Biology subjects

Zheng, X. Y.

Publications and source records attributed to Zheng, X. Y..

10 recordsLinked to original sources

bioRxiv2026

Enforced ZFP281 expression delays breast cancer initiation and can provide lifelong protection against breast cancer metastasis

Breast cancer metastatic reactivation and its links to mammary development are largely unknown. Here, using conditional knockout and overexpression in normal and HER2+ mammary glands, we show that the dormancy regulator ZFP281 promotes branching and dissemination while suppressing growth, and its overexpression can even override HER2-driven cancer initiation. Notably, while ZFP281 does not limit HER2-driven early dissemination, it constrains DCC plasticity, confining cells to a dormant mesenchymal/hybrid-like state and effectively suppressing metastasis throughout the mouse lifespan. ZFP281 is induced by estrogen, progesterone, and glucocorticoid signaling, and RNA sequencing of early lesions revealed that it regulates glutathione metabolism and ferroptosis, potentially supporting fitness during dormancy, while repressing angiogenesis, Th17-like inflammation, innate immune genes, and pro-inflammatory programs that might otherwise trigger awakening. Integrating these findings with human data, we show that DCIS and IBC (invasive breast cancer) lesions that later relapse are selectively enriched for ZFP281-regulated M-like and dormancy signatures and, after pregnancy, depleted for a ZFP281-induced stress-autophagy module, indicating that erosion or imbalance of these programs marks lesions that seed DCCs with higher reactivation potential. We propose that ZFP281 acts as a hormone-regulated dormancy gatekeeper that uncouples dissemination from growth, enforcing a metabolically fit, angiogenesis-low, immune-evasive dormant state in breast DCCs, thereby shaping the timing of metastatic relapse and potentially exploitable for durable prevention of metastasis. STATEMENT OF SIGNIFICANCEZFP281, a hormone-regulated dormancy gatekeeper, uncouples dissemination from growth and constrains DCCs into long-term arrest, defining human gene signatures that distinguish dormancy-prone from awakening-prone lesions and predict breast cancer relapse dynamics.

cancer biology↗

bioRxiv2024

Abstract rule generalization for composing novel meaning recruits the frontoparietal control network

The ability to generalize previously learned knowledge to novel situations is crucial for adaptive behavior, representing a form of cognitive flexibility that is particularly relevant in language. Humans excel at combining linguistic building blocks to infer the meanings of novel compositional words, such as "un-reject-able-ish". How do we accomplish this? While recent research on compositional generalization in relational memory, action planning and vision strongly implicates a medial prefrontal-hippocampal network (Baram et al., 2021; Barron et al., 2020; Schwartenbeck et al., 2023), it remains unclear whether the same network supports compositional inference in language. To this end, we trained participants on an artificial language in which the meanings of compositional words could be derived from known stems and unknown affixes, using abstract affixation rules (e.g., "good-kla" which means "bad", where "-kla" reverses the meaning of the stem word "good"). According to these rules, word meaning depended on the sequential relation between the stem and the affix (i.e., pre- vs. post-stem). During fMRI, participants performed a semantic priming task, with novel compositional words as either sequential order congruent (e.g., "white-kla") or incongruent primes (e.g., "kla-white"), and synonyms of the composed meaning as targets ("black"). Our results show that the compositional process engages a broad temporoparietal network, including the hippocampus, while the composed meanings are represented in left-lateralized language areas. Notably, newly composed meanings were decodable already at the time of the prime. Finally, we found that the composition process recruits abstract structure rule representations in a lateral frontoparietal network, rather than the predicted medial frontotemporal network, perhaps because abstract rules in language are more readily formatted as production rules rather than as relational map structures.

neuroscience↗

bioRxiv2024

H2AK119ub dynamics controls hair follicle stem cell quiescence

The transition of stem cells from a quiescent state to an active state is a finely tuned process that requires the dismantling of the quiescence program and the establishment of a cell cycle-promoting transcriptional landscape. Whether epigenetic processes control stem cell states to promote the regeneration of adult tissues remains elusive. In this study, we show that a repressive histone modification, H2AK119ub, is dynamic between quiescent and active hair follicle stem cells (HFSCs) in the adult murine skin. Ablation of H2AK119ub in HFSCs leads to impaired quiescence leading to premature activation and an eventual exhaustion of HFSC pool. Transcriptional and chromatin studies revealed that H2AK119ub directly represses a proliferation promoting transcriptional program in the HFSCs to preserve quiescence. Lastly, we identify that the inhibitory FGF signaling produced by the hair follicle niche keratinocytes maintains H2AK119ub in quiescent HFSCs. Together, these findings reveal that a repressive histone mark, H2AK119ub, is under the dynamic regulation of inhibitory niche signaling to prevent the untimely establishment of an activated state to preserve SC function and longevity.

cell biology↗

bioRxiv2024

Comprehensive single cell transcriptomics analysis of murine osteosarcoma uncovers Skp2 function in metastasis, genomic instability and immune activation and reveals additional target pathways

Osteosarcoma (OS) is the most common primary pediatric bone malignancy. One promising new therapeutic target is SKP2, encoding a substrate recognition factor of the SCF E3 ubiquitin ligase responsible for ubiquitination and proteasome degradation of substrate p27, thus driving cellular proliferation. We have shown previously that knockout of Skp2 in an immunocompetent transgenic mouse model of OS improved survival, drove apoptosis, and induced tumor inflammation. Here, we applied single-cell RNA-sequencing (scRNA-seq) to study primary OS tumors derived from Osx-Cre driven conditional knockout of Rb1 and Trp53. We showed that murine OS models recapitulate the tumor heterogeneity and microenvironment complexity observed in patient tumors. We further compared this model with OS models with functional disruption of Skp2: one with Skp2 knockout and the other with the Skp2-p27 interaction disrupted (resulting in p27 overexpression). We found reduction of T cell exhaustion and upregulation of interferon activation, along with evidence of replicative and endoplasmic reticulum-related stress in the Skp2 disruption models, and showed that interferon induction was correlated with improved survival in OS patients. Additionally, our scRNA-seq analysis uncovered decreased activities of metastasis-related gene signatures in the Skp2-disrupted OS, which we validated by observation of a strong reduction in lung metastasis in the Skp2 knockout mice. Finally, we report several potential mechanisms of escape from targeting Skp2 in OS, including upregulation of Myc targets, DNA copy number amplification and overexpression of alternative E3 ligase genes, and potential alternative lineage activation. These mechanistic insights into OS tumor biology and Skp2 function suggest novel targets for new, synergistic therapies, while the data and our comprehensive analysis may serve as a public resource for further big data-driven OS research.

cancer biology↗

bioRxiv2024

scDAPP: a comprehensive single-cell transcriptomics analysis pipeline optimized for cross-group comparison

Single-cell transcriptomics profiling has increasingly been used to evaluate cross-group differences in cell population and cell-type gene expression. This often leads to large datasets with complex experimental designs that need advanced comparative analysis. Concurrently, bioinformatics software and analytic approaches also become more diverse and constantly undergo improvement. Thus, there is an increased need for automated and standardized data processing and analysis pipelines, which should be efficient and flexible too. To address these, we develop the single-cell Differential Analysis and Processing Pipeline (scDAPP), a R-based workflow for comparative analysis of single cell (or nucleus) transcriptomic data between two or more groups and at the levels of single cells or "pseudobulking" samples. The pipeline automates many steps of pre-processing using data-learnt parameters, uses previously benchmarked software, and generates comprehensive intermediate data and final results that are valuable for both beginners and experts of scRNA-seq analysis. Moreover, the analytic reports, augmented by extensive data visualization, increase the transparency of computational analysis and parameter choices, while facilitate users to go seamlessly from raw data to biological interpretation. Availability and ImplementationscDAPP is freely available for non-commercial usage as an R package under the MIT license. Source code, documentation and sample data are available at the GitHub (https://github.com/bioinfoDZ/scDAPP).

bioinformatics↗

bioRxiv2024

Domain-general cognitive control processes in bilingual switching: evidence from midfrontal theta oscillations

Language control in bilingual speakers is thought to be implicated in effectively switching between languages, inhibiting the non-intended language, and continuously monitoring what to say and what has been said. It has been a matter of controversy concerning whether language control operates in a comparable manner to cognitive control processes in non-linguistic domains (domain-general) or if it is exclusive to language processing (domain-specific). As midfrontal theta oscillations have been considered as an index of cognitive control, examining whether a midfrontal theta effect is evident in tasks requiring bilingual control could bring new insights to the ongoing debate. To this end, we reanalysed the EEG data from two previous bilingual production studies where Dutch-English bilinguals named pictures based on colour cues. Specifically, we focused on three fundamental control processes in bilingual production: switching between languages, inhibition of the nontarget language, and monitoring of speech errors. Theta power increase was observed in switch trials compared to repeat trials, with a midfrontal scalp distribution. However, this midfrontal theta effect was absent in switch trials following a short sequence of same-language trials compared to a long sequence, suggesting a missing modulation of inhibitory control. Similarly, increased midfrontal theta power was observed when participants failed to switch to the intended language compared to correct responses. Altogether, these findings tentatively support the involvement of domain-general cognitive control mechanisms in bilingual switching.

neuroscience↗

bioRxiv2022

Parallel cognitive maps for short-term statistical and long-term semantic relationships in the hippocampal formation

The hippocampal-entorhinal system uses cognitive maps to represent spatial knowledge and other types of relational information, such as the transition probabilities between objects. However, objects can often be characterized in terms of different types of relations simultaneously, e.g. semantic similarities learned over the course of a lifetime as well as transitions experienced over a brief timeframe in an experimental setting. Here we ask how the hippocampal formation handles the embedding of stimuli in multiple relational structures that differ vastly in terms of their mode and timescale of acquisition: Does it integrate the different stimulus dimensions into one conjunctive map, or is each dimension represented in a parallel map? To this end, we reanalyzed functional magnetic resonance imaging (fMRI) data from Garvert et al. (2017) that had previously revealed an entorhinal map which coded for newly learnt statistical regularities. We used a triplet odd-one-out task to construct a semantic distance matrix for presented items and applied fMRI adaptation analysis to show that the degree of similarity of representations in bilateral hippocampus decreases as a function of semantic distance between presented objects. Importantly, while both maps localize to the hippocampal formation, this semantic map is anatomically distinct from the originally described entorhinal map. This finding supports the idea that the hippocampal-entorhinal system forms parallel cognitive maps reflecting the embedding of objects in diverse relational structures.

neuroscience↗

bioRxiv2022

Neural oscillations in the aging brain associated with interference control in word production

Speaking is not only about retrieving words and structuring them into sentences, but it also requires top-down control to plan and execute speech. In previous electrophysiological research with young-adult speakers, mid-frontal theta oscillations have been observed using a picture-word interference paradigm. With this paradigm, participants name pictures while ignoring superimposed distractor words. In particular, mid-frontal theta power increases for categorically related distractors relative to other types of distractors, reflecting the top-down interference control in resolving the competition between processing streams during word production (Piai, Roelofs, Jensen, Schoffelen, & Bonnefond, 2014). In the present study, we conceptually replicated the magnetoencephalography study by Piai et al. (2014) with an older group of healthy adults (mean age of 60 years). Behaviorally, we replicated distractor semantic interference and Stroop-like interference effects usually observed in young adults. However, we did not find the corresponding theta modulation associated with these interference effects on the neural level. Instead, we found beta power decreases for both effects, mostly pronounced in the left posterior temporal and inferior parietal cortex. The distinct spectro-spatial-temporal profile of the oscillatory effects in the older population suggests different underlying dynamics relative to the midline frontal effect previously found in young-adult speakers. Our results indicate that the neural underpinnings of top-down interference control may be modified by aging, and that the mid-frontal theta cannot be the exclusive mechanism enabling interference control during spoken word production.

neuroscience↗

bioRxiv2022

Midfrontal theta is associated with errors, but no evidence for a link with error-related memory

Midfrontal theta is widely observed in situations with increased demand for cognitive control, such as monitoring response errors. It also plays an important role in the cognitive control involved in memory, supporting processes like the binding of single items into a memory representation or encoding contextual information. In the current study, we explored the link between midfrontal theta and error-related memory. To this end, we recorded EEG from 31 participants while they performed a modified Flanker task. Their memory for the errors made during the task was assessed after each experimental block, and its relationship with error-related midfrontal theta effects was investigated. We have replicated the error-related increase in midfrontal theta power, reported in previous literature. However, this error-related theta effect could not predict subsequent memory of the committed errors. Our findings add to a growing literature on the prefrontal cortex-guided control process in error monitoring and episodic memory.

neuroscience↗

bioRxiv2018

RUNX proteins desensitize multiple myeloma to lenalidomide via protecting IKZFs from degradation

Ikaros family zinc finger protein 1 and 3 (IKZF1 and IKZF3) are transcription factors that promote multiple myeloma (MM) proliferation. The immunomodulatory imide drug (IMiD) lenalidomide promotes myeloma cell death via Cereblon (CRBN)-dependent ubiquitylation and proteasome-dependent degradation of IKZF1 and IKZF3. Although IMiDs have been used as first-line drugs for MM, the overall survival of refractory MM patients remains poor and demands the identification of novel agents to potentiate the therapeutic effect of IMiDs. Using an unbiased screen based on mass spectrometry, we identified the Runt-related transcription factor 1 and 3 (RUNX1 and RUNX3) as interactors of IKZF1 and IKZF3. Interaction with RUNX1 and RUNX3 inhibits CRBN-dependent binding, ubiquitylation and degradation of IKZF1 and IKZF3 upon lenalidomide treatment. Inhibition of RUNXs, via genetic ablation or a small molecule (AI-10-104), results in sensitization of myeloma cell lines and primary tumors to lenalidomide. Thus, RUNX inhibition represents a valuable therapeutic opportunity to potentiate IMiDs therapy for the treatment of multiple myeloma.

cancer biology↗