Exclusion of HDAC1/2 complexes by oncogenic nuclear condensates.

Nuclear condensates have been shown to regulate cell fate control, but its role in oncogenic transformation remains largely unknown. Here we show acquisition of oncogenic potential by nuclear condensate remodeling. The proto-oncogene SS18 and its oncogenic fusion SS18-SSX1 can both form condensates, but with drastically different properties and impact on 3D genome architecture. The oncogenic condensates, not wild type ones, readily exclude HDAC1 and 2 complexes, thus, allowing aberrant accumulation of H3K27ac on chromatin loci, leading to oncogenic expression of key target genes. These results provide the first case for condensate remodeling as a transforming event to generate oncogene and such condensates can be targeted for therapy. One sentence summary: Expulsion of HDACs complexes leads to oncogenic transformation.

c-Jun as a one-way valve at the naive to primed interface.

BACKGROUND: c-Jun is a proto-oncogene functioning as a transcription factor to activate gene expression under many physiological and pathological conditions, particularly in somatic cells. However, its role in early embryonic development remains unknown. RESULTS: Here, we show that c-Jun acts as a one-way valve to preserve the primed state and impair reversion to the naïve state. c-Jun is induced during the naive to primed transition, and it works to stabilize the chromatin structure and inhibit the reverse transition. Loss of c-Jun has surprisingly little effect on the naïve to primed transition, and no phenotypic effect on primed cells, however, in primed cells the loss of c-Jun leads to a failure to correctly close naïve-specific enhancers. When the primed cells are induced to reprogram to a naïve state, these enhancers are more rapidly activated when c-Jun is lost or impaired, and the conversion is more efficient. CONCLUSIONS: The results of this study indicate that c-Jun can function as a chromatin stabilizer in primed EpiSCs, to maintain the epigenetic cell type state and act as a one-way valve for cell fate conversions.

c-JUN is a barrier in hESC to cardiomyocyte transition.

Loss of c-JUN leads to early mouse embryonic death, possibly because of a failure to develop a normal cardiac system. How c-JUN regulates human cardiomyocyte cell fate remains unknown. Here, we used the in vitro differentiation of human pluripotent stem cells into cardiomyocytes to study the role of c-JUN. Surprisingly, the knockout of c-JUN improved cardiomyocyte generation, as determined by the number of TNNT2+ cells. ATAC-seq data showed that the c-JUN defect led to increased chromatin accessibility on critical regulatory elements related to cardiomyocyte development. ChIP-seq data showed that the knockout c-JUN increased RBBP5 and SETD1B expression, leading to improved H3K4me3 deposition on key genes that regulate cardiogenesis. The c-JUN KO phenotype could be copied using the histone demethylase inhibitor CPI-455, which also up-regulated H3K4me3 levels and increased cardiomyocyte generation. Single-cell RNA-seq data defined three cell branches, and knockout c-JUN activated more regulons that are related to cardiogenesis. In summary, our data demonstrated that c-JUN could regulate cardiomyocyte cell fate by modulating H3K4me3 modification and chromatin accessibility and shed light on how c-JUN regulates heart development in humans.

ZBTB7A regulates primed-to-naïve transition of pluripotent stem cells via recognition of the PNT-associated sequence by zinc fingers 1-2 and recognition of γ-globin -200 gene element by zinc fingers 1-4.

ZBTB7A, a transcription factor containing a tandem array of four Cys2-His2 zinc fingers (ZFs), is vital for multiple physiological events through directional binding to different genomic loci. Our previously determined crystal structure of ZBTB7A in complex with a GCCCCTTCCCC sequence revealed that all four ZFs (ZF1-4) are involved in binding to γ-globin -200 gene element to repress fetal haemoglobin expression. Recently, it has been reported that ZBTB7A drives primed-to-naïve transition (PNT) of pluripotent stem cells through binding to a 12-bp consensus sequence ([AAGGACCCAGAT], referred to as PNT-associated sequence). Here, we report a crystal structure of ZBTB7A ZF1-3 in complex with the PNT-associated sequence. The structure shows that ZF1 and ZF2 primarily contribute to recognizing the GACCC core sequence mimicking the half part (GCCCC) of γ-globin -200 gene element via specific hydrogen bonding and van der Waals contacts. The mutations of key residues in ZF1-2 remarkably reduce their binding affinities for the PNT-associated sequence in vitro and cannot restore epiblast stem cells to the naïve pluripotent state in vivo. Collectively, our studies demonstrate that ZBTB7A mainly employs its ZF1-2 to recognize the PNT-associated sequence but recognizes γ-globin -200 gene element via ZF1-4, providing insights into the molecular mechanism for the diversity of ZBTB7A's genomic localization.

Mechanism underlying delayed rectifying in human voltage-mediated activation Eag2 channel.

The transmembrane voltage gradient is a general physico-chemical cue that regulates diverse biological function through voltage-gated ion channels. How voltage sensing mediates ion flows remains unknown at the molecular level. Here, we report six conformations of the human Eag2 (hEag2) ranging from closed, pre-open, open, and pore dilation but non-conducting states captured by cryo-electron microscopy (cryo-EM). These multiple states illuminate dynamics of the selectivity filter and ion permeation pathway with delayed rectifier properties and Cole-Moore effect at the atomic level. Mechanistically, a short S4-S5 linker is coupled with the constrict sites to mediate voltage transducing in a non-domain-swapped configuration, resulting transitions for constrict sites of F464 and Q472 from gating to open state stabilizing for voltage energy transduction. Meanwhile, an additional potassium ion occupied at positions S6 confers the delayed rectifier property and Cole-Moore effects. These results provide insight into voltage transducing and potassium current across membrane, and shed light on the long-sought Cole-Moore effects.

Nerve regeneration by interferon intervention in aging brain.

Neural stem cells (NSCs) are shielded from viral infection by interferon (IFN) defense. As individuals age, activation of NSC decreases with a significant decline of stemness marker Sex-determining region Y box 2 (Sox2) while IFN signaling enhances (Kalamakis et al, 2019). Given that low-level type-I IFN under normal physiological conditions can promote dormant hematopoietic stem cell differentiation (Baldridge et al, 2010), whether there is an inner connection between IFN signaling and NSC function remains elusive. In this issue of EMBO Molecular Medicine, Carvajal Ibanez et al (2023) reveal that IFN-ß, a type-I interferon, induces cell-type-specific interferon-stimulated genes (ISGs) and regulates global protein synthesis by orchestrating mTOR1 activity and stem cell cycle that retain NSCs at the G0 phase and repress Sox2 expression. As a consequence, NSCs exit the activation state and become inclined to differentiation.

Species-specific rewiring of definitive endoderm developmental gene activation via endogenous retroviruses through TET1-mediated demethylation.

Transposable elements (TEs) are the major sources of lineage-specific genomic innovation and comprise nearly half of the human genome, but most of their functions remain unclear. Here, we identify that a series of endogenous retroviruses (ERVs), a TE subclass, regulate the transcriptome at the definitive endoderm stage with in vitro differentiation model from human embryonic stem cell. Notably, these ERVs perform as enhancers containing binding sites for critical transcription factors for endoderm lineage specification. Genome-wide methylation analysis shows most of these ERVs are derepressed by TET1-mediated DNA demethylation. LTR6B, a representative definitive endoderm activating ERV, contains binding sites for FOXA2 and GATA4 and governs the primate-specific expression of its neighboring developmental genes such as ERBB4 in definitive endoderm. Together, our study proposes evidence that recently evolved ERVs represent potent de novo developmental regulatory elements, which, in turn, fine-tune species-specific transcriptomes during endoderm and embryonic development.

Targeting G-quadruplex for rescuing impaired chondrogenesis in WRN-deficient stem cells.

BACKGROUND: Pathogenic mutations in WRN are a cause of premature aging disease Werner syndrome (WS). Besides accelerated aging phenotypes and cancer predisposition, patients with WS also display underdevelopment in the skeletal system, characterized by short stature, light body weight and unusually thin extremities. The reasons for these developmental defects are not completely understood and the underlying molecular mechanism remains to be elucidated. RESULTS: In this study, WRN was found to modulate transcription of short stature homeobox gene SHOX. Loss of WRN resulted in insufficient expression of SHOX, the gene dose of which is critical for driving chondrocyte differentiation. WRN could bind the G-quadruplex (G4) structures in the SHOX promoter and stimulate transcription. Aberrant formation of G4 structures in WRN-deficient cells impeded normal transcription of SHOX, thus resulting in impaired chondrogenesis. Chondrogenesis could be rescued by overexpression of WRN helicase or SHOX, suggesting that SHOX is a downstream target of WRN. Gene editing of the G4 structures in the SHOX promoter could increase SHOX expression, therefore rescuing the impaired chondrogenesis in WRN-deficient cells. CONCLUSIONS: Our data suggest that dysgenesis of the developing bone in WS might be caused by SHOX insufficiency. Aberrant formation of G4 structures in SHOX promoter suppresses SHOX expression and impairs chondrogenesis. Targeted mutagenesis in the G4 structures enhances SHOX expression and thus providing an opportunity to rescue the chondrogenic defect.

Single cell atlas of developing mouse dental germs reveals populations of CD24+ and Plac8+ odontogenic cells.

The spatiotemporal relationships in high-resolution during odontogenesis remain poorly understood. We report a cell lineage and atlas of developing mouse teeth. We performed a large-scale (92,688 cells) single cell RNA sequencing, tracing the cell trajectories during odontogenesis from embryonic days 10.5 to 16.5. Combined with an assay for transposase-accessible chromatin with high-throughput sequencing, our results suggest that mesenchymal cells show the specific transcriptome profiles to distinguish the tooth types. Subsequently, we identified key gene regulatory networks in teeth and bone formation and uncovered spatiotemporal patterns of odontogenic mesenchymal cells. CD24+ and Plac8+ cells from the mesenchyme at the bell stage were distributed in the upper half and preodontoblast layer of the dental papilla, respectively, which could individually induce nonodontogenic epithelia to form tooth-like structures. Specifically, the Plac8+ tissue we discovered is the smallest piece with the most homogenous cells that could induce tooth regeneration to date. Our work reveals previously unknown heterogeneity and spatiotemporal patterns of tooth germs that may lead to tooth regeneration for regenerative dentistry.

C3aR costimulation enhances the antitumor efficacy of CAR-T cell therapy through Th17 expansion and memory T cell induction.

Although chimeric antigen receptor (CAR)-modified adoptive T cell therapy is a promising immunotherapy for hematological malignancies, the efficacy improvement in relapsed/refractory acute lymphoblastic leukemia (ALL) with extramedullary infiltration and in multiple myeloma (MM) is still warranted. Since C3aR activation can promote the expansion of tumor-killing Th17 cells, we hypothesized that incorporating C3aR as a costimulatory domain would augment the antitumor activity of CAR-T. In this study, we introduced the C3aR domain into a CAR and generated BB-ζ-C3aR CAR-T targeting CD19 or BCMA. These new CAR-T exhibited a potent cytolytic ability to eradicate tumor cells expressing CD19 or BCMA in vitro. When administered intravenously to ALL or MM xenograft mouse models, BB-ζ-C3aR CAR-T reduced the tumor burden and improved the survival rate. Of note, these CAR-T could effectively eradicate subcutaneous CD19+ tumor cells, highlighting the therapeutic potential in extramedullary leukemia. Mechanistically, BB-ζ-C3aR CAR-T tended to exhibit a Th17 phenotype favoring tumor killing and suppressed Tregs. In addition, the induction of memory T cell in the BB-ζ-C3aR CAR-T cells indicated their long-term effects. Together, our findings suggest that the application of C3aR costimulation boosts the ability of CAR-T to eradicate aggressive tumor cells via Th17 expansion and memory T cell induction.

[Culture of pluripotent stem cell-derived hepatocytes and organoids].

Liver is one of the most important organs in the human body. Liver diseases are also a major threat to human health and longevity. Hepatic decompensation treatment is quite difficult due to multiple reasons. Extracorporeal liver support devices are unable to solve this problem, and there is a severe shortage of orthotopic liver transplant donors. Study of pluripotent stem cell-derived hepatocytes and organoids can determine not only hepatocyte fate, but also liver development, regeneration mechanisms, and pathophysiology. Furthermore, it can be used for drug screening in order to provide a stable source of functional hepatocytes for future transplantation therapy. Culture of pluripotent stem cell-derived hepatocytes and organoids has a self-organizing process similar to liver development, i.e., starting with changes in several key factors, and eventually forming functionally complex cells/organs. This paper introduces the main methods and progress of pluripotent stem cell-derived hepatocytes and organoids, with hope to provide clues for future research.

Human induced-T-to-natural killer cells have potent anti-tumour activities.

BACKGROUND: Adoptive cell therapy (ACT) is a particularly promising area of cancer immunotherapy, engineered T and NK cells that express chimeric antigen receptors (CAR) are being explored for treating hematopoietic malignancies but exhibit limited clinical benefits for solid tumour patients, successful cellular immunotherapy of solid tumors demands new strategies. METHODS: Inactivation of BCL11B were performed by CRISPR/Cas9 in human T cells. Immunophenotypic and transcriptional profiles of sgBCL11B T cells were characterized by cytometer and transcriptomics, respectively. sgBCL11B T cells are further engineered with chimeric antigen receptor. Anti-tumor activity of ITNK or CAR-ITNK cells were evaluated in preclinical and clinical studies. RESULTS: We report that inactivation of BCL11B in human CD8+ and CD4+ T cells induced their reprogramming into induced T-to-natural killer cells (ITNKs). ITNKs contained a diverse TCR repertoire; downregulated T cell-associated genes such as TCF7 and LEF1; and expressed high levels of NK cell lineage-associated genes. ITNKs and chimeric antigen receptor (CAR)-transduced ITNKs selectively lysed a variety of cancer cells in culture and suppressed the growth of solid tumors in xenograft models. In a preliminary clinical study, autologous administration of ITNKs in patients with advanced solid tumors was well tolerated, and tumor stabilization was seen in six out nine patients, with one partial remission. CONCLUSIONS: The novel ITNKs thus may be a promising novel cell source for cancer immunotherapy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03882840 . Registered 20 March 2019-Retrospectively registered.

The E3 Ligase MIB1 Promotes Proteasomal Degradation of NRF2 and Sensitizes Lung Cancer Cells to Ferroptosis.

Dysregulation of Notch signaling has been implicated in cellular transformation and tumorigenesis in a variety of cancers while potential roles of MIB1, an E3 ubiquitin ligase required for efficient Notch activation, remains to be investigated. We analyzed MIB1 expression levels in tumor samples and performed gain-of-function and loss-of-function studies in cell lines to investigate potential roles of MIB1 in epithelial-to-mesenchymal transition (EMT), cell migration, and cell survival. We found that overexpression of MIB1 is detected in a subset of lung squamous carcinoma and adenocarcinoma samples and negative correlation is observed between MIB1 expression and overall patient survival. Ectopic expression of MIB1 in A549 cells induces EMT and stimulates cell migration via a Notch-dependent pathway. Meanwhile, MIB1 stimulates the degradation of nuclear factor erythroid 2-related factor 2 (NRF2) in a Notch-independent manner and disrupts the antioxidant capacity of cells, rendering them more sensitive to inducers of ferroptosis. On the other hand, MIB1 knockout induces accumulation of NRF2 and resistance to ferroptosis. Collectively, these results indicate that MIB1 may function as a positive regulator of ferroptosis through targeted degradation of the master antioxidant transcription factor NRF2. IMPLICATIONS: This study identifies a MIB1-induced proteasomal degradation pathway for NRF2 and reveals elevated ferroptosis sensitivity in MIB1-overexpressing cells which may provide novel insights into the treatment of MIB1-overexpressing cancers.

UBE2O and USP7 co-regulate RECQL4 ubiquitinylation and homologous recombination-mediated DNA repair.

The human RecQ DNA helicase, RECQL4, plays a pivotal role in maintaining genomic stability by regulating the DNA double-strand breaks (DSBs) repair pathway, and is, thus, involved in the regulation of aging and cancer onset. However, the regulatory mechanisms of RECQL4, especially its post-translational modifications, have not been fully illustrated. Here, we report that the E2/E3 hybrid ubiquitin-conjugating enzyme, UBE2O, physically interacts with RECQL4, and mediates the multi-monoubiquitinylation of RECQL4, subsequently leading to its proteasomal degradation. Functionally, we showed that UBE2O inhibits homologous recombination (HR)-mediated DSBs repair, and this inhibition depends on its E2 catalytic activity and RECQL4 expression. Mechanistically, we showed that UBE2O attenuates the interaction of RECQL4 and DNA damage repair proteins, the MRE11-RAD50-NBS1 complex and CtIP. Furthermore, we show that deubiquitinylase USP7 interacts with both UBE2O and RECQL4, and in that it antagonizes UBE2O-mediated regulation of RECQL4 stability and function. Collectively, we found a novel regulatory mechanism of ubiquitin-mediated regulation of RECQL4 in HR-mediated DSBs repair process.

Cancer stem cells: advances in biology and clinical translation-a Keystone Symposia report.

The test for the cancer stem cell (CSC) hypothesis is to find a target expressed on all, and only CSCs in a patient tumor, then eliminate all cells with that target that eliminates the cancer. That test has not yet been achieved, but CSC diagnostics and targets found on CSCs and some other cells have resulted in a few clinically relevant therapies. However, it has become apparent that eliminating the subset of tumor cells characterized by self-renewal properties is essential for long-term tumor control. CSCs are able to regenerate and initiate tumor growth, recapitulating the heterogeneity present in the tumor before treatment. As great progress has been made in identifying and elucidating the biology of CSCs as well as their interactions with the tumor microenvironment, the time seems ripe for novel therapeutic strategies that target CSCs to find clinical applicability. On May 19-21, 2021, researchers in cancer stem cells met virtually for the Keystone eSymposium "Cancer Stem Cells: Advances in Biology and Clinical Translation" to discuss recent advances in the understanding of CSCs as well as clinical efforts to target these populations.

Evaluation of CML TKI Induced Cardiovascular Toxicity and Development of Potential Rescue Strategies in a Zebrafish Model.

Tyrosine kinase inhibitors (TKIs) to BCR-ABL1 have been successfully used to treat chronic myeloid leukemia (CML), however, multiple TKI-associated adverse events have been reported and become an emerging problem in patients. The mechanisms of TKI-induced toxicity are not fully understood and it remains challenging to predict potential cardiovascular toxicity of a compound. In this study, we established a zebrafish model to evaluate potential in vivo cardiovascular toxicity of TKIs. We treated the endothelium labeled Tg(kdrl:EGFP) transgenic zebrafish embryos with TKIs then performed confocal imaging to evaluate their vascular structure and function. We found that among FDA approved CML TKIs, ponatinib (the only approved TKI that is efficacious to T315I mutation) is the most toxic one. We then evaluated safety profiles of several clinical stage kinase inhibitors that can target T315I and found that HQP1351 treatment leads to vasculopathies similar to those induced by ponatinib while the allosteric ABL inhibitor asciminib does not induce noticeable cardiovascular defects, indicating it could be a promising therapeutic reagent for patients with T315I mutation. We then performed proof-of-principle study to rescue those TKI-induced cardiovascular toxicities and found that, among commonly used anti-hypertensive drugs, angiotensin receptor blockers such as azilsartan and valsartan are able to reduce ponatinib or HQP1351 induced cardiovascular toxicities. Together, this study establishes a zebrafish model that can be useful to evaluate cardiovascular toxicity of TKIs as well as to develop strategies to minimize TKI-induced adverse events.

Identification of New Transcription Factors that Can Promote Pluripotent Reprogramming.

BACKGROUND: Four transcription factors, Oct4, Sox2, Klf4, and c-Myc (the Yamanka factors), can reprogram somatic cells to induced pluripotent stem cells (iPSCs). Many studies have provided a number of alternative combinations to the non-Yamanaka factors. However, it is clear that many additional transcription factors that can generate iPSCs remain to be discovered. METHODS: The chromatin accessibility and transcriptional level of human embryonic stem cells and human urine cells were compared by Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) and RNA sequencing (RNA-seq) to identify potential reprogramming factors. Selected transcription factors were employed to reprogram urine cells, and the reprogramming efficiency was measured. Urine-derived iPSCs were detected for pluripotency by Immunofluorescence, quantitative polymerase chain reaction, RNA sequencing and teratoma formation test. Finally, we assessed the differentiation potential of the new iPSCs to cardiomyocytes in vitro. RESULTS: ATAC-seq and RNA-seq datasets predicted TEAD2, TEAD4 and ZIC3 as potential factors involved in urine cell reprogramming. Transfection of TEAD2, TEAD4 and ZIC3 (in the presence of Yamanaka factors) significantly improved the reprogramming efficiency of urine cells. We confirmed that the newly generated iPSCs possessed pluripotency characteristics similar to normal H1 embryonic stem cells. We also confirmed that the new iPSCs could differentiate to functional cardiomyocytes. CONCLUSIONS: In conclusion, TEAD2, TEAD4 and ZIC3 can increase the efficiency of reprogramming human urine cells into iPSCs, and provides a new stem cell sources for the clinical application and modeling of cardiovascular disease.

Hypoproliferative human neural progenitor cell xenografts survived extendedly in the brain of immunocompetent rats.

BACKGROUND: There is a huge controversy about whether xenograft or allograft in the "immune-privileged" brain needs immunosuppression. In animal studies, the prevailing sophisticated use of immunosuppression or immunodeficient animal is detrimental for the recipients, which results in a short lifespan of animals, confounds functional behavioral readout of the graft benefits, and discourages long-term follow-up. METHODS: Neuron-restricted neural progenitor cells (NPCs) were derived from human embryonic stem cells (ESCs, including H1, its gene-modified cell lines for better visualization, and HN4), propagated for different passages, and then transplanted into the brain of immunocompetent rats without immunosuppressants. The graft survivals, their cell fates, and HLA expression levels were examined over time (up to 4 months after transplantation). We compared the survival capability of NPCs from different passages and in different transplantation sites (intra-parenchyma vs. para- and intra-cerebroventricle). The host responses to the grafts were also investigated. RESULTS: Our results show that human ESC-derived neuron-restricted NPCs survive extendedly in adult rat brain parenchyma with no need of immunosuppression whereas a late-onset graft rejection seems inevitable. Both donor HLA antigens and host MHC-II expression level remain relatively low with little change over time and cannot predict the late-onset rejection. The intra-/para-cerebroventricular human grafts are more vulnerable to the immune attack than the intrastriatal counterparts. Prevention of graft hyperplasia by using hypoproliferative late passaged human NPCs further significantly extends the graft survival time. Our new data also shows that a subpopulation of host microglia upregulate MHC-II expression in response to the human graft, but fail to present the human antigen to the host immune system, suggestive of the immune-isolation role of the blood-brain barrier (BBB). CONCLUSIONS: The present study confirms the "immune privilege" of the brain parenchyma and, more importantly, unveils that choosing hypoproliferative NPCs for transplantation can benefit graft outcome in terms of both lower tumor-genic risk and the prolonged survival time without immunosuppression.

SS18 regulates pluripotent-somatic transition through phase separation.

The transition from pluripotent to somatic states marks a critical event in mammalian development, but remains largely unresolved. Here we report the identification of SS18 as a regulator for pluripotent to somatic transition or PST by CRISPR-based whole genome screens. Mechanistically, SS18 forms microscopic condensates in nuclei through a C-terminal intrinsically disordered region (IDR) rich in tyrosine, which, once mutated, no longer form condensates nor rescue SS18-/- defect in PST. Yet, the IDR alone is not sufficient to rescue the defect even though it can form condensates indistinguishable from the wild type protein. We further show that its N-terminal 70aa is required for PST by interacting with the Brg/Brahma-associated factor (BAF) complex, and remains functional even swapped onto unrelated IDRs or even an artificial 24 tyrosine polypeptide. Finally, we show that SS18 mediates BAF assembly through phase separation to regulate PST. These studies suggest that SS18 plays a role in the pluripotent to somatic interface and undergoes liquid-liquid phase separation through a unique tyrosine-based mechanism.

AP-1 activity is a major barrier of human somatic cell reprogramming.

Human induced pluripotent stem cells (iPSCs) technology has been widely applied to cell regeneration and disease modeling. However, most mechanism of somatic reprogramming is studied on mouse system, which is not always generic in human. Consequently, the generation of human iPSCs remains inefficient. Here, we map the chromatin accessibility dynamics during the induction of human iPSCs from urine cells. Comparing to the mouse system, we found that the closing of somatic loci is much slower in human. Moreover, a conserved AP-1 motif is highly enriched among the closed loci. The introduction of AP-1 repressor, JDP2, enhances human reprogramming and facilitates the reactivation of pluripotent genes. However, ESRRB, KDM2B and SALL4, several known pluripotent factors promoting mouse somatic reprogramming fail to enhance human iPSC generation. Mechanistically, we reveal that JDP2 promotes the closing of somatic loci enriching AP-1 motifs to enhance human reprogramming. Furthermore, JDP2 can rescue reprogramming deficiency without MYC or KLF4. These results indicate AP-1 activity is a major barrier to prevent chromatin remodeling during somatic cell reprogramming.