The RNA ligase RNA terminal phosphate cyclase B regulates mRNA alternative splicing and is required for mouse oocyte development and maintenance.

Recent large-scale mRNA sequencing has shown that introns are retained in 5-10% of mRNA, and these events are named intron retention (IR). IR has been recognized as a key mechanism in the regulation of gene expression. However, the role of this mechanism in female reproduction in mammals remains unclear. RNA terminal phosphate cyclase B (RTCB) is a RNA ligase; we found that RTCB conditional knockout mice have premature ovarian failure and that RTCB plays a crucial role in follicular development. RTCB regulated the splicing of transcripts related to DNA methylation and DNA damage repair. In addition, it regulated the resumption of oocyte meiosis by affecting CDK1 activation. Moreover, the loss of RTCB suppressed zygotic genome activation (ZGA) and decreased translation at the global level. In addition, Rtcb deletion resulted in the accumulation of maternal mRNAs containing unspliced introns and in a decline in the overall level of transcripts. As a result, the Rtcb-/- females were sterile. Our study highlights the important role of RTCB-regulated noncanonical alternative splicing in female reproduction.

CRL4DCAF13 E3 ubiquitin ligase targets MeCP2 for degradation to prevent DNA hypermethylation and ensure normal transcription in growing oocytes.

The DNA methylation is gradually acquired during oogenesis, a process sustained by successful follicle development. However, the functional roles of methyl-CpG-binding protein 2 (MeCP2), an epigenetic regulator displaying specifical binding with methylated DNA, remains unknown in oogenesis. In this study, we found MeCP2 protein was highly expressed in primordial and primary follicle, but was almost undetectable in secondary follicles. However, in aged ovary, MeCP2 protein is significantly increased in both oocyte and granulosa cells. Overexpression of MeCP2 in growing oocyte caused transcription dysregulation, DNA hypermethylation, and genome instability, ultimately leading to follicle growth arrest and apoptosis. MeCP2 is targeted by DCAF13, a substrate recognition adaptor of the Cullin 4-RING (CRL4) E3 ligase, and polyubiquitinated for degradation in both cells and oocytes. Dcaf13-null oocyte exhibited an accumulation of MeCP2 protein, and the partial rescue of follicle growth arrest induced by Dcaf13 deletion was observed following MeCP2 knockdown. The RNA-seq results revealed that large amounts of genes were regulated by the DCAF13-MeCP2 axis in growing oocytes. Our study demonstrated that CRL4DCAF13 E3 ubiquitin ligase targets MeCP2 for degradation to ensure normal DNA methylome and transcription in growing oocytes. Moreover, in aged ovarian follicles, deceased DCAF13 and DDB1 protein were observed, indicating a potential novel mechanism that regulates ovary aging.

Divergent projections of the prelimbic cortex mediate autism- and anxiety-like behaviors.

The comorbidity of autism spectrum disorder and anxiety is common, but the underlying circuitry is poorly understood. Here, Tmem74-/- mice showed autism- and anxiety-like behaviors along with increased excitability of pyramidal neurons (PNs) in the prelimbic cortex (PL), which were reversed by Tmem74 re-expression and chemogenetic inhibition in PNs of the PL. To determine the underlying circuitry, we performed conditional deletion of Tmem74 in the PNs of PL of mice, and we found that alterations in the PL projections to fast-spiking interneurons (FSIs) in the dorsal striatum (dSTR) (PLPNs-dSTRFSIs) mediated the hyperexcitability of FSIs and autism-like behaviors and that alterations in the PL projections to the PNs of the basolateral amygdaloid nucleus (BLA) (PLPNs-BLAPNs) mediated the hyperexcitability of PNs and anxiety-like behaviors. However, the two populations of PNs in the PL had different spatial locations, optogenetic manipulations revealed that alterations in the activity in the PL-dSTR or PL-BLA circuits led to autism- or anxiety-like behaviors, respectively. Collectively, these findings highlight that the hyperactivity of the two populations of PNs in the PL mediates autism and anxiety comorbidity through the PL-dSTR and PL-BLA circuits, which may lead to the development of new therapeutics for the autism and anxiety comorbidity.

Separase is recruited to mitotic chromosomes to dissolve sister chromatid cohesion in a DNA-dependent manner.

Sister chromatid separation is triggered by the separase-catalyzed cleavage of cohesin. This process is temporally controlled by cell-cycle-dependent factors, but its biochemical mechanism and spatial regulation remain poorly understood. We report that cohesin cleavage by human separase requires DNA in a sequence-nonspecific manner. Separase binds to DNA in vitro, but its proteolytic activity, measured by its autocleavage, is not stimulated by DNA. Instead, biochemical characterizations suggest that DNA mediates cohesin cleavage by bridging the interaction between separase and cohesin. In human cells, a fraction of separase localizes to the mitotic chromosome. The importance of the chromosomal DNA in cohesin cleavage is further demonstrated by the observation that the cleavage of the chromosome-associated cohesins is sensitive to nuclease treatment. Our observations explain why chromosome-associated cohesins are specifically cleaved by separase and the soluble cohesins are left intact in anaphase.

Mitoguardin Regulates Mitochondrial Fusion through MitoPLD and Is Required for Neuronal Homeostasis.

Mitochondria undergo frequent morphological changes through fission and fusion. Mutations in core members of the mitochondrial fission/fusion machinery are responsible for severe neurodegenerative diseases. However, the mitochondrial fission/fusion mechanisms are poorly understood. We found that the loss of a mitochondrial protein encoding gene, mitoguardin (miga), leads to mitochondrial defects and neurodegeneration in fly eyes. Mammals express two orthologs of miga: Miga1 and Miga2. Both MIGA1 and MIGA2 form homotypic and heterotypic complexes on the outer membrane of the mitochondria. Loss of MIGA results in fragmented mitochondria, whereas overexpression of MIGA leads to clustering and fusion of mitochondria in both fly and mammalian cells. MIGA proteins function downstream of mitofusin and interact with MitoPLD to stabilize MitoPLD and facilitate MitoPLD dimer formation. Therefore, we propose that MIGA proteins promote mitochondrial fusion by regulating mitochondrial phospholipid metabolism via MitoPLD.

Nuclear poly(A) binding protein 1 (PABPN1) mediates zygotic genome activation-dependent maternal mRNA clearance during mouse early embryonic development.

An embryo starts its life with maternal mRNA clearance, which is crucial for embryonic development. The elimination of maternal transcripts occurs by the joint action of two pathways: the maternally encoded mRNA decay pathway (M-decay) and the zygotic genome activation (ZGA)-dependent pathway (Z-decay). However, zygotic factors triggering maternal mRNA decay in early mammalian embryos remain largely unknown. In this study, we identified the zygotically encoded nuclear poly(A) binding protein 1 (PABPN1) as a factor required for maternal mRNA turnover, with a previously undescribed cytoplasmic function. Cytoplasmic PABPN1 docks on 3'-uridylated transcripts, downstream of terminal uridylyl transferases TUT4 and TUT7, and recruits 3'-5' exoribonuclease DIS3L2 to its targets, facilitating maternal mRNA decay. Pabpn1-knockout in mice resulted in preimplantation stage mortality due to early developmental arrest at the morula stage. Maternal mRNAs to be eliminated via the Z-decay pathway failed to be removed from Pabpn1-depleted embryos. Furthermore, PABPN1-mediated Z-decay is essential for major ZGA and regulates the expression of cell fate-determining factors in mouse preimplantation embryos. This study revealed an unforeseen cytoplasmic function of PABPN1 coupled with early embryonic development, characterized the presence of a zygotic destabilizer of maternal mRNA, and elucidated the Z-decay process mechanisms, which potentially contribute to human fertility.

USP16-mediated histone H2A lysine-119 deubiquitination during oocyte maturation is a prerequisite for zygotic genome activation.

Maternal-to-zygotic transition (MZT) is the first and key step in the control of animal development and intimately related to changes in chromatin structure and histone modifications. H2AK119ub1, an important epigenetic modification in regulating chromatin configuration and function, is primarily catalyzed by PRC1 and contributes to resistance to transcriptional reprogramming in mouse embryos. In this study, the genome-wide dynamic distribution of H2AK119ub1 during MZT in mice was investigated using chromosome immunoprecipitation and sequencing. The results indicated that H2AK119ub1 accumulated in fully grown oocytes and was enriched at the TSSs of maternal genes, but was promptly declined after meiotic resumption at genome-wide including the TSSs of early zygotic genes, by a previously unidentified mechanism. Genetic evidences indicated that ubiquitin-specific peptidase 16 (USP16) is the major deubiquitinase for H2AK119ub1 in mouse oocytes. Conditional knockout of Usp16 in oocytes did not impair their survival, growth, or meiotic maturation. However, oocytes lacking USP16 have defects when undergoing zygotic genome activation or gaining developmental competence after fertilization, potentially associated with high levels of maternal H2AK119ub1 deposition on the zygotic genomes. Taken together, H2AK119ub1 level is declined during oocyte maturation by an USP16-dependent mechanism, which ensures zygotic genome reprogramming and transcriptional activation of essential early zygotic genes.

NAT10-mediated N4-acetylcytidine modification is required for meiosis entry and progression in male germ cells.

Post-transcriptional RNA modifications critically regulate various biological processes. N4-acetylcytidine (ac4C) is an epi-transcriptome, which is highly conserved in all species. However, the in vivo physiological functions and regulatory mechanisms of ac4C remain poorly understood, particularly in mammals. In this study, we demonstrate that the only known ac4C writer, N-acetyltransferase 10 (NAT10), plays an essential role in male reproduction. We identified the occurrence of ac4C in the mRNAs of mouse tissues and showed that ac4C undergoes dynamic changes during spermatogenesis. Germ cell-specific ablation of Nat10 severely inhibits meiotic entry and leads to defects in homologous chromosome synapsis, meiotic recombination and repair of DNA double-strand breaks during meiosis. Transcriptomic profiling revealed dysregulation of functional genes in meiotic prophase I after Nat10 deletion. These findings highlight the crucial physiological functions of ac4C modifications in male spermatogenesis and expand our understanding of its role in the regulation of specific physiological processes in vivo.

Homozygous Mutations in BTG4 Cause Zygotic Cleavage Failure and Female Infertility.

Zygotic cleavage failure (ZCF) is a unique early embryonic phenotype resulting in female infertility and recurrent failure of in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI). With this phenotype, morphologically normal oocytes can be retrieved and successfully fertilized, but they fail to undergo cleavage. Until now, whether this phenotype has a Mendelian inheritance pattern and which underlying genetic factors play a role in its development remained to be elucidated. B cell translocation gene 4 (BTG4) is a key adaptor of the CCR4-NOT deadenylase complex, which is involved in maternal mRNA decay in mice, but no human diseases caused by mutations in BTG4 have previously been reported. Here, we identified four homozygous mutations in BTG4 (GenBank: NM_017589.4) that are responsible for the phenotype of ZCF, and we found they followed a recessive inheritance pattern. Three of them-c.73C>T (p.Gln25Ter), c.1A>G (p.?), and c.475_478del (p.Ile159LeufsTer15)-resulted in complete loss of full-length BTG4 protein. For c.166G>A (p.Ala56Thr), although the protein level and distribution of mutant BTG4 was not altered in zygotes from affected individuals or in HeLa cells, the interaction between BTG4 and CNOT7 was abolished. In vivo studies further demonstrated that the process of maternal mRNA decay was disrupted in the zygotes of the affected individuals, which provides a mechanistic explanation for the phenotype of ZCF. Thus, we provide evidence that ZCF is a Mendelian phenotype resulting from mutations in BTG4. These findings contribute to our understanding of the role of BTG4 in human early embryonic development and provide a genetic marker for female infertility.

CXXC finger protein 1-mediated histone H3 lysine-4 trimethylation is essential for proper meiotic crossover formation in mice.

The most significant feature of meiosis is the recombination process during prophase I. CXXC finger protein 1 (CXXC1) binds to CpG islands and mediates the deposition of H3K4me3 by the SETD1 complex. CXXC1 is also predicted to recruit H3K4me3-marked regions to the chromosome axis for the generation of double-strand breaks (DSBs) in the prophase of meiosis. Therefore, we deleted Cxxc1 before the onset of meiosis with Stra8-Cre The conditional knockout mice were completely sterile with spermatogenesis arrested at MII. Knockout of Cxxc1 led to a decrease in the H3K4me3 level from the pachytene to the MII stage and caused transcriptional disorder. Many spermatogenesis pathway genes were expressed early leading to abnormal acrosome formation in arrested MII cells. In meiotic prophase, deletion of Cxxc1 caused delayed DSB repair and improper crossover formation in cells at the pachytene stage, and more than half of the diplotene cells exhibited precocious homologous chromosome segregation in both male and female meiosis. Cxxc1 deletion also led to a significant decrease of H3K4me3 enrichment at DMC1-binding sites, which might compromise DSB generation. Taken together, our results show that CXXC1 is essential for proper meiotic crossover formation in mice and suggest that CXXC1-mediated H3K4me3 plays an essential role in meiotic prophase of spermatogenesis and oogenesis.

Erk and MAPK signaling is essential for intestinal development through Wnt pathway modulation.

Homeostasis of intestinal stem cells (ISCs) is maintained by the orchestration of niche factors and intrinsic signaling networks. Here, we have found that deletion of Erk1 and Erk2 (Erk1/2) in intestinal epithelial cells at embryonic stages resulted in an unexpected increase in cell proliferation and migration, expansion of ISCs, and formation of polyp-like structures, leading to postnatal death. Deficiency of epithelial Erk1/2 results in defects in secretory cell differentiation as well as impaired mesenchymal cell proliferation and maturation. Deletion of Erk1/2 strongly activated Wnt signaling through both cell-autonomous and non-autonomous mechanisms. In epithelial cells, Erk1/2 depletion resulted in loss of feedback regulation, leading to Ras/Raf cascade activation that transactivated Akt activity to stimulate the mTor and Wnt/ß-catenin pathways. Moreover, Erk1/2 deficiency reduced the levels of Indian hedgehog and the expression of downstream pathway components, including mesenchymal Bmp4 - a Wnt suppressor in intestines. Inhibition of mTor signaling by rapamycin partially rescued Erk1/2 depletion-induced intestinal defects and significantly prolonged the lifespan of mutant mice. These data demonstrate that Erk/Mapk signaling functions as a key modulator of Wnt signaling through coordination of epithelial-mesenchymal interactions during intestinal development.

A long-acting recombinant FSH supports high-quality mouse follicle development and oocyte maturation in vitro by coordinating somatic and germ cell transcriptomes.

Strategies to maximize individual fertility chances are constant requirements of ART. In vitro folliculogenesis may represent a valid option to create a large source of immature ovarian follicles in ART. Efforts are being made to set up mammalian follicle culture protocols with suitable FSH stimuli. In this study, a new type of recombinant FSH (KN015) with a prolonged half-life is proposed as an alternative to canonical FSH. KN015 supports the in vitro development of mouse follicles from primary to preovulatory stage with higher efficiency than canonical FSH and enhanced post-fertilization development rates of the ovulated oocytes. The use of KN015 also allows us to compare the dynamic transcriptome changes in oocytes and granulosa cells at different stages, in vivo and in vitro. In particular, KN015 facilitates mRNA accumulation in growing mouse oocytes and prevents spontaneous luteinization of granulosa cells in vitro. Novel analyses of transcriptome changes in this study reveal that the in vivo oocytes were more efficient than in vitro oocytes in terms of maternal mRNA clearing during meiotic maturation. KN015 promotes the degradation of maternal mRNA during in vitro oocyte maturation, improves cytoplasmic maturation and, therefore, enhances embryonic developmental potential. These findings establish new transcriptome data for oocyte and granulosa cells at the key stages of follicle development, and should help to widen the use of KN015 as a valid and commercially available hormonal support enabling optimized in vitro development of follicles and oocytes.

CRL4(VprBP) E3 ligase promotes monoubiquitylation and chromatin binding of TET dioxygenases.

DNA methylation at the C-5 position of cytosine (5mC) regulates gene expression and plays pivotal roles in various biological processes. The TET dioxygenases catalyze iterative oxidation of 5mC, leading to eventual demethylation. Inactivation of TET enzymes causes multistage developmental defects, impaired cell reprogramming, and hematopoietic malignancies. However, little is known about how TET activity is regulated. Here we show that all three TET proteins bind to VprBP and are monoubiquitylated by the VprBP-DDB1-CUL4-ROC1 E3 ubiquitin ligase (CRL4(VprBP)) on a highly conserved lysine residue. Deletion of VprBP in oocytes abrogated paternal DNA hydroxymethylation in zygotes. VprBP-mediated monoubiquitylation promotes TET binding to chromatin. Multiple recurrent TET2-inactivating mutations derived from leukemia target either the monoubiquitylation site (K1299) or residues essential for VprBP binding. Cumulatively, our data demonstrate that CRL4(VprBP) is a critical regulator of TET dioxygenases during development and in tumor suppression.

Revisiting ZAR proteins: the understudied regulator of female fertility and beyond.

Putative RNA-binding proteins (RBPs), zygote arrested-1 (ZAR1), and ZAR2 (also known as ZAR1L), have been identified as maternal factors that mainly function in oogenesis and embryogenesis. Despite divergence in their spatio-temporal expression among species, the CxxC structure of the C-terminus of ZAR proteins is highly conserved and is reported to be the functional domain for the activity of the RBPs of ZAR proteins. In oocytes from Xenopus laevis and zebrafish, ZAR proteins have been reported to bind to maternal transcripts and inhibit translation in immature growing oocytes, whereas in fully grown mouse oocytes, they promote the translation during meiotic maturation. Thus, ZAR1 and ZAR2 may be required for the maternal-to-zygotic transition by stabilizing the maternal transcriptome in oocytes with partial functional redundancy. In addition, recent studies have suggested non-ovarian expression and function of ZAR proteins, particularly their involvement in tumorigenesis. ZAR proteins are potentially associated with tumor suppressors and can serve as epigenetically inactivated cancer biomarkers. In this review, studies on Zar1/2 are systematically summarized, and some issues that require discussion and further investigation are introduced as perspectives.

Biallelic variants in ZFP36L2 cause female infertility characterised by recurrent preimplantation embryo arrest.

BACKGROUND: Recurrent preimplantation embryo developmental arrest (RPEA) is the most common cause of assisted reproductive technology treatment failure associated with identified genetic abnormalities. Variants in known maternal genes can only account for 20%-30% of these cases. The underlying genetic causes for the other affected individuals remain unknown. METHODS: Whole exome sequencing was performed for 100 independent infertile females that experienced RPEA. Functional characterisations of the identified candidate disease-causative variants were validated by Sanger sequencing, bioinformatics and in vitro functional analyses, and single-cell RNA sequencing of zygotes. RESULTS: Biallelic variants in ZFP36L2 were associated with RPEA and the recurrent variant (p.Ser308_Ser310del) prevented maternal mRNA decay in zygotes and HeLa cells. CONCLUSION: These findings emphasise the relevance of the relationship between maternal mRNA decay and human preimplantation embryo development and highlight a novel gene potentially responsible for RPEA, which may facilitate genetic diagnoses.

Revisiting poly(A)-binding proteins: Multifaceted regulators during gametogenesis and early embryogenesis.

Post-transcriptional regulation faces a distinctive challenge in gametes. Transcription is limited when the germ cells enter the division phase due to condensed chromatin, while gene expression during gamete maturation, fertilization, and early cleavage depends on existing mRNA post-transcriptional coordination. The dynamics of the 3'-poly(A) tail play crucial roles in defining mRNA fate. The 3'-poly(A) tail is covered with poly(A)-binding proteins (PABPs) that help to mediate mRNA metabolism and recent work has shed light on the number and function of germ cell-specific expressed PABPs. There are two structurally different PABP groups distinguished by their cytoplasmic and nuclear localization. Both lack catalytic activity but are coupled with various roles through their interaction with multifunctional partners during mRNA metabolism. Here, we present a synopsis of PABP function during gametogenesis and early embryogenesis and describe both conventional and current models of the functions and regulation of PABPs, with an emphasis on the physiological significance of how germ cell-specific PABPs potentially affect human fertility.

Oocyte meiosis-coupled poly(A) polymerase α phosphorylation and activation trigger maternal mRNA translation in mice.

Mammalian oocyte maturation is driven by strictly regulated polyadenylation and translational activation of maternal mRNA stored in the cytoplasm. However, the poly(A) polymerase (PAP) that directly mediates cytoplasmic polyadenylation in mammalian oocytes has not been determined. In this study, we identified PAPα as the elusive enzyme that catalyzes cytoplasmic mRNA polyadenylation implicated in mouse oocyte maturation. PAPα was mainly localized in the germinal vesicle (GV) of fully grown oocytes but was distributed to the ooplasm after GV breakdown. Inhibition of PAPα activity impaired cytoplasmic polyadenylation and translation of maternal transcripts, thus blocking meiotic cell cycle progression. Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPα, 537, 545 and 558, thereby leading to increased activity. This mechanism is responsible for translational activation of transcripts lacking cytoplasmic polyadenylation elements in their 3'-untranslated region (3'-UTR). In turn, activated PAPα stimulated polyadenylation and translation of the mRNA encoding its own (Papola) through a positive feedback circuit. ERK1/2 promoted Papola mRNA translation in a 3'-UTR polyadenylation signal-dependent manner. Through these mechanisms, PAPα activity and levels were significantly amplified, improving the levels of global mRNA polyadenylation and translation, thus, benefiting meiotic cell cycle progression.

Role of CxxC-finger protein 1 in establishing mouse oocyte epigenetic landscapes.

During oogenesis, oocytes gain competence and subsequently undergo meiotic maturation and prepare for embryonic development; trimethylated histone H3 on lysine-4 (H3K4me3) mediates a wide range of nuclear events during these processes. Oocyte-specific knockout of CxxC-finger protein 1 (CXXC1, also known as CFP1) impairs H3K4me3 accumulation and causes changes in chromatin configurations. This study investigated the changes in genomic H3K4me3 landscapes in oocytes with Cxxc1 knockout and the effects on other epigenetic factors such as the DNA methylation, H3K27me3, H2AK119ub1 and H3K36me3. H3K4me3 is overall decreased after knocking out Cxxc1, including both the promoter region and the gene body. CXXC1 and MLL2, which is another histone H3 methyltransferase, have nonoverlapping roles in mediating H3K4 trimethylation during oogenesis. Cxxc1 deletion caused a decrease in DNA methylation levels and affected H3K27me3 and H2AK119ub1 distributions, particularly at regions with high DNA methylation levels. The changes in epigenetic networks implicated by Cxxc1 deletion were correlated with the transcriptional changes in genes in the corresponding genomic regions. This study elucidates the epigenetic changes underlying the phenotypes and molecular defects in oocytes with deleted Cxxc1 and highlights the role of CXXC1 in orchestrating multiple factors that are involved in establishing the appropriate epigenetic states of maternal genome.

Mutations in OOEP and NLRP5 identified in infertile patients with early embryonic arrest.

The subcortical maternal complex (SCMC), composed of several maternal-effect genes, is vital for the development of oocytes and early embryos. Variants of SCMC-encoding genes (NLRP2, NLRP5, TLE6, PADI6, and KHDC3L, but not OOEP and ZBED3) are associated with human oocyte maturation dysfunction, fertilization failure, and early embryonic arrest. In this study, we enrolled 118 Chinese patients who experienced recurrent preimplantation embryonic arrest during assisted reproductive technology treatments and performed whole-exome sequencing. We discovered compound heterozygous missense variants (c.110G>C and c.109C>G) in the OOEP gene in one patient who experienced recurrent preimplantation embryonic arrest. Arrested embryos from this affected patient were analyzed by single-cell RNA sequencing, which showed a downregulated transcriptome. In addition, six novel NLRP5 variants (c.971T>A, c.3341T>C, c.1575_1576delAG, c.1830_1831delGT, c.1202C>T, and c.2378T>G) were identified in four patients with arrested and severely fragmented embryos. These suspicious mutations were examined by in vitro studies in HEK293T cells. Western blot analysis and immunofluorescence experiments showed that OOEP and partial NLRP5 mutations caused decreased protein levels. Our findings first demonstrated that biallelic variants in OOEP gene could also cause human early embryonic arrest, similar to other SCMC components. We expanded the genetic mutation spectrum of SCMC genes related to early embryogenesis in humans, especially early embryonic arrest.

DCAF13 promotes pluripotency by negatively regulating SUV39H1 stability during early embryonic development.

Mammalian oocytes and zygotes have the unique ability to reprogram a somatic cell nucleus into a totipotent state. SUV39H1/2-mediated histone H3 lysine-9 trimethylation (H3K9me3) is a major barrier to efficient reprogramming. How SUV39H1/2 activities are regulated in early embryos and during generation of induced pluripotent stem cells (iPSCs) remains unclear. Since expression of the CRL4 E3 ubiquitin ligase in oocytes is crucial for female fertility, we analyzed putative CRL4 adaptors (DCAFs) and identified DCAF13 as a novel CRL4 adaptor that is essential for preimplantation embryonic development. Dcaf13 is expressed from eight-cell to morula stages in both murine and human embryos, and Dcaf13 knockout in mice causes preimplantation-stage mortality. Dcaf13 knockout embryos are arrested at the eight- to sixteen-cell stage before compaction, and this arrest is accompanied by high levels of H3K9me3. Mechanistically, CRL4-DCAF13 targets SUV39H1 for polyubiquitination and proteasomal degradation and therefore facilitates H3K9me3 removal and zygotic gene expression. Taken together, CRL4-DCAF13-mediated SUV39H1 degradation is an essential step for progressive genome reprogramming during preimplantation embryonic development.