Divergent roles for KLF4 and TFCP2L1 in naive ground state pluripotency and human primordial germ cell development

Hancock, Grace; Liu, Wanlu; Peretz, Lior; Chen, Di; Gell, Joanna J.; Collier, Amanda J.; Zamudio, Jesse R.; Plath, Kathrin; Clark, Amander T.

doi:10.1016/j.scr.2021.102493

Cited by 5 publications

(3 citation statements)

References 46 publications

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“…Further supporting evidence for this conclusion is the observation that over expression of KLF4-KLF17 in the primed state of pluripotency is sufficient to open the LTR5Hs TEENhancers and regulate neighboring gene expression 30 . Our recent study suggests that KLF17 is not expressed in hPGCLCs, whereas KLF4 is up-regulated upon hPGCLC induction but is not functionally required for the induction or proliferation of hPGCLCs 52 . Thus, we propose that unlike naïve pluripotent stem cells where KLF4 and KLF17 bind to TEENhancers, the LTR5Hs TEENhancers in hPGCLCs utilize SOX17, SOX15, TFAP2C, NANOG, and ETV5.…”

Section: Discussionmentioning

confidence: 91%

“…Despite lack of KLF4 activity and KLF17 expression in germ cell specification, hPGCLCs in vitro and hPGCs in vivo exhibit a naïve-like pluripotent molecular program that has similarities to the naïve state in pre-implantation human embryos. This includes two active X chromosomes in females, genome-wide DNA demethylation and expression of naïve pluripotent TFs including KLF4, TFCP2L1, and TFAP2C 9 , 16 , 52 – 54 . Similar to KLF4-KLF17, TFAP2C also regulates transcription and the identity of naïve pluripotent stem cells by opening naïve-specific enhancers to regulate neighboring gene expression 17 , 30 .…”

Section: Discussionmentioning

confidence: 99%

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Human reproduction is regulated by retrotransposons derived from ancient Hominidae-specific viral infections

Xiang

DiRusso

et al. 2022

Nat Commun

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Germ cells are essential to pass DNA from one generation to the next. In human reproduction, germ cell development begins with the specification of primordial germ cells (PGCs) and a failure to specify PGCs leads to human infertility. Recent studies have revealed that the transcription factor network required for PGC specification has diverged in mammals, and this has a significant impact on our understanding of human reproduction. Here, we reveal that the Hominidae-specific Transposable Elements (TEs) LTR5Hs, may serve as TEENhancers (TE Embedded eNhancers) to facilitate PGC specification. LTR5Hs TEENhancers become transcriptionally active during PGC specification both in vivo and in vitro with epigenetic reprogramming leading to increased chromatin accessibility, localized DNA demethylation, enrichment of H3K27ac, and occupation of key hPGC transcription factors. Inactivation of LTR5Hs TEENhancers with KRAB mediated CRISPRi has a significant impact on germ cell specification. In summary, our data reveals the essential role of Hominidae-specific LTR5Hs TEENhancers in human germ cell development.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Human reproduction is regulated by retrotransposons derived from ancient Hominidae-specific viral infections

Xiang

DiRusso

et al. 2022

Nat Commun

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show abstract

“…After 2 weeks of culture and maintenance through single-cell dissociation passages, naive state conversion generated cells exhibiting naive-like iPSC characteristics with the morphology changing from flat to domed. This specific phenotype of the colonies and their ability to tolerate single-cell dissociation is a strong indication of successful conversion of primed iPSCs to a naive state but we also assessed the expression of KLF4 and TFCP2L1 genes known to be expressed in the naive state 28 . RT-PCR results showed a weak increase of KLF4 which is already highly expressed in primed iPSCs, but a significant increase of TFCP2L1 expression in patient naive iPSCs compared to the primed cells, confirming the successful conversion of the patient’s iPSCs from primed to naive state (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

iPSCs derived from infertile men carrying complex genetic abnormalities can generate primordial germ-like cells

Mouka

Arkoun

Moison

et al. 2022

Sci Rep

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Despite increasing insight into the genetics of infertility, the developmental disease processes remain unclear due to the lack of adequate experimental models. The advent of induced pluripotent stem cell (iPSC) technology has provided a unique tool for in vitro disease modeling enabling major advances in our understanding of developmental disease processes. We report the full characterization of complex genetic abnormalities in two infertile patients with either azoospermia or XX male syndrome and we identify genes of potential interest implicated in their infertility. Using the erythroblasts of both patients, we generated primed iPSCs and converted them into a naive-like pluripotent state. Naive-iPSCs were then differentiated into primordial germ-like cells (PGC-LCs). The expression of early PGC marker genes SOX17, CD-38, NANOS3, c-KIT, TFAP2C, and D2-40, confirmed progression towards the early germline stage. Our results demonstrate that iPSCs from two infertile patients with significant genetic abnormalities are capable of efficient production of PGCs. Such in vitro model of infertility will certainly help identifying causative factors leading to early germ cells development failure and provide a valuable tool to explore novel therapeutic strategies.

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Temporal and spatial staging of lung alveolar regeneration is determined by the grainyhead transcription factor Tfcp2l1

Cardenas-Diaz¹,

Liberti²,

Leach³

et al. 2023

Cell Reports

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Divergent roles for KLF4 and TFCP2L1 in naive ground state pluripotency and human primordial germ cell development

Cited by 5 publications

References 46 publications

Human reproduction is regulated by retrotransposons derived from ancient Hominidae-specific viral infections

Human reproduction is regulated by retrotransposons derived from ancient Hominidae-specific viral infections

iPSCs derived from infertile men carrying complex genetic abnormalities can generate primordial germ-like cells

Temporal and spatial staging of lung alveolar regeneration is determined by the grainyhead transcription factor Tfcp2l1

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