Biology subjects

Wang, S.-P.

Publications and source records attributed to Wang, S.-P..

5 recordsLinked to original sources

bioRxiv2026

Autoimmune diabetes-dependent c-Maf SUMOylation licenses inflammatory bowel disease by reshaping the gut microbiota

We have previously demonstrated a critical role of c-Maf SUMOylation in the regulation of autoimmune diabetogenesis, but its physiological relevance to and potential clinical impact on gut inflammation need further elucidation. Here, integrating a 14-year population-based time-trend cohort study of 139,204 type 1 diabetes patients with experiments in non-obese diabetic mice, we illustrated that autoimmune diabetes confers resistance to colitis mediated by an impaired c-Maf SUMOylation-driven IL-21-IgA axis. Utilizing T cell-specific c-Maf SUMOylation site-mutated mice, we further demonstrated that SUMOylation-defective c-Maf enhances IL-21 expression in CD4+ T cells to promote fecal IgA production and colitis resistance via microbiota remodeling, specifically through Lactobacillus johnsonii enrichment and activating lithocholic acid (LCA)-mediated AMPK anti-inflammatory pathway. Pharmacological HDAC2 inhibition by BRD6688 promotes c-Maf-mediated IL-21 and suppresses colitis in PBMC-humanized mice. Altogether, we revealed how SUMOylation reciprocally modulates the inflammatory process between autoimmune diabetes and colitis in a T cell-restricted and single transcription factor-based manner.

immunology↗

bioRxiv2024

The tumor-maintaining function of UTX/KDM6A in DNA replication and the PARP1-dependent repair pathway

Histone H3K27 demethylase UTX (aka KDM6A) is mutated in many human cancers, suggesting its tumor suppressive role during cancer development. However, most tumors still express wild-type UTX/KDM6A and its function is not always linked to tumor suppression. Here, we present evidence of UTX/KDM6As role in sustaining tumor growth, revealing its function in tumor maintenance. We find that UTX/KDM6A sustains tumor cell cycling and survival via regulating DNA replication-associated transcriptional programs in a demethylase-independent manner. UTX/KDM6A can also interact with PARP1 and facilitate its recruitment to DNA lesions. Therefore, UTX/KDM6A depletion disrupts DNA replication and repair pathways, activating ATM-CHK2 and ATR-CHK1 signaling pathways and triggering S and G2/M checkpoints, leading to a pronounced defect in tumor growth. Analysis of human cancer xenograft models further demonstrates that knockdown of UTX/KDM6A by RNA-interference, rather than inhibition of its enzymatic activity via GSK-J4, shows potent anticancer effects. Dual inhibition of UTX/KDM6A and ATR further demonstrates synergistic anticancer activities. Our work highlights UTX/KDM6A as a potential therapeutic target for cancer treatment, especially when combined with ATR inhibition. HighlightsO_LIUTX/KDM6A contributes to tumor maintenance by promoting the growth and survival of tumor cells C_LIO_LITumor cells rely on UTX/KDM6A to maintain DNA replication, cell cycling, and DNA damage repair C_LIO_LIUTX/KDM6A depletion triggers S and G2/M checkpoints via activating ATM-CHK2 and ATR-CHK1 signaling pathways C_LIO_LITargeting UTX/KDM6A may prove to be an innovative strategy for cancer therapy, whether employed independently or in conjunction with ATR inhibitors. C_LI The Paper ExplainedO_ST_ABSProblemC_ST_ABSThe aggressive growth of tumors relies significantly on heightened proliferation rates and genomic instability, which necessitate robust DNA replication machinery and efficient DNA damage repair mechanisms for tumor cell survival and proliferation. UTX/KDM6A, a histone demethylase central to chromatin and epigenetic regulation, is commonly mutated in various human cancers. However, its role as a tumor suppressor or promoter remains unclear across different cancer contexts. This study delves into the potential tumor-maintaining role of UTX/KDM6A in cancer progression and tumorigenesis, establishing the mechanistic foundation for its tumor-promoting function. ResultsWe uncover UTX/KDM6As crucial role in tumor maintenance via its participation in DNA replication and repair pathways. Surprisingly, we find that its histone demethylase activity is dispensable for these functions, implying an alternative role as a scaffold protein. Consequently, our findings suggest that targeting the entire UTX/KDM6A gene or protein, rather than inhibiting its enzymatic activity, holds promise as a therapeutic strategy for tumors dependent on its tumor-maintaining function. ImpactThis study unveils UTX/KDM6As multifaceted role in cancer progression, shedding light on its diverse contributions to tumorigenesis. Our findings suggest promising therapeutic strategies for cancer treatment, highlighting the importance of targeting UTX/KDM6A and its impact on DNA replication and repair pathways. These discoveries set the stage for further exploration of UTX/KDM6A-mediated mechanisms in clinical settings, indicating potential applications in future clinical trials and combination therapy strategies.

cancer biology↗

bioRxiv2023

Multidimensional responses of ecological stability to eutrophication in grasslands

Eutrophication usually impacts biodiversity, species composition, and functioning of grassland communities. Whether such effects propagate to influence the stability of these community aspects is unknown. Using standardized experiments across 55 global grasslands, we quantified the effects of nutrient addition on five stability facets (i.e., temporal invariability and resistance during and recovery after dry and wet growing seasons) for three community aspects (i.e., aboveground biomass, community composition, and species richness). Nutrient addition reduced the temporal invariability and resistance of species richness and community composition, but not biomass, during dry and wet growing seasons. Temporal invariability and resistance during, but not recovery after, dry and wet growing seasons were strongly positively correlated in both ambient and eutrophic conditions. This indicates that maintaining and restoring the stability of plant communities requires increasing resistance rather than recovery. Harnessing the complexity of ecological stability provides new insights for grassland ecosystem sustainability in a changing world.

ecology↗

bioRxiv2022

Nutrient addition increases grassland resistance during dry and wet climate extremes despite functional diversity loss

O_LINutrient enrichment impacts grassland plant diversity such as species richness, functional trait composition and diversity, but whether and how these changes affect ecosystem stability in the face of increasing climate extremes remains largely unknown. C_LIO_LIWe quantified the direct and diversity-mediated effects of nutrient addition (by nitrogen, phosphorus, and potassium) on the stability of aboveground biomass production in 10 long-term grassland experimental sites. We measured five facets of stability as the temporal invariability, resistance during and recovery after extreme dry and wet growing seasons. C_LIO_LILeaf traits (leaf carbon, nitrogen, phosphorus, potassium, and specific leaf area) were measured under ambient and nutrient addition conditions in the field and were used to construct the leaf economic spectrum (LES). We calculated functional trait composition and diversity of LES and of single leaf traits. We quantified the contribution of intraspecific trait shifts and species replacement to change in functional trait composition as responses to nutrient addition and its implications for ecosystem stability. C_LIO_LINutrient addition decreased functional trait diversity and drove grassland communities to the faster end of the LES primarily through intraspecific trait shifts, suggesting that intraspecific trait shifts should be included for accurately predicting ecosystem stability. Moreover, the change in functional trait diversity of the LES in turn influenced different facets of stability. That said, these diversity-mediated effects were overall weak and/or overwhelmed by the direct effects of nutrient addition on stability. As a result, nutrient addition did not strongly impact any of the stability facets. These results were generally consistent using individual leaf traits but the dominant pathways differed. Importantly, major influencing pathways differed using average trait values extracted from global trait databases (e.g. TRY). C_LIO_LISynthesis. Investigating changes in multiple facets of plant diversity and their impacts on multidimensional stability under global changes such as nutrient enrichment can improve our understanding of the processes and mechanisms maintaining ecosystem stability. C_LI

ecology↗

bioRxiv2021

Dominant species determine ecosystem stability across scales in Inner Mongolian grassland

There is an urgent need to extend knowledge on ecosystem temporal stability to larger spatial scales because presently available local-scale studies generally do not provide effective guide for management and conservation decisions at the level of an entire region with diverse plant communities. We investigated temporal stability of plant biomass production across spatial scales and hierarchical levels of community organization and analyzed impacts of dominant species, species diversity and climatic factors using a multi-site survey of Inner Mongolian grassland. We found that temporal stability at a large spatial scale, i.e. a large area aggregating multiple local communities, was related to temporal stability of and asynchrony among spatially separated local communities and large-scale population dynamics of dominant species, yet not to species richness. Additionally, a lower mean and higher variation of yearly precipitation destabilized communities at local and large scales by destabilizing dominant species population dynamics. We argue that, for semi-arid temperate grassland, dynamics and precipitation responses of dominant species and asynchrony among local communities stabilize ecosystems at large spatial scales. Our results indicate that reduced amounts and increased variation of precipitation may present key threats to the sustainable provision of biological products and services to human well-being in this region.

ecology↗