Journal of Genetics and Genomics最新文献

Pancreatitis is a common gastrointestinal disorder that causes hospitalization with significant morbidity and mortality. The mechanistic pathophysiology of pancreatitis is complicated, limiting the discovery of pharmacological intervention methods. Here, we show that the administration of ATN-161, an antagonist of Integrin-α5, significantly mitigates the pathological condition of acute pancreatitis induced by caerulein. We find that CK19-positive pancreatic ductal cells align parallel to blood vessels in the pancreas. In the caerulein-induced acute pancreatitis model, the newly emergent CK19-positive cells are highly vascularized, with a significant increase in vascular density and endothelial cell number. Single-cell RNA sequencing analysis shows that ductal and endothelial cells are intimate interacting partners, suggesting the existence of a ductal-endothelial interface in the pancreas. Pancreatitis dramatically reduces the crosstalk in the ductal-endothelial interface but promotes the Spp-1/Integrin-α5 signaling. Blocking this signaling with ATN-161 significantly reduces acinar-to-ductal metaplasia, pathological angiogenesis, and restores other abnormal defects induced by caerulein. Our work reveals the therapeutic potential of ATN-161 as an uncharacterized pharmacological method to alleviate the symptoms of pancreatitis.

Heart disease remains the leading cause of death worldwide. Iron imbalance, whether deficiency or overload, contributes to heart failure. However, the molecular mechanisms governing iron homeostasis in the heart are poorly understood. Here, we demonstrate that mutation of bmp10, a heart-born morphogen crucial for embryonic heart development, results in severe anemia and cardiac hypertrophy in zebrafish. Initially, bmp10 deficiency causes cardiac iron deficiency, which later progresses to iron overload due to the dysregulated hepcidin/ferroportin axis in cardiac cells, leading to ferroptosis and heart failure. Early iron supplementation in bmp10^-/- mutants rescues erythropoiesis, while iron chelation in juvenile fishes significantly alleviates cardiac hypertrophy. We further demonstrate that the interplay between HIF1α-driven hypoxic signaling and the IL6/p-STAT3 inflammatory pathways is critical for regulating cardiac iron metabolism. Our findings reveal BMP10 as a key regulator of iron homeostasis in the vertebrate heart and highlight the potential of targeting the BMP10-hepcidin-iron axis as a therapeutic strategy for iron-related cardiomyopathy.

Multi-nucleotide variants (MNVs) are critical genetic variants associated with various genetic diseases. However, tools for precisely installing MNVs are limited. In this study, we present the development of a dual-base editor, BDBE, by integrating TadA-dual and engineered human N-methylpurine DNA glycosylase (eMPG) into nCas9 (D10A). Our results demonstrate that BDBE effectively converts A-to-G/C/T (referred to as A-to-B) and C-to-T/G/A (referred to as C-to-D) simultaneously, yielding nine types of dinucleotides from adjacent CA nucleotides while maintaining minimal off-target effects. Notably, BDBE4 exhibits exceptional performance across multiple human cell lines and successfully simulated all nine dinucleotide MNVs from the gnomAD database. These findings indicate that BDBE significantly expands the product range of base editors and offers a valuable resource for advancing MNV research.

The impact of sex chromosomes and their turnover in speciation remains a subject of ongoing debate in the field of evolutionary biology. Fishes are the largest group of vertebrates, and they exhibit unparalleled sexual plasticity, as well as diverse sex-determining (SD) genes, sex chromosomes, and sex-determination mechanisms. This diversity is hypothesized to be associated with the frequent turnover of sex chromosomes in fishes. Although it is evident that amh and amhr2 are repeatedly and independently recruited as SD genes, their relationship with the rapid turnover of sex chromosomes and the biodiversity of fishes remains unknown. We summarize the canonical models of sex chromosome turnover and highlight the vital roles of gene mutation and hybridization with empirical evidence. We revisit Haldane's rule and the large X-effect and propose the hypothesis that sex chromosomes accelerate speciation by multiplying genotypes via hybridization. By integrating recent findings on the turnover of SD genes, sex chromosomes, and sex-determination systems in fish species, this review provides insights into the relationship between sex chromosome evolution and biodiversity in fishes.

CtBP-interacting protein (CtIP) is known for its multifaceted roles in DNA repair and genomic stability, directing the homologous recombination-mediated DNA double-stranded break repair pathway via DNA end resection, an essential error-free repair process vital for genome stability. Mammalian oocytes are highly prone to DNA damage accumulation due to prolonged G2/prophase arrest. Here, we explore the functions of CtIP in meiotic cell cycle regulation via a mouse oocyte model. Depletion of CtIP by siRNA injection results in delayed germinal vesicle breakdown and failed polar body extrusion. Mechanistically, CtIP deficiency increases DNA damage and decreases the expression and nuclear entry of CCNB1, resulting in marked impairment of meiotic resumption, which can be rescued by exogenous CCNB1 overexpression. Furthermore, depletion of CtIP disrupts microtubule-organizing centers coalescence at spindle poles as indicated by failed accumulation of γ-tubulin, p-Aurora kinase A, Kif2A, and TPX2, leading to abnormal spindle assembly and prometaphase arrest. These results provide valuable insights into the important roles of CtIP in the G2/M checkpoint and spindle assembly in mouse oocyte meiotic cell cycle regulation.

The reconstruction of demographic history using ancient and modern genomic resources reveals extensive interactions and admixture between ancient nomadic pastoralists and the social organizations of the Chinese Central Plain. However, the extent to which Y-chromosome genetic legacies from nomadic emperor-related ancestral lineages influence the Chinese paternal gene pool remains unclear. Here, we genotype 2717 ethnolinguistically diverse samples belonging to C2a lineages, perform whole-genome sequencing on 997 representative samples and integrate these data with ancient genomic sequences. We reconstruct the evolutionary histories of Northern Zhou-, Qing emperor-, and pastoralist-related lineages to assess their genetic impact on modern Chinese populations. This reassembled fine-scale Y-chromosome phylogeny identifies deep divergence and five Neolithic expansion events contributing differently to the formation of northern Chinese populations. Phylogeographic modeling indicates that the nomadic empires of the Northern Zhou and Qing dynasties genetically originated from the Mongolian Plateau. Phylogenetic topology and shared haplotype patterns show that three upstream ancestors of Northern Zhou (C2a1a1b1a2a1b-FGC28857), Donghu tribe (C2a1a1b1-F1756), and Qing (C2a1a3a2-F10283) emperor-related lineages expanded during the middle Neolithic, contributing significantly to genetic flow between ancient northeastern Asians and modern East Asians. Notably, this study reveals limited direct contributions of Emperor Wu of Northern Zhou's lineages to modern East Asians.

The cell fate of primordial germ cells (PGCs) in zebrafish is pre-determined by maternally deposited germ plasm, which is packaged into ribonucleoprotein complex in oocytes and inherited into PGCs-fated cells in embryos. However, the maternal factors regulating the assembly of germ plasm and PGC development remain poorly understood. In this study, we report that the maternal transcription factor Znf706 regulates the assembly of germ plasm factors into a granule-like structure localized perinuclearly in PGCs during migration. Maternal and zygotic mutants of znf706 (MZznf706) exhibit deficient germ plasm scattering at the early embryonic stage, decreased PGC numbers with some mislocation during PGC migration, and a lower female ratio in adulthood. Notably, the implementation of Znf706 CUT&Tag and RNA-seq on immature oocytes uncovers that Znf706 in stage I oocytes may promote transcription of several mitochondrial genes in addition to other functions. Hence, we propose that Znf706 is implicated in germ plasm assembly and PGC development in zebrafish.

Chakouyi (CKY) horses from the Qinghai‒Xizang Plateau are well known for their unique lateral gaits and high-altitude adaptation, but genetic mechanisms underlying these phenotypes remain unclear. This study presents a comparison of 60 newly resequenced genomes of gaited CKY horses with 139 public genomes from 19 horse breeds. Population structure analyses (admixture, PCA, and neighbor-joining tree) reveal a close genetic relationship between CKY and other highland breeds (Tibetan and Chaidamu horses). Compared with other Chinese breeds, CKY horses present reduced nucleotide diversity (θπ) and lower inbreeding (F_ROH coefficient), suggesting possible selective pressures. A key region on chromosome 23 (Chr23: 22.3 -22.6 Mb) is associated with the lateral gaits and harbors a highly prevalent nonsense mutation (Chr 23:22,391,254 C>A, Ser301STOP) in the DMRT3 gene, with an 88% homozygosity rate, which is strongly correlated with the distinctive gait of CKY horses. Furthermore, selection signals reveal that the EPAS1 gene is related to high-altitude adaptation, and the CAT gene contributes to altitude resilience in CKY horses. These findings suggest that preserving genetic diversity is essential for maintaining the unique gaits and high-altitude adaptations of CKY horses.

Maize (Zea mays), which is a vital source of food, feed, and energy feedstock globally, has significant potential for higher yields. However, environmental stress conditions, including drought and salt stress, severely restrict maize plant growth and development, leading to great yield losses. Leucine-rich repeat receptor-like kinases (LRR-RLKs) function in biotic and abiotic stress responses in the model plant Arabidopsis (Arabidopsis thaliana), but their roles in abiotic stress responses in maize are not entirely understood. In this study, we determine that the LRR-RLK ZmMIK2, a homolog of the Arabidopsis LRR-RK MALE DISCOVERER 1 (MDIS1)-INTERACTING RECEPTOR LIKE KINASE 2 (MIK2), functions in resistance to both drought and salt stress in maize. Zmmik2 plants exhibit enhanced resistance to both stresses, whereas overexpressing ZmMIK2 confers the opposite phenotypes. Furthermore, we identify C2-DOMAIN-CONTAINING PROTEIN 1 (ZmC2DP1), which interacts with the intracellular region of ZmMIK2. Notably, that region of ZmMIK2 mediates the phosphorylation of ZmC2DP1, likely by increasing its stability. Both ZmMIK2 and ZmC2DP1 are mainly expressed in roots. As with ZmMIK2, knockout of ZmC2DP1 enhanced resistance to both drought and salt stress. We conclude that ZmMIK2-ZmC2DP1 acts as a negative regulatory module in maize drought- and salt-stress responses.