bims-rimeca 2023-10-08 papers

bims-rimeca

Biomed News

on RNA methylation in cancer

Issue of 2023–10–08
thirteen papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics

The Role and Mechanism of Ferroptosis Mediated by METTL3-m6A Modification in Regulating Radioresistance of Esophageal Cancer.
N6-methyladenosine Methyltransferase METTL3 Enhances PTGER2 Expression to Increase Ovarian Cancer Stemness and Chemoresistance.
LIMK1 m6A-RNA methylation recognized by YTHDC2 induces 5-FU chemoresistance in colorectal cancer via endoplasmic reticulum stress and stress granule formation.
N6-Methyladenosine (m6A) Methylation Is Associated with the Immune Microenvironments in Acute Intracerebral Hemorrhage (ICH).
Low expression of m6A reader YTHDC1 promotes progression of ovarian cancer via PIK3R1/STAT3/GANAB axis.
Loss of YTHDF2 Alters the Expression of m6A-Modified Myzap and Causes Adverse Cardiac Remodeling.
m6A Reader YTHDC1 Inhibits Ferroptosis and Radiosensitivity by Promoting SREBF1 mRNA Nuclear Export in Nasopharyngeal Carcinoma.
FTO fuels diabetes-induced vascular endothelial dysfunction associated with inflammation by erasing m6A methylation of TNIP1.
A deregulated m6A writer complex axis driven by BRD4 confers an epitranscriptomic vulnerability in combined DNA repair-targeted therapy.
N6-methyladenosine (m6A) reader YTHDF2 accelerates endothelial cells ferroptosis in cerebrovascular atherosclerosis.
YTHDF2 facilitates aggresome formation via UPF1 in an m6A-independent manner.
HIF-1α-induced upregulation of m6A reader IGF2BP1 facilitates peripheral nerve injury recovery by enhancing SLC7A11 mRNA stabilization.
Deciphering m6A dynamics at a single-base level during planarian anterior-posterior axis specification.

Int J Radiat Oncol Biol Phys. 2023 Oct 01. pii: S0360-3016(23)05622-5. [Epub ahead of print]117(2S): e248-e249

The Role and Mechanism of Ferroptosis Mediated by METTL3-m6A Modification in Regulating Radioresistance of Esophageal Cancer.

R Ma, L Zhao.

PURPOSE/OBJECTIVE(S): Radioresistance remains the major cause of recurrence within two years after radical radiotherapy in approximately 50% of patients with esophageal cancer (ESCC). Recently, it has been reported that enhancing ferroptosis can reverse tumor radioresistance. However, the underlying mechanisms remain elusive. The aim of this study was to elucidate the role and mechanism of ferroptosis mediated by METTL3 N6-methyladenosine (m6A) modification in regulating radioresistance of Esophageal Cancer. We hypothesize that inhibition of ferroptosis confers radioresistance in Esophageal Cancer by METTL3-induced m6A modification which increase the expression of m6A in the 3'UTR region of SOCS6 and inhibits its expression.
MATERIALS/METHODS: To explore the relationship between radioresistance and ferroptosis. Firstly, ferroptosis was analyzed by 4-HNE staining in ESCC specimens; Furthermore, cell death was detected by propidium iodide (PI) or SYTOX Green staining combined with microscopy or flow cytometry in ESCC radioresistance cells and parental cells, and Iron Assay Kit,C11-BODIPY were used to examine whether ferroptosis were inhibited in radioresistance cells. Subsequently, MeRIP-seq and MeRIP-PCR were performed for discussing the relationship between ferroptosis and m6A. Finally, Mettl3 depleted cells were generated with CRISPR/Cas9-mediated knockout system. Then, m6A methylation level, sensitivity to radiation and ferroptosis of Mettl3 depleted cells by EpiQuik m6A RNA methylation quantification kit, colony formation, C11-BODIPY and Western Blot.
RESULTS: Firstly, we found that the level of lipid peroxide 4-HNE in ESCC samples that recurred after radical radiotherapy was significantly lower than that in radiotherapy (40Gy), and the ferroptosis of radioresistance cells was inhibited. MeRIP-seq found that the level of m6A in radioresistance cells increased significantly, and then the KEGG pathway analysis of MeRIP-seq results showed that hypermethylation of m6A was closely related to ferroptosis signal pathway. and we also found that the level of m6A was significantly decreased by adding agonist (Erastin), whereas the modification level was significantly increased by adding inhibitor Fer-1. Meanwhile, we found that the level of m6A was significantly decreased in radioresistance cells silencing METTL3, while the ferroptosis was activated, which caused the radiosensitivity of ESCC. Lastly, MeRIP-PCR data showed that METTLT3 induced a significant increase in m6A level in 3' UTR region of SOCS6 mRNA and inhibited its expression, which eventually led to radioresistance of ESCC.
CONCLUSION: m6A-regulated ferroptosis inhibition confers radioresistance of ESCC. METTL3 up-regulated m6A in SOCS6 3' UTR and inhibited the expression of SOCS6, which caused the inhibition of ferroptosis.

DOI: https://doi.org/10.1016/j.ijrobp.2023.06.1188
Front Biosci (Landmark Ed). 2023 Sep 14. 28(9): 199

N6-methyladenosine Methyltransferase METTL3 Enhances PTGER2 Expression to Increase Ovarian Cancer Stemness and Chemoresistance.

Yi-Bin Lin, Ben-Hua Xu.

   BACKGROUND: Ovarian cancer is the second leading cause of gynecologic cancer-associated deaths. Cancer stemness and chemoresistance are responsible for ovarian cancer metastasis and the poor prognosis of patients. In this study, we determined the function of N6-methyladenine (m6A) RNA methylation and prostaglandin E receptor 2 (PTGER2) in ovarian cancer progression.
METHODS: The m6A RNA methylation-associated PTGER2 in ovarian cancer was identified using bioinformatics analysis. The role of PTGER2 in ovarian cancer was elucidated in cell lines and clinical samples with cellular and molecular experiments.
RESULTS: In this investigation, bioinformatics analysis based on a public cancer database was used to elucidate the impact of m6A modification on the prognosis of patients with ovarian cancer. Moreover, PTGER2 was identified as a potential oncogene associated with the distant metastasis of ovarian cancer and poor patient prognosis. Interestingly, PTGER2 expression was experimentally shown to be enhanced by N6-adenosine-methyltransferase 70 kDa subunit (METTL3)-mediated m6A modification. In addition, PTGER2 enhanced cancer stem cell self-renewal properties, the epithelial-mesenchymal transition, and DNA damage repair, thus potentiating cell stemness, therapy resistance to carboplatin, proliferation, and metastasis of ovarian cancer. Importantly, PTGER2 expression in clinical samples was associated with distant metastasis, predicted poor patient prognosis, and independently served as a prognostic predictor in ovarian cancer.
CONCLUSIONS: Our work defines PTGER2 as an oncogene and reveals that PTGER2 is a prognostic predictor and novel therapeutic target for the management of ovarian cancer.

Keywords:  N6-methyladenosine; PTGER2; chemoresistance; ovarian cancer; stemness

DOI:  https://doi.org/10.31083/j.fbl2809199
Cancer Lett. 2023 Sep 29. pii: S0304-3835(23)00371-3. [Epub ahead of print] 216420

LIMK1 m6A-RNA methylation recognized by YTHDC2 induces 5-FU chemoresistance in colorectal cancer via endoplasmic reticulum stress and stress granule formation.

Lu Chen, Kangyue Sun, Wenjie Qin, Bing Huang, Changjie Wu, Junsheng Chen, Qiuhua Lai, Xinke Wang, Rui Zhou, Aimin Li, Side Liu, Yue Zhang.

LIM kinase 1 (LIMK1) is a member of the LIMK family that has been considered to be involved in chemoresistance in various tumors, and N6-methyladenosine (m6A) is the most abundant nucleotide modification on mRNA. However, whether elevated expression of LIMK1 leads to chemoresistance due to m6A modification remains to be further studied. The findings of our study indicate that high LIMK1 expression in colorectal cancer (CRC) cells promotes cell proliferation and increases resistance to 5-fluorouracil (5-FU). Moreover, downregulation of YTH domain-containing 2 (YTHDC2), an m6A "reader", in CRC cells resulted in decreased recognition and binding to the m6A site "GGACA" in LIMK1 mRNA, thereby increasing LIMK1 mRNA stability and expression. Furthermore, the overexpression of LIMK1 facilitated eIF2α phosphorylation, which induced endoplasmic reticulum (ER) stress and promoted stress granule (SG) formation, ultimately leading to 5-FU resistance. This study evaluated the specificity of the YTHDC2/LIMK1/eIF2α signalling axis and the efficacy of related drugs in modulating 5-FU sensitivity in CRC.

DOI: https://doi.org/10.1016/j.canlet.2023.216420
Mol Neurobiol. 2023 Sep 30.

N6-Methyladenosine (m6A) Methylation Is Associated with the Immune Microenvironments in Acute Intracerebral Hemorrhage (ICH).

Hong Yang, Chong Xie, Yi-Fan Wu, Yuan Cheng, De-Sheng Zhu, Yang-Tai Guan.

  Researchers have recently found that N6-methyladenosine (m6A) is a type of internal posttranscriptional modification that is essential in mammalian mRNA. However, the features of m6A RNA methylation in acute intracerebral hemorrhage (ICH) remain unknown. To explore differential methylations and to discover their functions in acute ICH patients, we recruited three acute ICH patients, three healthy controls, and an additional three patients and healthy controls for validation. The m6A methylation levels in blood samples from the two groups were determined by ultrahigh-performance liquid chromatography coupled with triple quadruple mass spectrometry (UPLC-QQQ-MS). Methylated RNA immunoprecipitation sequencing (MeRIP-seq) was employed to identify differences in m6A modification, and the differentially expressed m6A-modified genes were confirmed by MeRIP-qPCR. We found no significant differences in the total m6A levels between the two groups but observed differential methylation peaks. Compared with the control group, the coding genes showing increased methylation following acute ICH were mostly involved in processes connected with osteoclast differentiation, the neurotrophin signaling pathway, and the spliceosome, whereas genes with reduced m6A modification levels after acute ICH were found to be involved in the B-cell and T-cell receptor signaling pathways. These results reveal that differentially m6A-modified genes may influence the immune microenvironments in acute ICH.

Keywords:  Acute intracerebral hemorrhage; Differential methylation; Immune microenvironments; MeRIP-qPCR; MeRIP-seq; m6A methylation

DOI:  https://doi.org/10.1007/s12035-023-03643-x
Int J Biol Sci. 2023 ;19(14): 4672-4688

Low expression of m6A reader YTHDC1 promotes progression of ovarian cancer via PIK3R1/STAT3/GANAB axis.

Xiaogang Wang, Qianyu Chen, Ziqian Bing, Shizhen Zhou, Zhen Xu, Yayi Hou, Yue Zhao, Shuli Zhao, Tingting Wang.

  Background: N6-Methyladenosine (m6A) is considered to be the most prevalent and abundant internal modification observed in mRNA between viruses and mammals. As a reversible epigenetic modification, m6A controls gene expression in diverse physiological and pathological processes. Accumulating evidence in recent years reveals that aberrant expression of m6A reader proteins may have tumor-suppressing or carcinogenic functions. However, the biological role and mechanism of m6A reader YTH Domain Containing 1 (YTHDC1) in ovarian cancer progression remain inadequately understood. Methods: Quantitative RT-PCR, immunohistochemistry, Western blot, and bioinformatics analyses were undertaken for studying the YTHDC1 expression in ovarian cancer. In vitro and in vivo models were used to examine the role of YTHDC1. RNA sequencing, RNA immunoprecipitation sequencing, m6A-modified RNA immunoprecipitation, actinomycin-D assay, chromatin immunoprecipitation, and Western blot were used in the investigation the regulatory mechanisms among YTHDC1, Signal Transducer and Activator of Transcription 3 (STAT3), Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1), and Glucosidase II Alpha Subunit (GANAB). Results: Here, we found that YTHDC1 expression is decreased in ovarian cancer. Overexpression of YTHDC1 inhibited ovarian cancer development both in vivo and in vitro. Mechanistically, PIK3R1 was identified to be the direct target for YTHDC1. YTHDC1 enhanced PIK3R1 stability in an m6A-dependent manner, which subsequently inhibited GANAB expression in the N-glycan biosynthesis via the STAT3 signaling. Conclusions: Our findings unveil YTHDC1 as a tumor suppressor in the progression of ovarian cancer and as a potential prognostic biomarker that could serve as a target in ovarian cancer treatment.

Keywords:  PIK3R1; RNA stability; YTHDC1; m6A reader; ovarian cancer

DOI:  https://doi.org/10.7150/ijbs.81595
JACC Basic Transl Sci. 2023 Sep;8(9): 1180-1194

Loss of YTHDF2 Alters the Expression of m6A-Modified Myzap and Causes Adverse Cardiac Remodeling.

Volha A Golubeva, Lisa E Dorn, Christopher J Gilbert, Charles P Rabolli, Anindhya Sundar Das, Vishmi S Wanasinghe, Roland Veress, Dmitry Terentyev, Federica Accornero.

  How post-transcriptional regulation of gene expression, such as through N6-methyladenosine (m6A) messenger RNA methylation, impacts heart function is not well understood. We found that loss of the m6A binding protein YTHDF2 in cardiomyocytes of adult mice drove cardiac dysfunction. By proteomics, we found myocardial zonula adherens protein (MYZAP) within the top up-regulated proteins in knockout cardiomyocytes. We further demonstrated that YTHDF2 binds m6A-modified Myzap messenger RNA and controls its stability. Cardiac overexpression of MYZAP has been associated with cardiomyopathy. Thus, our findings provide an important new mechanism for the YTHDF2-dependent regulation of this target and therein its novel role in the maintenance of cardiac homeostasis.

Keywords:  RNA binding protein; hypertrophy; post-transcriptional gene regulation

DOI:  https://doi.org/10.1016/j.jacbts.2023.03.012
Int J Radiat Oncol Biol Phys. 2023 Oct 01. pii: S0360-3016(23)05620-1. [Epub ahead of print]117(2S): e248

m6A Reader YTHDC1 Inhibits Ferroptosis and Radiosensitivity by Promoting SREBF1 mRNA Nuclear Export in Nasopharyngeal Carcinoma.

Z Q Long, W Zheng, T Q Quan, P Y Yang, Z H Huang, X D Xu, D Wei, Y Sun.

PURPOSE/OBJECTIVE(S): Radioresistance is the main reason for nasopharyngeal carcinoma (NPC) recurrence leading to treatment failure, and inducing ferroptosis has gradually been a new way to enhance radiosensitivity. N6-methyladenosine (m6A) is involved in regulation of numerous biological processes. However, whether m6A affects ferroptosis in NPC is still unclear. In this study, we conducted a siRNA library screening to identify m6A reader YTHDC1 as an essential oncogene that suppressed ferroptosis and radiosensitivity by promoting SREBF1 mRNA nuclear export in nasopharyngeal carcinoma.
MATERIALS/METHODS: The expression and function of YTHDC1 were assessed via CCK8 cell viability assay, immunostaining, real-time PCR, western blot, radiation clonogenic assay and fluorescence in situ hybridization assay. Ferroptosis was determined by detecting cell viability, lipid peroxidation, abnormal mitochondrial and cell death rate. The in vivo effects of YTHDC1 were examined with RSL3 treatment or lentivirus modification of YTHDC1 expression in radiated mouse models.
RESULTS: Based on RSL3-induced ferroptotic cell death model and a siRNA library about m6A modification associated gene screening, we identified m6A reader YTHDC1 could inhibit ferroptosis as well as radiosensitivity of NPC, both in vivo and in vitro. Mechanistically, YTHDC1 protein could recognize m6A sites in the CDS region and 3' untranslated region (3'UTR) of SREBF1 mRNA and promote SREBF1 mRNA nuclear export, which finally resulted in transcriptional upregulation of genes key to ferroptosis such as SCD and FASN. Furthermore, the high expression of YTHDC1 was negatively regulated by ZNF598 via ubiquitination and associated with unfavorable survival in NPC patients due to radioresistance.
CONCLUSION: Our findings reveal the critical role of YTHDC1 specifically in inhibiting ferroptosis and radiosensitivity via m6A-dependent mechanism and provide an exploitable target and therapeutic strategy for overcoming radioresistance in NPC.

DOI: https://doi.org/10.1016/j.ijrobp.2023.06.1186
J Clin Invest. 2023 10 02. pii: e160517. [Epub ahead of print]133(19):

FTO fuels diabetes-induced vascular endothelial dysfunction associated with inflammation by erasing m6A methylation of TNIP1.

Chuandi Zhou, Xinping She, Chufeng Gu, Yanan Hu, Mingming Ma, Qinghua Qiu, Tao Sun, Xun Xu, Haibing Chen, Zhi Zheng.

  Endothelial dysfunction is a critical and initiating factor of the vascular complications of diabetes. Inflammation plays an important role in endothelial dysfunction regulated by epigenetic modifications. N6-methyladenosine (m6A) is one of the most prevalent epigenetic modifications in eukaryotic cells. In this research, we identified an m6A demethylase, fat mass and obesity-associated protein (FTO), as an essential epitranscriptomic regulator in diabetes-induced vascular endothelial dysfunction. We showed that enhanced FTO reduced the global level of m6A in hyperglycemia. FTO knockdown in endothelial cells (ECs) resulted in less inflammation and compromised ability of migration and tube formation. Compared with EC Ftofl/fl diabetic mice, EC-specific Fto-deficient (EC FtoΔ/Δ) diabetic mice displayed less retinal vascular leakage and acellular capillary formation. Furthermore, methylated RNA immunoprecipitation sequencing (MeRIP-Seq) combined with RNA-Seq indicated that Tnip1 served as a downstream target of FTO. Luciferase activity assays and RNA pull-down demonstrated that FTO repressed TNIP1 mRNA expression by erasing its m6A methylation. In addition, TNIP1 depletion activated NF-κB and other inflammatory factors, which aggravated retinal vascular leakage and acellular capillary formation, while sustained expression of Tnip1 by intravitreal injection of adeno-associated virus alleviated endothelial impairments. These findings suggest that the FTO-TNIP1-NF-κB network provides potential targets to treat diabetic vascular complications.

Keywords:  Diabetes; Endothelial cells; Epigenetics; Inflammation; Vascular Biology

DOI:  https://doi.org/10.1172/JCI160517
Proc Natl Acad Sci U S A. 2023 Oct 10. 120(41): e2304534120

A deregulated m6A writer complex axis driven by BRD4 confers an epitranscriptomic vulnerability in combined DNA repair-targeted therapy.

Xiao Lu, Lichao Peng, Jiancheng Ding, Yuanpei Li, Qing Li, Mengchen Rao, Tong Shu, Xiaoniu He, Chen Liu, Jing Ye, Wen Liu, Han You.

  Aberrant transcripts expression of the m6A methyltransferase complex (MTC) is widely found across human cancers, suggesting a dysregulated signaling cascade which integrates m6A epitranscriptome to drive tumorigenesis. However, the responsible transcriptional machinery directing the expression of distinct MTC subunits remains unclear. Here, we identified an unappreciated interplay between the histone acetyl-lysine reader BRD4 and the m6A writer complex across human cancers. BRD4 directly stimulates transcripts expression of seven MTC subunits, allowing the maintenance of the nuclear writer complex integrity. Upon BET inhibition, this BRD4-MTC signaling cascade accounts for global m6A reduction and the subsequent dynamic alteration of BRD4-dependent transcriptome, resulting in impaired DNA damage response that involves activation of homologous recombination (HR) repair and repression of apoptosis. We further demonstrated that the combined synergy upon BET/PARP inhibition largely relies on disrupted m6A modification of HR and apoptotic genes, counteracting PARP inhibitor (PARPi) resistance in patient-derived xenograft models. Our study revealed a widespread active cross-talk between BRD4-dependent epigenetic and MTC-mediated epitranscriptomic networks, which provides a unique therapeutic vulnerability that can be leveraged in combined DNA repair-targeted therapy.

Keywords:  BET; DNA repair; m6A

DOI:  https://doi.org/10.1073/pnas.2304534120
Mol Cell Biochem. 2023 Oct 04.

N6-methyladenosine (m6A) reader YTHDF2 accelerates endothelial cells ferroptosis in cerebrovascular atherosclerosis.

Jia Li, Changlin Zou, Zhiming Zhang, Feng Xue.

  Cerebrovascular diseases have extreme high mortality and disability rate worldwide, and endothelial cells injury-induced atherosclerosis acts as the main cause of cerebrovascular disease. Ferroptosis is a novel type of programmed cell death depending on iron-lipid peroxidation. Recent studies have revealed that ferroptosis might promote the progression of atherosclerosis (AS). Here, this research aimed to investigate the function and its profound mechanism on vascular endothelial cells in atherosclerosis. Research results revealed that YTHDF2 expression up-regulated in ox-LDL treated human umbilical vein endothelial cells (HUVECs). Gain/loss functional assays indicated that YTHDF2 overexpression inhibited HUVECs' proliferation and accelerated the ferroptosis in ox-LDL-administered HUVECs. Meanwhile, YTHDF2 silencing promoted cell proliferation and reduced the ferroptosis in ox-LDL-administered HUVECs. Mechanistically, in silico analysis suggested that there were potential m6A-modified sites on SLC7A11 mRNA, and YTHDF2 could bind with SLC7A11 mRNA via m6A-dependent manner. YTHDF2 promoted the degradation of SLC7A11 mRNA, thereby reducing its mRNA stability. Taken together, these findings suggest that YTHDF2 accelerates endothelial cells ferroptosis in cerebrovascular atherosclerosis, helping us enhance our comprehension on cerebrovascular disease pathological physiology.

Keywords:  Atherosclerosis; Ferroptosis; N6-methyladenosine; SLC7A11; YTHDF2

DOI:  https://doi.org/10.1007/s11010-023-04858-1
Nat Commun. 2023 Oct 06. 14(1): 6248

YTHDF2 facilitates aggresome formation via UPF1 in an m6A-independent manner.

Hyun Jung Hwang, Tae Lim Park, Hyeong-In Kim, Yeonkyoung Park, Geunhee Kim, Chiyeol Song, Won-Ki Cho, Yoon Ki Kim.

YTHDF2 has been extensively studied and typified as an RNA-binding protein that specifically recognizes and destabilizes RNAs harboring N6-methyladenosine (m6A), the most prevalent internal modification found in eukaryotic RNAs. In this study, we unravel the m6A-independent role of YTHDF2 in the formation of an aggresome, where cytoplasmic protein aggregates are selectively sequestered upon failure of protein homeostasis mediated by the ubiquitin-proteasome system. Downregulation of YTHDF2 in HeLa cells reduces the circularity of aggresomes and the rate of movement of misfolded polypeptides, inhibits aggresome formation, and thereby promotes cellular apoptosis. Mechanistically, YTHDF2 is recruited to a misfolded polypeptide-associated complex composed of UPF1, CTIF, eEF1A1, and DCTN1 through its interaction with UPF1. Subsequently, YTHDF2 increases the interaction between the dynein motor protein and the misfolded polypeptide-associated complex, facilitating the diffusion dynamics of the movement of misfolded polypeptides toward aggresomes. Therefore, our data reveal that YTHDF2 is a cellular factor involved in protein quality control.

DOI: https://doi.org/10.1038/s41467-023-42015-w
In Vitro Cell Dev Biol Anim. 2023 Oct 02.

HIF-1α-induced upregulation of m6A reader IGF2BP1 facilitates peripheral nerve injury recovery by enhancing SLC7A11 mRNA stabilization.

Shuai An, Jingfei Shi, Jiang Huang, Zheng Li, Mingli Feng, Guanglei Cao.

  The recovery of peripheral nerve injury (PNI) is not ideal in clinic. Our previous study revealed that hypoxia treatment promoted PNI repair by inhibiting ferroptosis. The aim of this study was to investigate the underlying molecular mechanism of HIF-1α in hypoxia-PNI recovery. M6A dot blot was used to determine the total level of m6A modification. Besides, HIF-1α small interfering RNA (siRNA) or IGF2BP1 overexpression vector was transfected into dorsal root ganglion (DRG) neurons to alter the expression of HIF-1α and IGF2BP1. Subsequently, MeRIP-PCR analysis was applied to validate the m6A methylation level of SLC7A11. We demonstrated the hypoxia stimulated HIF-1α-dependent expression of IGF2BP1 and promoted the overall m6A methylation levels of DRG neurons. Overexpression of HIF-1α increased the expressions of neurotrophic factors including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial-derived neurotrophic factor (GDNF), which could be effectively reversed by siRNA knockdown of IGF2BP1. Moreover, upregulation of HIF-1α contributed to the m6A methylation level and mRNA stabilization of SLC7A11. This study revealed that the HIF-1α/IGF2BP1/SLC7A11 regulatory axis facilitated the recovery of injured DRG neurons. Our findings suggest a novel insight for the m6A methylation modification in PNI recovery.

Keywords:  HIF-1α; IGF2BP1; Peripheral nerve injury; SLC7A11; m6A

DOI:  https://doi.org/10.1007/s11626-023-00812-z
Comput Struct Biotechnol J. 2023 ;21 4567-4579

Deciphering m6A dynamics at a single-base level during planarian anterior-posterior axis specification.

Liqian Chen, Hui Zhen, Zixin Chen, Mujie Huang, Daniel W Mak, Wei Jin, Yuxiu Zou, Mingjie Chen, Mingyue Zheng, Qingqiang Xie, Zhongjun Zhou, Guoxiang Jin.

   Background: The establishment of the anterior-posterior (A-P) axis is a crucial step during tissue repair and regeneration. Despite the association reported recently of N6-methyladenosine (m6A) with regeneration, the mechanism underlying the regulation of m6A in A-P axis specification during regeneration remains unknown. Herein, we deciphered the m6A landscape at a single-base resolution at multiple time points during A-P axis regeneration and constructed the de novo transcriptome assembly of the Dugesia japonica planarian.
Results: Immunofluorescence staining and comparative analysis revealed that m6A is widespread across the planarian and dynamically regulated during regeneration along the A-P axis, exhibiting a strong spatiotemporal feature. The resulting datasets of m6A-modified genes identified 80 anterior-specific genes and 13 posterior-specific genes, respectively. In addition, we showed that YTHDC1 serves as the primary m6A reader to be involved in the m6A-mediated specification of A-P axis during regeneration in Dugesia japonica planarian.
Conclusions: Our study provides an RNA epigenetic explanation for the specification of the A-P axis during tissue regeneration in planarian.

Keywords:  Anterior-posterior axis specification; Dugesia japonica planarian; N6-methyladenosine; Regeneration; YTHDC1

DOI:  https://doi.org/10.1016/j.csbj.2023.09.018