Corrigendum to Genome-wide CRISPR screen identifies a cytokine-enhancer circuit driving HIF-2α activation in renal cancer.
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Published Erratum↗
Biomedical subjects
Jin Zhou
Publications and source records attributed to Jin Zhou.
Multi-omics analysis identifies key genes and functional loci affecting teat number in American Large White and Landrace pigs and their application in optimizing genomic selection models.
BACKGROUND: Teat number is a crucial economic trait in pigs. It directly affects the ability of sows to lactate, which in turn influences the survival and health of piglets. The teat number of French Large White pigs is close to 16, while the teat number of American Large White and Landrace pigs is about 14. In order to improve the teat number of American Landrace and Large White pigs through molecular approaches and precise breeding techniques, we genotyped 2,131 American Landrace and 4,564 American Large White with teat number phenotype using a 50 K SNP chip. Then, the SNP-chip data was imputed to the level of whole-genome sequencing (iWGS). Based on iWGS data, we conducted GWAS to identify novel, significant SNPs associated with teat number and to incorporate them into genomic selection. RESULTS: In Landrace pigs, significant SNPs for TTN mapped to SSC2, SSC7, SSC8, and SSC14; the SSC8 and SSC14 effects are novel. LTN mapped to SSC7, RTN to SSC7 and SSC8. The lead SSC7 SNP explained 2.60% of TTN phenotypic variance. In Large White pigs, significant SNPs were detected on SSC7 and SSC10 for TTN; SSC7, SSC10, and SSC12 for LTN; and SSC7 and SSC10 for RTN. The most significant locus on SSC7 accounted for 2.99% of the phenotypic variance in TTN. Additionally, a multi-population meta-analysis detected significant novel SNPs for LTN on SSC1 and SSC8. By utilizing Bayesian fine mapping, the most precise QTL confidence interval on SSC7 for both TTN and RTN in Large White pigs was reduced to 40 kb. By integrating functional gene annotation with RNA-seq and ATAC-seq data from Erhualian and Bamaxiang pigs mammary placodes at embryonic day 26, we prioritized PTPN13, TRPV3, ZDHHC13, and BRD2 as novel candidate genes for teat number. We then incorporated the significant SNPs to GBLUP and benchmarked genomic-selection accuracy. In both breeds, fitting the top SNP as fixed maximized prediction for TTN and RTN, whereas treating all significant loci as an additional random effect optimized LTN. CONCLUSIONS: Our findings provide a theoretical basis for dissecting new key genes affecting teat number and for advancing molecular breeding of teat number in pigs.
Animals↗
Genome-wide CRISPR screen identifies a cytokine-enhancer circuit driving HIF-2α activation in renal cancer.
Resistance to HIF-2α inhibitors such as belzutifan underscores the need to better understand how HIF-2α is transcriptionally regulated in clear cell renal cell carcinoma (ccRCC). Here, we uncover a cytokine-driven enhancer mechanism that sustains HIF-2α expression through the JAK1/STAT3 signaling pathway. Using a genome-wide CRISPR screen in von Hippel-Lindau-deficient (VHL-deficient) ccRCC cells, we identified SOCS3 as a key negative regulator of HIF-2α. Mechanistically, loss of SOCS3 activates JAK1/STAT3 signaling, leading to the recruitment of STAT3 to distal enhancers upstream of endothelial PAS domain-containing protein (EPAS1) that physically loop to its promoter to drive HIF-2α transcription. This cytokine-enhancer circuit was recapitulated in samples from patients with ccRCC and functionally validated using CRISPR interference (CRISPRi), which disrupted enhancer-promoter looping and reduced tumor growth in HIF-2α-dependent models. SOCS3 overexpression or pharmacologic inhibition of JAK1/STAT3 markedly suppressed HIF-2α expression and tumor progression both in vitro and in vivo. Unlike prior studies focusing on VHL/HIF occupancy-driven enhancer activation, this work defines a trans-acting cytokine-JAK1/STAT3 pathway that transcriptionally controls EPAS1. Together, these findings reveal a targetable enhancer mechanism that sustains HIF-2α expression and suggest that combined inhibition of JAK1/STAT3 and HIF-2α may overcome therapeutic resistance in kidney cancer.
Basic Helix-Loop-Helix Proteins↗
Hepatocyte-specific CLSTN3B ablation impairs lipid droplet maturation and alleviates diet-induced steatohepatitis in mice.
Excessive lipid accumulation in hepatocytes, a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD), can lead to progressive liver damage. Understanding the molecular mechanisms governing lipid storage in hepatocytes is essential for identifying therapeutic targets to halt MASLD progression. Here, we show a pivotal role for the protein calsyntenin 3β (CLSTN3B) in promoting lipid droplet (LD) maturation and lipid storage in hepatocytes. Previously characterized as an endoplasmic reticulum (ER)-LD contact protein that facilitates LD maturation in adipocytes, we now show that CLSTN3B expression is strongly induced in mouse hepatocytes by peroxisome proliferator-activated receptor gamma (PPARγ) in response to dietary caloric excess. Hepatocyte-specific deletion of CLSTN3B in mice significantly increases energy expenditure, reduces metabolic efficiency, and protects against diet-induced hepatic steatosis and fibrosis. Mechanistically, CLSTN3B deficiency causes reduced LD phospholipid coverage and increased lipase recruitment. This results in enhanced fatty acid oxidation driven by a futile cycle of lipolysis and re-esterification. Notably, human clinical data reveal a positive correlation between hepatic CLSTN3B expression and MASLD severity and progression, emphasizing its relevance to human disease. Together, our findings establish CLSTN3B as a key regulator of hepatocyte lipid storage and metabolic efficiency and highlight its potential as a therapeutic target in MASLD.
Journal Article↗
Effects of different temperatures on chondrocyte growth: a transcriptomic analysis.
BACKGROUND: Our previous study demonstrated that temperature-related microwave ablation (MWA) can safely modulate growth plates of piglets' vertebrae. Therefore, this study is designed to investigate the effects of different temperatures on chondrocyte viability and the underlying molecular mechanisms in vitro. METHODS: Following a 10-minute treatment at different temperatures (37 °C, 40 °C, 42 °C, 44 °C, 46 °C, 48 °C, and 50 °C), CCK-8 assay was used to examine the viability of ATDC5 cells at 12 h. Differentially expressed genes (DEGs) and the hub genes in ATDC5 cells treated at 37 °C, 40 °C and 44 °C were identified using RNA-seq. The expression of hub genes in ATDC5 cells was validated using RT-qPCR. RESULTS: Compared with 37 °C, exposure to 40 °C significantly increased the viability of ATDC5 cells, while 42 °C had no significant effect. Additionally, exposure to 44 °C, 46 °C, 48 °C, and 50 °C exhibited the opposite pattern, with ATDC5 cells being particularly less than 50% active after treatment at 46 °C, 48 °C, and 50 °C. Differential expression analysis identified 179, 374 and 221 DEGs in the comparisons of 40 °C vs. 37 °C, 44 °C vs. 37 °C, and 44 °C vs. 40 °C, respectively. These DEGs predominantly regulated proliferation, differentiation, necrosis, inflammatory and immune responses, and ECM synthesis/degradation. Furthermore, they were associated with the Ras, PI3K/AKT, mTOR, cAMP, and MAPK pathways. Agt, Hspa1a, Hspb1, and Nlrc4 were identified as hub genes in DEGs, and RT-qPCR confirmed that the mRNA expression patterns of these hub genes in ATDC5 cells were largely consistent with the RNA-seq results. CONCLUSION: The regulation of chondrocyte viability by temperature is associated with Ras, PI3K/AKT, mTOR, cAMP, and MAPK pathways. Additionally, Agt, Hspa1a, Hspb1, and Nlrc4 may be the key regulatory genes in this process.
Chondrocytes↗