Table 1 Knockout mouse models concerning epigenetic-related enzymes with negative effect on spermatogenesis (including gene IDs from: NCBI – National Center for Biotechnology Information [55] and MGI – Mouse Genome Informatics identifying number [56])

Embryonic development

Kdm6a (Utx)

lysine (K)-specific demethylase 6A

22,289/1095419

Persistence of H3K27me3

Disturbed PGC embryonic development due to lack of PGC marker genes expression and aberrant chromatin dynamics

[57]

Mthfr

methylenetetrahydrofolate reductase

17,769/106639

Disturbed SAM synthesis

Reduced number of early germ cell due to failure of mitotic reactivation and enhanced apoptosis resulting in reduced fertility or infertility (depending on mouse model)

[58, 59]

Nsd1

nuclear receptor-binding SET-domain protein 1

18,193/1276545

Reduction of H3K36me2

Absence of spermatogonia in adult testis due to aberrant de novo DNA methylation in prospermatogonia

[60]

Prmt7

protein arginine N-methyltransferase 7

214,572/2384879

Loss of histone arginine monomethylation

Reduced number of PGC

[61]

Prmt5

protein arginine N-methyltransferase 5

27,374/1351645

Reduction of symmetric H4R3me2

Reduced number of PGC due to lack of transposon repression during the hypomethylated DNA state

[62]

Setdb1

SET domain, bifurcated 1

84,505/1934229

Reduction of H3K9me3 and H3K27me3 within endogenous retrotransposon regions

Decreased number of PGCs due to reactivation of endogenous retroviruses

[63]

Self-renewal and commitment to meiosis

Dnmt3a

DNA methyltransferase 3A

13,435/1261827

Disturbed DNA methylation

Complete spermatogenesis arrest at the spermatogonia level

[64, 65]

Fancd2/Fanci

Fanconi anemia, complementation group D2

MGI:2,448,480

Fanconi anemia, complementation group I

211,651/2384790

Altered H3K9me3 and H3K4me2 in diplotene

Apoptosis of undifferentiated spermatogonia with unknown underlying mechanism, decreased number of mature sperm cells, meiotic progression not affected

[66]

Kdm1a

lysine (K)-specific demethylase 1A

99,982/1196256

Increase of H3K4me2

Complete spermatogenesis arrests upon exit from the stem cell state due to persistent expression of OCT4 gene

[67, 68]

Kmt2d (Mll2)

lysine (K)-specific methyltransferase 2D

381,022/2682319

Loss of H3K4me3

Complete spermatogenesis arrests upon exit from the stem cell state due to lack of repression of Magoh2 promotor

[69]

Tet1

tet methylcytosine dioxygenase 1

52,463/1098693

Decrease of 5hmC in spermatogonial cells

Premature reproductive aging (decreased SSCs, increased apoptosis, compromised imprinting)

[70]

Meiosis

Cxxc1 (Cfp1)

CXXC finger 1

74,322/1921572

Reduction of H3K4me3

Complete meiotic arrest at the prophase I due to reduced expression of meiotic genes and reduced homologous recombination process

[71]

Dnmt3l

DNA (cytosine-5-)-methyltransferase 3-like

54,427/1859287

Disturbed DNA methylation

Complete meiotic arrest at pachytene checkpoint due to loss of chromatin compaction and unpaired chromosomes

[72]

Ehmt2 (G9a)

euchromatic histone lysine N-methyltransferase 2

110,147/2148922

Reduction of H3K9me1/2

Meiotic arrest at early pachytene stage due to incomplete synaptonemal complex formation

[73]

Hdac3

histone deacetylase 3

15,183/1343091

Persistence of H3K9ac and H3K27ac

Spermatogenesis arrest upon exit from meiosis due to upregulation of meiosis related genes and downregulation of spermiogenesis related genes in the epigenetically independent manner (deletion of catalytic domain does not result in infertility)

[74]

Hr6b (Ube2b)

ubiquitin-conjugating enzyme E2B

22,210/102944

Disturbed H2Aub

Increased apoptosis of primary spermatocytes due to synaptonemal complex aberration and increased crossing-over frequency

[75]

Kat8 (Mof)

K(lysine) acetyltransferase 8

67,773/1915023

Loss of H4K16ac

Meiotic arrest due to impaired chromatin-wide expansion of γH2AX phosphorylation in leptotene and zygotene stage of meiosis

[76]

Kdm2b (Fbxl10)

lysine (K)-specific demethylase 2B

30,841/1354737

Change in H3K4me3 distribution in testicular germ cells in the age-dependent manner

Gradual loss of fertility due to progressive inhibition of cell cycle

[77]

Paxip1 (Ptip)

PAX interacting (with transcription-activation domain) protein 1

55,982/1890430

Reduction of H3K4me

Meiotic arrest at the zygotene stage

[78]

Prdm9

PR domain containing 9

213,389/2384854

Reduction of H3K4me3

and H3K36me3 within recombination hotspots

Disturbed homologous recombination due to DSB formation impairment within recombination hotspots

[79]

Prmt1

protein arginine N-methyltransferase 1

15,469/107846

Loss of asymmetric H4R3me2

Complete meiotic arrest at the zygotene-like stage due to an elevated number of DSB

[80]

Rnf20

ring finger protein 20

109,331/1925927

Reduction of H2Bub

Meiotic arrest at the pachytene stage due to impaired programmed double-strand break (DSB) repair

[81]

Setdb1

SET domain, bifurcated 1

84,505/1934229

Reduction of H3K9me3 within pericentromeric heterochromatin and X chromosome

Meiotic arrest at zygotene stage due to aberrant centromere clustering, bouquet formation, failure in pairing and synapsis of homologous chromosomes and MSCI failure

[82, 83]

Suv39h1/2

suppressor of variegation 3–9 1/2

20,937/1099440

64,707/1890396

Reduction of H3K9me

Meiotic arrest at mid- to late pachytene stage due to delayed chromosome synapsis or incomplete pairing

[84]

Ubr2

ubiquitin protein ligase E3 component n-recognin 2

224,826/1861099

Disturbed H2Aub

Increased apoptosis of primary spermatocytes due to synaptonemal complex aberration and increased crossing-over frequency

[85]

Uhrf1

ubiquitin-like, containing PHD and RING finger domains, 1

18,140/1338889

Loss of H3K9me3 at the retrotransposon region and global loss of 5mC

Meiotic arrest at pachytene stage due to reactivation of retrotransposons

[86]

Spermiogenesis

Camk4

calcium/calmodulin-dependent protein kinase IV

12,326/88258

Loss of Protamine 2 phosphorylation

Spermiogenesis arrest in late elongating spermatids stage due to specific loss of protamine-2 and prolonged retention of transition protein 2

[87]

Cdyl

chromodomain protein, Y chromosome-like

12,593/1339956

Reduction in histone lysine crotonylation

Reduction of male fertility with a decreased epididymal sperm count and sperm cell motility due to aberrant reactivation of sex chromosome-linked genes in round spermatids

[88]

Chd5

chromodomain helicase DNA binding protein 5

269,610/3036258

Reduction of H4ac

Spermiogenesis arrest due to aberrant histone removal during histone-to-protamine replacement

[89]

Epc1

enhancer of polycomb homolog 1

13,831/1278322

Reduced H4 hyperacetylation

Spermiogenesis arrest at the transition from round spermatids to elongating spermatid due to aberrant histone to protamine transition

[90]

JmJd1c

jumonji domain containing 1C

108,829/1918614

Reduction of H4K16ac and

HSP90 hypermethylation

Reduction of germ cells, abnormal histone-protamine remodeling and incomplete elongation of spermatids

[91]

Kat5 (Tip60)

K(lysine) acetyltransferase 5

81,601/1932051

Reduced H4 hyperacetylation

Spermiogenesis arrest at the transition from round spermatids to elongating spermatid due to aberrant histone to protamine transition

[90]

Kdm3a (Jhmd2a/ Jmjd1a)

lysine (K)-specific demethylase 3A

MGI:

104,263/98847

Persistence of H3K9me1/2 in promoter region of Tnp1 and Prm1 genes

Spermiogenesis arrest due to incomplete chromatin condensation, extensive apoptosis and blocked spermatid elongation caused by reduced cAMP-response element modulator (CREM) regulated gene expression

[92, 93]

Parp1/2

poly (ADP-ribose) polymerase family, member 1/2

11,545/1340806

11,546/1341112

Abnormal ADP ribosylation of DNA damage response proteins

Reduced fertility caused by abnormal sperm morphology due to abnormal histone retention

[94]

Pygo2

pygopus 2

68,911/1916161

Reduction of H3K9/14ac

Spermiogenesis failure due to reduced expression of Prm1, Prm2, Tnp2 and H1fnt

[95]

Rnf8

ring finger protein 8

58,230/1929069

Reduction of H2Aub and H2Bub

Spermiogenesis arrest at late spermatid stage due to aberrant histone removal during histone-to-protamine replacement

[96]

Scml2

Scm polycomb group protein like 2

107,815/1340042

Persistence of H2AK119ub on sex chromosome

Disturbed reactivation of escape genes located on sex chromosome during spermiogenesis

[97]

Setd2

SET domain containing 2

235,626/1918177

Loss of H3K36me3

Complete spermatogenesis arrests at round-spermatid stage due to acrosomal malformation and histone-to-protamine replacement malfunction

[98]

Sirt1

sirtuin 1

93,759/2135607

Reduction of H4 hyperacetylation

Reduced fertility due to defects in the histone to protamine transition

[99]

Sly

Dot1l

Sycp3 like Y-linked

DOT1-like, histone H3 methyltransferase

382,301/2687328

208,266/2143886

Reduction of H3K79me2 and H4 hyperacetylation

Impaired histone to protamine transition due to aberrant chromatin structure

[100]

Tssk6

testis-specific serine kinase 6

83,984/2148775

Loss of γH2AX phosphorylation

Spermiogenesis arrest due to retention of histone H3 and H4 during histone-to-protamine transition

[12]