Table 1 Epigenetic regulators with known functions in lung development.

DNA methylation

Dnmt1

Promotes proper branching morphogenesis, maintains proximal endodermal cell fate, and suppresses premature activation of the distal epithelial fate

Maintain lung morphogenesis and epithelial fate specification

[17]

Apaf-1

Proximal promoter methylation causes DNA damage-induced apoptosis

Maintain embryonic lung development

[19]

TP53BP2

CpG island-related proximal promoter regions methylation inhibits embryonic morphogenesis

Maintain embryonic lung development

[19]

VEGF-A

Promoter methylation of primary fetal distal lung epithelial cells plays a crucial role in the vascular growth of the cardiopulmonary system

Regulates lung development at pseudoglandular/canalicular stage

[20]

Non-coding RNA

miR-142-3p

Contributes to the proper proliferation of mesenchymal progenitors by controlling the level of WNT signaling

Inhibition of miR-142-3p leads to differentiation of mouse embryonic lung parbronchial smooth muscle cell progenitor cells

[26]

miR302-367

Represses expression of the tumor suppressors Rbl2 and Cdkn1a

Promotes the proliferation of both proximal and distal lung progenitors but prevents their subsequent differentiation

[27]

miR-326

Not evaluated

Regulates the expansion and normal branching pattern of the distal epithelium of the embryonic lung and plays an important role in the breakdown of interstitial integrity

[28]

miR-17, miR-20a, miR-106b

Not evaluated

Downregulation of miR-17, miR-20a, and miR-106b caused significant branching defects in embryonic lung epithelial explants

[29]

miR-449a

Increase the Mycn and Sox9 mRNA levels, and the Ki-67 and SOX9 protein levels

Stimulating distal epithelial progenitor proliferation and mucociliary differentiation

[30]

miR-26a

Not evaluated

Inhibits the formation of dilated lumens and aerated regions and maturation of the alveolar structure

[31, 32]

miR-127

Not evaluated

Regulates the number and size of terminal buds during lung development

[33]

miR-17-92

Hdac3 regulates appropriate TGF-β signaling during pulmonary capsulation by inhibiting the expression of miR-17-92

Promotes alveolar type 1 cell spreading and lung sacculation

[35]

Negatively correlated with promoter methylation and DNA methyltransferase expression

Contributes to the molecular pathogenesis of bronchopulmonary dysplasia

[38]

Promotes proliferation of lung epithelial progenitor cells partly through repressing Rbl2 expression

Participates in early lung development and lung epithelial fate determination

[36]

miR449/34

Inhibits the expression of Notch1 and Dll1 to repress ciliated cell differentiation

Facilitates multiciliogenesis and regulates postnatal maturation of airway epithelial cells

[39, 40]

miR375

Upregulates β-catenin signaling

Regulates trans-differentiation of AEC2 into AEC1

[41]

RP11-380D23.2

Downregulated by PARP1 binding to its genomic sequence, which in turn modulates the expression of PITX2

Influencing distal lung differentiation

[45]

LL18/NANCI

Acts upstream of Nkx2.1 and downstream from Wnt signaling

Regulates lung endoderm gene expression

[46]

Histone modification

Hat1

Maintain cell proliferation and genomic stability

Promotes lung development

[51]

Hdac1/2

Inhibits H3K9 acetylation at the Rb1 (cell-cycle inhibitor) promoter to regulate proper proliferation of early lung endoderm

Promote endoderm progenitor proliferation during lung development and airway regeneration

[53]

HDAC3

Represses miR-17-92 expression to allow for proper TGF-β signaling during lung sacculation

Regulates lung alveolar epithelial cell remodeling

[35]

Hopx

Interacts with Hdac2 to mediate repression of cardiac-specific genes

Regulates lung epithelial maturation

[55]

Suv39H1 Suv39H2

Induces transcriptional silencing through histone H3 lysine 9 methylation, and directly repress the expression of Sftpa1 during hypoxia

Regulates fetal lung development

[56]

Chromatin remodeling

Jmjd3

Jmjd3-mediated alterations in gene expression (AQP-5, SP-B) are associated with locus-specific changes in the methylation status of H3K27 and H3K4

Promotes embryonic lung development

[58]

MCRIP1

Interferes with interactions of CtBP with the lung-enriched transcriptional repressors, Foxp1 and Foxp2, thereby preventing the recruitment of the CtBP co-repressor complex to the SP-B and SP-C promoters and maintaining them in an active chromatin state

Maintains fatal respiratory function

[59]

Ezh2

Represses Trp63 expression in lung epithelial development; Promotes smooth muscle differentiation from the mesothelium through activation of myocardin and Tbx18

Maintains normal lung endoderm development

[60, 61]

Represses Igf1 expression and prevents basal cell differentiation in the developing lung

Promotes airway lineage specification and alveolarization

[62]