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Transcriptomic RNA structure mapping unveils the structure dynamic induced by DHX36 binding (RBNS)

ABSTRACT: RNA binding proteins can modulate RNA secondary structures, thus participating in post-transcriptional regulation. The DEAH-box helicase 36 (DHX36) has a remarkable ability to bind and unwind RNA G-quadruplex (rG4) and duplex. However, the transcriptome-wide RNA structure dynamic induced by DHX36 and how structure change subsequently influences RNA fate remain poorly understood. Here, we first identify the endogenous binding sites and specificity of DHX36 based on binding profiles. Next, we capture in vivo RNA structuromes to investigate the structure change of DHX36-bound mRNAs following DHX36 knockout. DHX36 induces structure remodeling on not only the localized binding sites but also the other sites across the entire mRNA especially in 3’UTR. DHX36-induced more accessible structures of 3’UTR are revealed to correlate with post-transcriptional mRNA decrease. Furthermore, we demonstrate that DHX36 binding sites are enriched for N6-methyladenosine (m6A) modification and YTHDF1 binding. Finally, we experimentally validate that YTHDF1 binding is repelled to DHX36 loss-induced structure inaccessibility and YTHDF1 loss-induced mRNA stabilization could be a source of DHX36 loss-induced mRNA increase. Altogether, our findings uncover the effect of DHX36 binding on in vivo mRNA structure and propose a plausible mechanism of how RNA secondary structure change involves in post-transcriptional regulation through orchestrating YTHDF1 binding.

ORGANISM(S): synthetic construct

PROVIDER: GSE237159 | GEO | 2024/10/03

REPOSITORIES: GEO

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Transcriptomic RNA structure mapping unveils the structure dynamic induced by DHX36 binding (Structure-seq)

Project description:RNA binding proteins can modulate RNA secondary structures, thus participating in post-transcriptional regulation. The DEAH-box helicase 36 (DHX36) has a remarkable ability to bind and unwind RNA G-quadruplex (rG4) and duplex. However, the transcriptome-wide RNA structure dynamic induced by DHX36 and how structure change subsequently influences RNA fate remain poorly understood. Here, we first identify the endogenous binding sites and specificity of DHX36 based on binding profiles. Next, we capture in vivo RNA structuromes to investigate the structure change of DHX36-bound mRNAs following DHX36 knockout. DHX36 induces structure remodeling on not only the localized binding sites but also the other sites across the entire mRNA especially in 3’UTR. DHX36-induced more accessible structures of 3’UTR are revealed to correlate with post-transcriptional mRNA decrease. Furthermore, we demonstrate that DHX36 binding sites are enriched for N6-methyladenosine (m6A) modification and YTHDF1 binding. Finally, we experimentally validate that YTHDF1 binding is repelled to DHX36 loss-induced structure inaccessibility and YTHDF1 loss-induced mRNA stabilization could be a source of DHX36 loss-induced mRNA increase. Altogether, our findings uncover the effect of DHX36 binding on in vivo mRNA structure and propose a plausible mechanism of how RNA secondary structure change involves in post-transcriptional regulation through orchestrating YTHDF1 binding.

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2021-04-27 | GSE151124 | GEO

System-wide analysis of Dhx36 function in skeletal muscle satellite cells reveals its binding with 5’UTR G4 structure to promote Gnai2 RNA translation [CLIP-seq]

Project description:In this study, we deciphered the functions of Dhx36 and related molecular mechanisms in muscle stem cells and muscle regeneration. We found Dhx36 was highly induced in activated muscle stem cells during regeneration induced by injury. Conditional inactivation of Dhx36 in mouse muscle stem cells caused significant impaired regeneration, which was due to the dramatically decreased cell proliferation. Dhx36 was a well-known RNA helicase for binding/unbinding DNA/RNA G-quadruplexes and it was dominantly expressed in cytoplasm of proliferating myoblast. Therefore CLIP-seq was conducted to identify the mRNAs interacting with Dhx36 in myoblast cells.

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N6-methyladenosine Modulates Messenger RNA Translation Efficiency

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Lockd promotes myoblast proliferation and skeletal muscle regeneration through binding with DHX36 to facilitate unwinding of 5’UTR rG4 and translation of Anp32e mRNA

Project description:Adult muscle stem cells, also known as satellite cells (SCs) play pivotal roles in injury induced muscle regeneration and our knowledge of long non-coding RNA (lncRNA) functions in SCs remains limited. Here we identify a lncRNA, Lockd which is induced in activated SCs upon acute muscle injury. We demonstrate that Lockd promotes SC proliferation; deletion of Lockd leads to cell cycle arrest at G1/S phase. Consistently, in vivo repression of Lockd in mouse muscles hinders muscle regeneration process. Mechanistically, we uncover that Lockd lncRNA molecule directly interacts with an RNA helicase DHX36; structural probing further shows that the 5’end of the Lockd possesses the strongest binding activity with DHX36 protein. Furthermore, we demonstrate that Lockd stabilizes the interaction between DHX36 and EIF3B proteins; and synergistically this complex unwinds the RNA G-quadruplex (rG4) structure formed at the 5’UTR of Anp32e mRNA and promotes the translation of ANP32E protein which is required for myoblast cell proliferation. Altogether, our findings thus identify a regulatory circuitry consisting of Lockd/DHX36/Anp32e that functions to promote myoblast proliferation, thus enabling the acute injury induced muscle regeneration to progress.

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