Skip to main content
. 2022 Mar 17;28(3):313–345. doi: 10.1093/humupd/dmac002

Table I.

Transcription factors expressed in developing human germ cells, determined by single-cell RNA-sequencing.

Developmental stage Cell types analyzed Transcription factors Indicated functions of gene products in human reproduction or development References
EPI Human EPI, hESCs ESRRB, KLF17, KLF4, KLF5, SOX2, NANOG, ZFP57, FOXP1

  • FOXP1, SOX2, NANOG and KLF4 are involved in the creation of pluripotency in EPI cells.

  • ESSRB: maintain ESCs with OCT4 and SOX2.

 Yan et al. (2013)
Human preimplantation Embryos ESRRB, NANOG, POU5F1, SOX2, PRDM14, NR5A2, TFCP2L1, KLF17, SMAD2, SMAD4, ETV4

  • PRDM14: essential for pluripotency and germ cell formation. NR5A2: important for embryonic development.

  • SMAD: cell proliferation, apoptosis, and differentiation.

 Blakeley et al. (2015)
Human embryonic cells ARGFX, PRDM14, SOX2, NANOG, KLF17

  • KLF17: involved to spermatid differentiation and oocyte development.

  • ARGFX: related to pre-implantation embryo.

 Petropoulos et al. (2016)
Human pre-implantation embryos PRDM14, TFCP2L1, ZFP42, ARGFX, ESRRB, DPPA2

  • TFCP2L1: important for establishment and maintenance of pluripotency in ESCs.

  • ZFP42: involved in the reprogramming of X-chromosome inactivation during the acquisition of pluripotency and ESCs self-renewal.

  • DPPA2: associated with developmental pluripotency

 Stirparo et al. (2018)
Human preimplantation embryos NANOG, PRDM14, SOX2, SOX21, SALL1, HAND1, SP7, PAX6, UTF1, ELF5

  • SALL1: transcriptional regulation of PSCs.

  • HAND1: acts as a transcriptional repressor of SOX15.

  • UTF1: involved in differentiation of embryonic carcinoma and ESCs.

  • ELF5: involved in tumorigenesis.

 Zhou et al. (2019)
PGC Human 4–19 weeks of gestation (WG) PGCs; gonadal somatic cells

  • Early PGC: NANOG, POU5F1, SALL4, KLF4, ZFP42, TFAP2C, T, SOX15, SOX17

  • Mitotic PGC: NANOG, POU5F1, SALL4, SOX17, SOX15, SOX13, PRDM1, PRDM14, TFAP2C, TFCP2L1, KLF4

  • Male PGC mitotic arrest: EBF3, SATB2, ZNF267, FEZF1, SOX12, DMRTB1, ZSCAN5A, SOX30, GATA3, FOXD1

  • Pro-Meiotic FGC: ZNF208, YBX1, ZNF791, PRDM9, LHX8, NR4A2, ZNF382, MGA, ZIC4, HSF2, DMRTA2, L3MBTL1, SOX30, GATA3, FOXD1

  • EBF3: inhibits cell survival through the regulation of genes involved in cell cycle arrest and apoptosis.

  • ZNF267 and ZSCAN5A: involved in transcriptional regulation.

  • FEZF1:(GO) annotations related to this gene include RNA polymerase II proximal promoter sequence-specific DNA binding.

  • DMRTB1: gene Ontology (GO) annotations related to this gene include DNA-binding transcription factor activity and sequence-specific DNA binding.

  • ZIC3: this nuclear protein probably functions as a transcription factor in early stages of left-right body axis formation.

 Guo et al. (2015)
Li et al. (2017)
Human prenatal germline cells SOX17, SOX12, KLF6, LEF1

  • KLF6: transcriptional activator.

  • LEF1: participates in the WNT signaling pathway.

 Gkountela et al. (2015)
Wk4–Wk9 human embryos NANOG, OCT4, KLF4, TFCP2L1, T, SOX17, TFAP2C, BLIMP1, UTF1, PRDM14 KLF2: activates cell transcription Tang et al. (2015)
Human fetal tissues from first and second trimester NANOG, POU5F1, SOX4 Vértesy et al. (2018)
PCG (cont.) Prenatal gonads from 4 to 16 weeks post- fertilization PGC: POU5F1, NANOG, PRDM1, SOX17, TFAP2C Chitiashvili et al. (2020)
Male SSEA4+hSSCs and c-KIT+spermatogonia from whole adult human testis

  • PGC: NANOG, POU5F1, SALL4, TCF3, KLF4, STAT3, MBD3, DMRT1

  • SSC: DMRT1/6, BCL6, ID4, SALL4, ETV5, TCF3, KLF4, KLF2, STAT3, MBD3

  • SPG: NR6A1, SOHLH2, TCF3, KLF4, KLF2, STAT3, DMRT1

  • DMRT1/6: plays a central role in spermatogonia by inhibiting meiosis in undifferentiated spermatogonia and promoting mitosis, leading to spermatogonial development and allowing abundant and continuous production of sperm.

  • BCL6: downregulated during maturation of dendritic cells by selective stimuli such as bacterial lipopolysaccharide.

  • ID4: implicated in regulating a variety of cellular processes, including cellular growth, senescence, differentiation, and apoptosis.

  • SALL4: plays a key role in the maintenance and self-renewal of embryonic and hematopoietic stem cells.

  • NR6A1: may be involved in the regulation of gene expression in germ cell development during gametogenesis.

 Guo et al. (2017)
Spermatogenic cells from immature and adult male mice and adult men

  • SPG: ETV5, ID4, SOHLH1, RHOXF1, ZBTB16, BCL6B, FOXO1, DMRT1, SOHLH2, NEUROG3, MYBL1, CHD5, GATA4, NR5A1

  • SSC: ETV5, ID4, SOHLH1, RHOXF1, ZBTB16, BCL6B, FOXO1, DMRT1

  • SPC: ETV5, SOHLH1, SOHLH2, NEUROG3

  • SPT: ETV5, ZBTB16, BCL6B, FOXO1, NEUROG3, HSFY2, WT1, GATA4, NR5A1, DMRTB1

 RHOXF1: maybe involved in reproductive processes. Modulates expression of target genes encoding proteins involved in processes relevant to spermatogenesis. Hermann et al. (2018)
Testicular cells from donors with normal spermatogenesis and one with non-obstructive azoospermia (NOA)

  • SPG: MYBL2, E2F4, ZNF709, HINFP, DMRTB1, CTCFL

  • SSC: JUND, HMGA1, ZBTB16, POU3F1, UTF1, SALL4, FGF2, SMAD1, SMAD5, SMAD9, ID1, ID2, ID4, TCF7L2, SSRP1, SOX4, CLOCK, RHOXF1, TFDP2, PARP1, PMS1, E2F4, HINFP, DMRT1

  • SPC: OVOL1, OVOL2, BRCA1,

  • CREB1, PMS1, MTF1, CEBPZ,

  • MYT1L, PARP1

  • SPT: HDAC4, NFKBIB, CHD5

 OVOL2: plays a critical role in maintaining the identity of epithelial lineages by suppressing epithelial-to mesenchymal transition Wang et al. (2018)
Testicular cells from there healthy donors: 17,24 and 25 years old

  • SPG: DMRT1, DMRTB1, SOHLH1, SOHLH2, BRCA1, TBX3, HOXA3

  • SSC: UTF1, SOHLH1, EGR4, ID4, TCF3, ETV5, DMRT1, MSL3

  • SPC: DMRT1, DMRTB1, DMRTC2, DMRT3, SOX4, SOX5, SOX30, SOHLH1, SOHLH2, HOXB4, HOXC6, PRDM9

  • SPT: DMRTB1, CREM, SOX30

  • CREM: plays a role also in human spermatogenesis and that the absence of the CREM switch can be associated to spermatogenic arrest.

  • TBX3: acts as a negative regulator of PML function in cellular senescence.

 Guo et al. (2018)
Testicular samples from obstructive azoospermia or non-obstructive hypergonadotropic azoospermia SPG: RHOXF1 RHOXF1: the encoded protein is likely a DNA-binding transcription factor that may play a role in human reproduction. Laurentino et al., (2019)
Neonatal and adult human testicular cells

  • SSC: EGR4

  • SPG: SOHLH1/2, DMRT1

  • EGR4: the functional loss of EGR4 blocked spermatogenesis, leading to a significant reduction in spermatozoa production.

  • SOHLH1: plays a pivotal role in the transition of germ cells from primordial to primary follicles and in the differentiation of spermatogonia.

  • SOHLH2: plays a pivotal role in the transition of germ cells from primordial to primary follicles and in the differentiation of spermatogonia.

 Sohni et al. (2019)
Pre- and peri-pubertal human testicular samples were obtained from four healthy boys aged 7, 11, 13 and 14 years

  • SPG: UTF1

  • SPC: PRDM9

 PRDM9: mutations in PRDM9 may cause idiopathic infertility in human males. Expressed highest in testis. Guo et al., (2020)
Human testis tissues from 3 embryonic stages, 3 fetal stages and 1 young infant stage

  • PGC: POU5F1, NANOG, TFAP2C SOX17

  • SSC: EGR4, MSL3

 MSL3: plays a role in chromatin remodeling, in X inactivation and transcriptional regulation. Guo et al. (2021)
Female Human 4-26-week fetal germ cells

  • RA-Responsive female FGC: ID3, RARB, ZGLP1, HES6, ZNF362, ZBTB11, HOXA5, HOXB6, HMGB3, PBX1, SOX30, GATA3, FOXD1

  • Oogenesis: NOBOX, FIGLA, STAT1, TBX3, AFF1, JARID2, NFKB2, NR3C2, SOX30, GATA3, FOXD1

  • ID3: luteinization, oogenesis, oocyte maturation.

  • RARB: receptor for retinoic acid.

  • ZGLP1: germ cell development

  • HES6: members of this gene family regulate cell differentiation in numerous cell types.

  • ZNF362, ZBTB11: may be involved in transcriptional regulation.

  • HOXA5, HOXB6: provides cells with specific positional identities on the anterior-posterior axis.

  • HMGB3: plays a fundamental role in DNA replication, nucleosome assembly and transcription.

  • PBX1: may have a role in steroidogenesis, sexual development and differentiation.

  • PRDM9: the zinc finger array recognizes a short sequence motif, leading to local H3K4me3, and meiotic recombination hotspot activity.

  • LHX8: plays a role in tooth morphogenesis, oogenesis and in neuronal differentiation.

  • NR4A2: encodes a member of the steroid-thyroid hormone-retinoid receptor superfamily.

  • ZNF382: may play roles in differentiation, proliferation and apoptosis.

  • MGA: functions as a dual-specificity transcription factor, regulating the expression of both MAX-network and T-box family target genes.

  • ZIC4: members of this family are important during development.

  • HSF2: activates heat-shock response genes.

  • DMRTA2: may be involved in sexual development.

  • L3MBTL1: probably plays a role in cell proliferation.

  • NOBOX: oogenesis.

  • FIGLA: functions in postnatal oocyte-specific gene expression.

  • STAT1: induces a cellular antiviral state.

  • TBX3: regulates developmental processes.

  • AFF1: implicated in human childhood lymphoblastic leukemia.

  • NFKB2: the endpoint of a series of signal transduction events.

  • JARID2: stem cell differentiation and normal embryonic development.

  • NR3C2: functions as a ligand-dependent transcription factor that binds to mineralocorticoid response elements.

 Li et al. (2017)
Human fresh ovarian tissues from 7 female donors ranging from 24 to 32 years (yr), with a median age of 28 yr

  • Primordial follicle: SOX30

  • Primary follicles: GTF2I, CSDE1, SOHLH2, SMARCE1, TUB, HBP1, SOX30, HIF1A

  • Secondary follicles: KLF2, YBX2, FOXO6, SOX13, ETV5, TEAD2, OTX2

  • Antral follicles: PINX1, PBX1, MTF1, SOX15, UBTF, SOX13

  • MII oocytes of preovulatory follicles: ATF2, EOMES

  • In the oocytes, the expressions of GTF2I, CSDE1,

  • SOHLH2, SMARCE1, TUB, HBP1, SOX30 and HIF1A were upregulated in primary follicles, indicating that these TFs may play a critical role in the transition from the primordial to the primary stage.

  • KLF2, YBX2, FOXO6, SOX13, ETV5, TEAD2 and OTX2 were overexpressed in the oocytes from secondary follicles compared to those from primary follicles, implying that they are likely the regulators of the primary-to-secondary stage transition.

  • PINX1, PBX1, MTF1, SOX15, UBTF, SOX13 and POU2F1 had higher expression levels in the oocytes of antral follicles compared to those of secondary follicles, indicating possible regulatory roles in the cytoplasmic and nuclear maturation of oocyte at the antral stage.

  • ATF2 and EOMES were abundantly expressed in the MII oocytes of preovulatory follicles, indicating their potential roles in the unique transcription networks.

 Zhang et al. (2018)
Ovarian cortex samples from 21 patients Oocytes: FIGLA, PRDM1 FIGLA: involved in continued oocyte survival as primordial follicles form in the human. Wagner et al. (2020)
In vivo and In vitro matured human metaphase II (MII) oocytes Oocytes: FIGLA, SOHLH2 SOHLH2: involved in follicle development, initiation of primordial follicle growth, primary follicle growth, and germ cell development. Ye et al. (2020)

EPI, epiblast; FGC, fetal germ cells; hESCs, human embryonic stem cells; PGC, primordial germ cells; PSC, pluripotent stem cells; SPG, spermatogonia; SSC, spermatogonia stem cells; WNT, Wingless-related integration site.