Page 69 - GTM-1-2

Global Translational Medicineranslational Medicine
Global T Risk factors of idiopathic pulmonary fibrosis
Risk factors of idiopathic pulmonary fibrosis

SFRP4 have been reported to result in impaired transcription clinical treatment of cancer. Meanwhile, SAHA was found
and decreased expression, which in turn affects fibrosis to be able to induce apoptosis in IPF myofibroblasts .
[34]
progression . The reduction of hypermethylated genes Therefore, histone acetylation has a key epigenetic
[23]
in IPF patients promotes the activation of fibroblasts and regulatory role in the pathogenesis of pulmonary fibrosis,
accelerates the fibrosis process. Methyltransferase also which may facilitate the development of novel therapeutic
plays an important role in the process of fibrosis. Elkouris strategies against IPF (Table 1).
et al. found that the methyltransferase Set9 binds to E3
[24]
ligase by promoting SMAD7 methylation, thereby inducing 3.4. Non-coding RNAs (ncRNAs) and pulmonary
ubiquitin-dependent degradation of SRSF7 and enhancing fibrosis
TGF-β signaling. Inhibition of DNA methyltransferases 3.4.1. Classification and functions of non-coding RNAs
can alleviate pulmonary fibrosis by reducing abnormal To date, according to the NONCODE (available from:
DNA methylation using a classic inhibitor, 5-aza-2′- http://www.noncode.org) database of non-coding RNA
deoxycytidine. Among the regulatory mechanisms of (ncRNA), approximately more than 170,000 ncRNAs and
pulmonary fibrosis, methylations of histone H3 lysine 27 about 96,000 genes encoding the ncRNAs exist in humans.
(H3K27) and histone H3 lysine 9 (H3K9) are the most Conventionally, ncRNAs are classified as “housekeeping
common histone methylations. H3K27 methylation is ncRNAs,” which are directly involved in the processes of
mainly catalyzed by the histone-lysine N-methyltransferase protein synthesis, splicing, telomerase activity (mRNA,
EZH2 and inhibited by histone demethylases KDM5, tRNA, rRNA, small nuclear RNA [snRNA], etc.), and
KDM6A and KDM6B . Methylation of H3K9 is catalyzed as “regulatory ncRNAs,” such as microRNA (miRNA),
[25]
by G9a or G9a analogs .
[26]
small interfering RNA (siRNA), enhancer RNA (eRNA),
A variety of disease-specific biomarkers that are used circular RNA (circRNA), and lncRNA, which regulate
for detecting diseases clinically are based methylation; for transcription and post-transcriptional processes of cells.
instance, SDC2 methylation detection kits are used to detect LncRNAs are single-stranded RNA containing more
colorectal cancer , but there is no mature DNA methylation than 200 base pairs. They are divided into several groups:
[27]
biomarker for diagnosis of pulmonary fibrosis. Therefore, (i) Intergenic lncRNA, which is transcribed from both
in-depth exploration of the mechanism of DNA methylation DNA strands in intergenic regions; (ii) intron lncRNA,
in pulmonary fibrosis is of great significance for the diagnosis, which is transcribed from introns of protein-coding genes;
treatment, and prognosis of pulmonary fibrosis. (iii) overlapping lncRNA, which is transcribed from the
sense strand of DNA, overlapping with protein-coding
3.3. DNA acetylation genes; and (iv) antisense lncRNA, which is transcribed
Histone acetylation is one of the most common from the antisense strand, overlapping with exon or intron
modifications of histone tails, which regulate DNA regions . LncRNAs can also be divided into cis-acting
[35]
accessibility to various transcriptional factors to control lncRNAs that regulate nearby genes and trans-acting
gene expression . Acetyl groups are conjugated to lysine lncRNAs that regulate distant genes. In addition, lncRNAs
[28]
by histone acetyltransferases and removed from lysine by can be spliced to form both short ncRNAs, such as miRNA,
[29]
[36]
histone deacetylases (HDACs) . It has been reported that piRNA, and lncRNA isoforms . LncRNAs have a variety
HDAC plays an important role in setting up the imbalance of functions, for example, nuclear lncRNAs are involved in
of histone acetylation/deacetylation, and is the main driving the enhancement and silencing of transcription, chromatin
force for the progression of pulmonary fibrosis. HDAC2 is remodeling, and compartmentalization of the nucleus. In
mainly involved in the chronic progression of pulmonary the cytoplasm, lncRNAs inhibit miRNAs (being competing
fibrosis, while HDAC4 is mainly involved in the early endogenous RNAs for miRNAs), post-translational
stress response of pulmonary fibrosis . HDAC3 promotes modification of the protein structure and formation of a
[30]
EMT, inflammation, and pulmonary fibrosis development “framework” for proteins of various signaling pathways,
by activating Notch1 and STAT1 signaling . Saito et al. maintenance of mitochondrial homeostasis, regulation of
[31]
observed an increased expression level of HDAC8 in IPF pre-mRNA splicing (lncRNA NEAT1), and stabilization of
lung tissue as well as in TGF-β1-treated normal human intercellular contacts through interaction with membrane
lung fibroblasts, and HDAC8 inhibitors could be employed complexes PECAM1, p120 catenin [1,36-39] .
as potential treatment of IPF as well as other fibrotic lung
diseases . In addition, ERK5 plays a key role in TGF- 3.4.2. LncRNAs in pathogenesis of diseases
[32]
β1-induced pulmonary fibrosis by enhancing Smad3 Given such an active role of lncRNA, it is not surprising
acetylation . Suberoylanilide hydroxamic acid (SAHA), that they are involved in the pathogenesis of many diseases,
[33]
a histone deacetylase inhibitor, is currently approved for especially cancers. For example, increased level of lncRNA

Volume 1 Issue 2 (2022) 5 https://doi.org/10.36922/gtm.v1i2.107