation (Mahmoud et al 2019 ). Meanwhile, the PAUPAR LncRNA was studied in human organoids and shown to regulate cortical differentiation (Xu et al 2021 ). These ex vivo model systems represent a higher order level of investigation over simple, two-dimensional cell culture models.…”

Section: Challenges Limitations and Alternative Approaches To Humanized Bac Micementioning

confidence: 99%

Of mice and human-specific long noncoding RNAs

2022

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The number of human LncRNAs has now exceeded all known protein-coding genes. Most studies of human LncRNAs have been conducted in cell culture systems where various mechanisms of action have been worked out. On the other hand, efforts to elucidate the function of human LncRNAs in an in vivo setting have been limited. In this brief review, we highlight some strengths and weaknesses of studying human LncRNAs in the mouse. Special consideration is given to bacterial artificial chromosome transgenesis and genome editing. The integration of these technical innovations offers an unprecedented opportunity to complement and extend the expansive literature of cell culture models for the study of human LncRNAs. Two different examples of how BAC transgenesis and genome editing can be leveraged to gain insight into human LncRNA regulation and function in mice are presented: the random integration of a vascular cell-enriched LncRNA and a targeted approach for a new LncRNA immediately upstream of the ACE2 gene, which encodes the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent underlying the coronavirus disease-19 (COVID-19) pandemic.

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“…A relevant lncRNA with a cis -acting mechanism is Paupar ( Pax6 upstream antisense RNA), which is transcribed upstream the Pax6 gene in the opposite direction [ 104 ]. Paupar acts in cis regulating PAX6-dependent functions since its knockdown leads to an increase in PAX6 expression and interferes with eye development, progenitor cell potency and proliferation in the brain [ 104 , 105 ]. The exact molecular mechanism of regulation on the Pax6 is not entirely known, although it could be speculated that its transcription affects the nearby promoter region of Pax6 , either stabilizing transcription factor binding or inducing promoter-enhancer looping.…”

Section: Functional Classification Of Neuronal Lncrnasmentioning

confidence: 99%

“…In parallel, Paupar has probably evolved a more elaborate mechanism of action. In addition to regulating the expression of Pax6 , it also regulates the binding of PAX6 to its neural target genes [ 105 ] and acts in trans by forming a ribonucleoprotein (RNP) complex together with PAX6 and KAP1 (coded by Trim28 ), which is involved in transcriptional control [ 104 , 106 ]. It seems that Paupar promotes the association of KAP1 with the DNA resulting in H3K9me3 modifications on the promoter of genes involved in neural stem cell renewal and differentiation, inducing heterochromatin and inactivation [ 106 ].…”

Section: Functional Classification Of Neuronal Lncrnasmentioning

confidence: 99%

Brain Long Noncoding RNAs: Multitask Regulators of Neuronal Differentiation and Function

2021

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The extraordinary cellular diversity and the complex connections established within different cells types render the nervous system of vertebrates one of the most sophisticated tissues found in living organisms. Such complexity is ensured by numerous regulatory mechanisms that provide tight spatiotemporal control, robustness and reliability. While the unusual abundance of long noncoding RNAs (lncRNAs) in nervous tissues was traditionally puzzling, it is becoming clear that these molecules have genuine regulatory functions in the brain and they are essential for neuronal physiology. The canonical view of RNA as predominantly a ‘coding molecule’ has been largely surpassed, together with the conception that lncRNAs only represent ‘waste material’ produced by cells as a side effect of pervasive transcription. Here we review a growing body of evidence showing that lncRNAs play key roles in several regulatory mechanisms of neurons and other brain cells. In particular, neuronal lncRNAs are crucial for orchestrating neurogenesis, for tuning neuronal differentiation and for the exact calibration of neuronal excitability. Moreover, their diversity and the association to neurodegenerative diseases render them particularly interesting as putative biomarkers for brain disease. Overall, we foresee that in the future a more systematic scrutiny of lncRNA functions will be instrumental for an exhaustive understanding of neuronal pathophysiology.

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PAUPARand PAX6 sequentially regulate human embryonic stem cell cortical differentiation

Cited by 22 publications

References 40 publications

LncRNA SOX1‐OT V1 acts as a decoy of HDAC10 to promote SOX1‐dependent hESC neuronal differentiation

LncRNA SOX1‐OT V1 acts as a decoy of HDAC10 to promote SOX1‐dependent hESC neuronal differentiation

Of mice and human-specific long noncoding RNAs

Brain Long Noncoding RNAs: Multitask Regulators of Neuronal Differentiation and Function

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