Page 68 - GTM-1-2

Global Translational Medicine Risk factors of idiopathic pulmonary fibrosis

like receptor-mediated signaling pathway of innate Table 1. Genetic factors that contribute to IPF pathogenesis
immunity) also contribute to the onset of the disease [6,7] .
The role of the group of Wnt genes encoding a family of Genetic factors Examples
19 glycoproteins has been studied. Glycoproteins bind to Genes TERT, TERC [1,5-7] [7]
Frizzeled-receptors on the cytoplasmic cell membrane and TINF2, DKC1, RTEL1, PARN, NAF1
MUC5B
[5,6]
activate the β-catenin-mediated signaling pathway, leading TOLLIP [6,7]
to the upregulation of the expression of T-cell factor genes, Wnt gene family [10]
matrix metalloproteinases (MMPs), oncogenes, cell cycle SHH gene family [12]
regulators, and angiogenic growth factors. The second NOCH1, FBXO32 [19]
[25]
[17]
signaling pathway, which is calcium- and protein kinase DNA methylation Histones: H3K9 , H3K27 , MBD2 [18]
C-dependent, regulates the differentiation of red bone Genes and other DNA sequences: Thy-1 promoter
region , COX-2 , 14ARF , promoters of SFRP1
[22]
[20]
[21]
marrow cells, cell migration and their polarity, which and SFRP4 , SMAD7, NOCH1, FBXO32 [19]
[23]
are modulators of embryonic development of tissues and DNA acetylation HDAC2, HDAC4 [30]
their regeneration in response to damage. An association HDAC3 [31]
has been found between activation of the β-catenin- HDAC8 [32]
mediated signaling pathway and increased expression of LncRNAs PFAR [3]
IL-1β in type 2 alveolocytes, MMP-7 activation, increased MALAT1 [4]
profibrotic activity, and fibroblast proliferation. The latter Н19 [50-52]
was also found in the Wnt5a gene when it activated the MEG3 [53] [54]
second signaling pathway. There are scientific data on the TERRA
[55]
PVT1
contribution of Wnt1, Wnt7b, Wnt10b, and Frizzeled-2 HOXAAS3 [56]
and -3 receptors in the development of human IPF, which PFAL [57]
was further confirmed in murine experiments . In mice, DNM3OS [58]
[10]
Wnt1-induced protein 1 increased proliferation of type 2 ZFAS1 [59] [51]
alveolocytes, EMT of lung and renal epithelial cells, and FENDRR
enhanced synthesis of extracellular substance . The HDAC: Histone deacetylase
[1]
Sonic hedgehog (SHH) gene family is responsible for
the morphogenesis of many organs, including the lungs. the transcriptional repression of fibrotic gene expression.
[17]
Signal transduction into the cell is carried out using SHH Coward et al. found that histone H3 lysine 9 (H3K9)
protein and three groups of receptors, which are cell- methylation inhibits the expression of the anti-fibrotic
surface receptors Ptch1 and Ptch2, transmembrane protein gene C-X-C motif chemokine ligand 10. Methylated DNA
Smo, and DNA-binding proteins-“zinc fingers” Gli1, Gli2, can also specifically bind to methyl-binding-proteins and
Gli3. Increased SHH signal transduction exacerbates the recruit joint repressors, thereby inhibiting fibrosis-related
[18]
course of pulmonary fibrosis; an increase in fibroblast genes. For example, Wang et al. found that methyl-CPG-
proliferation and resistance to apoptosis was confirmed binding domain 2 (MBD2) stimulates the differentiation of
in vitro (Table 1). fibroblasts to muscle tissue by binding to the methylated
[12]
CPG site, the Erdr1 promoter, and inhibiting the expression
3.2. DNA methylation and transcription of its downstream genes. Differentiation
DNA methylation is the most common form of epigenetic of fibroblasts leads to fibrotic processes. Clinical data have
modification, which may not only regulate gene expression, shown that fibroblast genes in patients with pulmonary
but also play a role in various life activities, such as fibrosis are abnormally methylated at multiple CPG sites
embryonic development, aging and tumor formation. in the genome of patients compared with those in healthy
In recent years, DNA methylation has been proven to be subjects, and the degree of abnormal DNA methylation
involved in the process of multiple organ fibrosis. The in patients with fibrosis at different stages is different:
in-depth studies of methylation in pulmonary fibrosis , Hypomethylation was associated with increased expression
[13]
renal fibrosis , and myocardial fibrosis have confirmed of profibrotic genes (NOCH1, FBXO32, and TOLLIP),
[15]
[14]
that DNA methylation plays an important role in fibrosis whereas hypermethylation was associated with decreased
[19]
[16]
development by regulating the expression of key genes . expression of profibrotic genes .
It has been reported that changes in DNA methylation Despite the low expression, many genes are
in CPG islands are related to the pathogenesis of IPF. hypermethylated in IPF patients, such as Thy-1 promoter
[21]
DNA methylation can block the binding of transcription region , cyclooxygenase-2 (COX-2) , P14ARF , and so
[20]
[22]
factors to cognate DNA sequences, thereby preventing on. Significantly hypermethylated promoters of SFRP1 and
Volume 1 Issue 2 (2022) 4 https://doi.org/10.36922/gtm.v1i2.107