PMID- 37972699
OWN - NLM
STAT- MEDLINE
DCOM- 20240105
LR  - 20240105
IS  - 1879-0038 (Electronic)
IS  - 0378-1119 (Linking)
VI  - 894
DP  - 2024 Feb 5
TI  - Characteristics of n6-methyladenosine (m6A) regulators and role of FTO/TNC in 
      scleroderma.
PG  - 147989
LID - S0378-1119(23)00830-2 [pii]
LID - 10.1016/j.gene.2023.147989 [doi]
AB  - BACKGROUND: m6A regulators have important roles in a variety of autoimmune 
      diseases, but their potential function in scleroderma, a refractory connective 
      tissue disease, remains unclear. Tenascin C (TNC) is known to be a factor 
      promoting collagen deposition in the development of scleroderma, but the 
      regulatory relationship between TNC and m6A regulators is unknown. METHODS: We 
      extracted GSE33463 data consisting of forty-one healthy controls and sixty-one 
      patients with scleroderma, and we analyzed the expression levels of twenty-one 
      m6A regulators as well as the associations between them. In addition, we obtained 
      random forest (RF) and nomogram models to predict the likehood of scleroderma. 
      Next, we categorized the m6Aclusters and geneclusters by consensus clustering, 
      and we performed an immune cell infiltration analysis for each cluster. Finally, 
      we injected adenoviruses into a bleomycin (BLM)-induced mouse model of 
      scleroderma, which was used to overexpress FTO and TNC. We assess the extent of 
      skin fibrosis in the mice samples using pathology stains and measuring their 
      hydroxyproline content and collagen mRNA. RESULTS: We initially identified 
      fourteen differentially expressed m6A regulators (WTAP, RBM15, CBLL1, FTO, 
      ALKBH5, YTHDC1, YTHDC2, YTHDF1, YTHDF2, YTHDF3, RBMX, HNRNPC, IGFBP1 and IGFBP2). 
      We found ALKBH5 to be positively associated with CBLL1 and RBM15, and FTO to be 
      negatively associated with WTAP. In addition, we identified four m6A regulators 
      (CBLL1, IGFBP1, YTHDF2 and IGFBP2) using a RF model, and we designed a nomogram 
      model with those variables that proved reliable according to the calibration 
      curve and clinical impact curve. We found that the m6Acluster A was correlated 
      with Type 1 T helper cell infiltration and the genecluster A was correlated with 
      regulatory T cell infiltration. Finally, we showed that FTO overexpression 
      downregulated the m6A and mRNA levels of TNC, and alleviated skin fibrosis in the 
      mouse model of scleroderma. Thus, our overexpression experiments provide 
      preliminary evidence suggesting that TNC is an adverse factor in scleroderma. 
      CONCLUSION: Our approach might be useful as a new and accurate scleroderma 
      diagnosis method. Moreover, our results suggested that FTO/TNC might be a novel 
      scleroderma therapeutic target.
CI  - Copyright (c) 2023 Elsevier B.V. All rights reserved.
FAU - Yu, Yue
AU  - Yu Y
AD  - Department of Dermatology, Tongji Hospital, School of Medicine, Tongji 
      University, Shanghai, China.
FAU - Liang, Chen
AU  - Liang C
AD  - Department of Dermatology, Tongji Hospital, School of Medicine, Tongji 
      University, Shanghai, China.
FAU - Tang, Qinyu
AU  - Tang Q
AD  - Department of Dermatology, The Affiliated Changzhou Second People's Hospital of 
      Nanjing Medical University, Changzhou, China.
FAU - Shi, Yuling
AU  - Shi Y
AD  - Department of Dermatology, Shanghai Skin Disease Hospital, School of Medicine, 
      Tongji University, Shanghai, China; Institute of Psoriasis, School of Medicine, 
      Tongji University, Shanghai, China. Electronic address: 
      shiyuling1973@tongji.edu.cn.
FAU - Shen, Liangliang
AU  - Shen L
AD  - Department of Dermatology, Tongji Hospital, School of Medicine, Tongji 
      University, Shanghai, China. Electronic address: shenliangliang8@163.com.
LA  - eng
PT  - Journal Article
DEP - 20231114
PL  - Netherlands
TA  - Gene
JT  - Gene
JID - 7706761
RN  - K72T3FS567 (Adenosine)
RN  - EC 1.14.11.33 (Alpha-Ketoglutarate-Dependent Dioxygenase FTO)
RN  - EC 2.3.2.27 (CBLL1 protein, human)
RN  - 9007-34-5 (Collagen)
RN  - EC 1.14.11.33 (FTO protein, human)
RN  - EC 1.14.11.- (FTO protein, mouse)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tenascin)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - 0 (TNC protein, human)
RN  - 0 (Tnc protein, mouse)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - Adenosine
MH  - Alpha-Ketoglutarate-Dependent Dioxygenase FTO
MH  - *Basidiomycota
MH  - Collagen
MH  - Disease Models, Animal
MH  - Fibrosis
MH  - RNA, Messenger
MH  - *Tenascin
MH  - Ubiquitin-Protein Ligases
OTO - NOTNLM
OT  - FTO
OT  - RNA modification
OT  - Random forest
OT  - Scleroderma
OT  - m6A regulators
COIS- Declaration of competing interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/11/17 15:29
MHDA- 2024/01/02 11:44
CRDT- 2023/11/16 19:25
PHST- 2023/07/08 00:00 [received]
PHST- 2023/10/23 00:00 [revised]
PHST- 2023/11/13 00:00 [accepted]
PHST- 2024/01/02 11:44 [medline]
PHST- 2023/11/17 15:29 [pubmed]
PHST- 2023/11/16 19:25 [entrez]
AID - S0378-1119(23)00830-2 [pii]
AID - 10.1016/j.gene.2023.147989 [doi]
PST - ppublish
SO  - Gene. 2024 Feb 5;894:147989. doi: 10.1016/j.gene.2023.147989. Epub 2023 Nov 14.