Epigenetics in the etiology and management of infertility

Table 1 Mechanistic links between epigenetic disruptions and infertility

Epigenetic mechanisms	Links (Pathophysiology)	Ref.
DNA methylation	Hypermethylation or hypomethylation disrupts genomic imprinting and parental epigenetic mark erasure, resulting in abnormal expression of some genes and imprinted genes involved in gametogenesis and embryogenesis	[3,4,12,13,17,20,25,29-42,44-49]
Histone post-translational modification	Abnormal histone modification alters the expression of certain genes important in gametogenesis and embryogenesis. Also, it disrupts sperm DNA protamination, causing sperm abnormalities	[7,43,56-63]
miRNA	Up-regulation or down-regulation alters the expression of certain genes important in gametogenesis and embryogenesis	[15,68-75]

Table 2 Status of some microRNAs in infertile men and women

miRNAs	Status	Effect	Ref.
miR-34b	Up-regulated	Asthenozoospermia	[73]
miR-122	Up-regulated	Asthenozoospermia	[73]
miR-1973	Up-regulated	Asthenozoospermia	[73]
miR-15b	Up-regulated	Asthenozoospermia	[73]
miR-34c-5p	Up-regulated	Oligoasthenozoospermia	[73]
miR-449a	Up-regulated	Oligoasthenozoospermia	[73]
miR-16	Up-regulated	Oligoasthenozoospermia	[73]
miR-19a	Up-regulated	Oligoasthenozoospermia	[73]
miR-17-92	Deficient	Abnormal oogenesis	[74]
miR-145	Up-regulated	Implantation failure	[75]
miR-23b	Up-regulated	Implantation failure	[75]
miR-99a	Up-regulated	Implantation failure	[75]
hsa-miR-32	Down-regulated	Implantation failure	[75]
hsa-miR-628-5p	Down-regulated	Implantation failure	[75]
hsa-miR-874	Down-regulated	Implantation failure	[75]

miRNAs: MicroRNAs.

Table 3 Selected epigenetic drugs and their activities

Epigenetic drug	Target	Effect	Ref.
Choline	HDAC3	Increases DNA methylation	[15]
Betaine	HDAC3	Increases DNA methylation	[15]
Bobcat339	TETs and TET2	Increases DNA methylation	[15]
C35	TET	Increases DNA methylation	[91]
Zebularine	DNMTs	Reduces hypermethylation	[92]
Disulfiran	DNMTs	Reduces hypermethylation	[92]
Decitabine	DNMTs	Reduces hypermethylation	[92]
Azacitidine	DNMTs	Reduces hypermethylation	[92]
Chaeton	DNMTs	Reduces hypermethylation	[92]
RGFP966	HDAC3	Inhibits histone modification	[95,96]
RG108	Anti-miRNA	Reduces gene expression	[98,99]

DNMTs: DNA methyltransferase; HDAC: Histone deacetylases; TETs: Ten-eleven translocation; miRNA: MicroRNA.