Journal of Genetics and Genomics最新文献

CTCF is a highly conserved zinc finger protein that plays critical roles in transcriptional regulation and three-dimensional (3D) genome organization. An alternative splice isoform of CTCF (CTCF-s), lacking the N-terminal domain and 2.5 zinc fingers, competes with CTCF for genomic occupancy and reduces CTCF-mediated chromatin interactions. However, the functional differences between CTCF and CTCF-s remain unclear. In this study, by using an auxin-inducible degron (AID2) system with doxycycline-inducible transgene expression, we systematically investigate the roles of CTCF and CTCF-s in human embryonic stem cells (hESCs). Acute degradation of endogenous CTCF and CTCF-s, followed by isoform-specific rescue, reveals that CTCF is essential for cell morphology and proliferation, whereas CTCF-s exerts much weaker effects. Genome-wide ChIP-seq and Hi-C analysis uncover distinct binding landscapes for CTCF and CTCF-s, as well as their differential contributions to chromatin conformation. Notably, our data indicate that CTCF-s, like CTCF, could either act as a boundary insulator or bind to gene promoters to modulate expression of a fraction of genes. Overall, our study reveals that CTCF is dominant in regulating chromatin boundary stability and gene regulation, while CTCF-s contributes to a lesser degree.

Intellectual disability (ID) arises from complex pathogenic mechanisms. Although myelin dysfunction and white matter damage have been implicated, the cellular and molecular mechanisms linking impaired myelination to cognitive deficits remain largely unknown. Here, we identify a de novo heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2) variant, c.638C>T (p.Pro213Leu), in patients with ID. The Hnrnph2^P213L knock-in mice display spatial learning deficits, representing a partial phenotypic overlap with HNRNPH2-related neurodevelopmental disorder. Notably, Hnrnph2^P213L mice exhibit significant myelination defects, primarily due to the impaired differentiation of oligodendrocyte progenitor cells. Furthermore, the myelin-enhancing drug benztropine rescues myelination, restores myelin-related gene expression, and ameliorates cognitive deficits, highlighting the role of hnRNPH2 P213L-induced myelin abnormalities in the pathogenesis of ID. Mechanistically, the P213L mutation disrupts the interaction between hnRNPH2 and its target transcripts, leading to the downregulation of myelination-related genes. Collectively, these findings reveal a critical mechanistic connection between myelin dysfunction and ID, thereby offering potential therapeutic insights for X-linked neurodevelopmental disorders.

Meiotic DNA double-strand break (DSB) formation is pivotal for oocyte development, regulating both ovarian reserve and oocyte developmental potential. Mutations in DSB formation genes have been associated with premature ovarian insufficiency (POI) and adverse pregnancy outcomes in women. Whole exome sequencing in 1530 POI patients across two Chinese cohorts identifies loss-of-function variants in the DSB formation gene, MEI4, enriched in POI. These MEI4 variants impair DSB formation in vitro and reveal a previously unrecognized function of the MEI4 C-terminus in stabilizing the MEI4-REC114 subcomplex on the chromosome axes. Additionally, Mei4^{Arg356*/Arg356*} mice display severe defects in DSB formation, leading to massive apoptosis in oocytes triggered by the HORMAD1-dependent synapsis checkpoint in late prophase I. The few mutant oocytes surviving past the checkpoint exhibit low developmental potential, characterized by complete early embryonic arrest due to aneuploidy. Notably, heterozygous Mei4^+/Arg356* mice show intermediate follicle depletion and embryonic development arrest consistent with the phenotype of heterozygous POI and preimplantation embryonic arrest, suggesting a haploinsufficiency effect. This study defines the impacts of MEI4 mutation on oocyte quantity and quality, which can guide genetic diagnosis and intervention in patients with POI and early embryonic arrest, especially those with mutations in meiotic DSB formation genes.

Phenolic acid metabolites have important physiological functions, and many genetic loci affecting phenolic acid metabolism traits have been identified in several crops. Although barley is one of the important cereal crops, research on the genetic basis of phenolic acid synthesis in barley grains remains limited. Here, we analyze the 39 phenolic acid metabolites detected in mature grains of barley double haploid (DH) population and further identify 154 metabolite quantitative trait loci (mQTLs) related to 36 phenolic acids using four mapping methods. Subsequently, we identify 12 candidate genes that affect the content of phenolic acid metabolites, and overexpression of one candidate gene, HvCOMT-1, in barley reveals its involvement in the synthesis of phenolic acids. Moreover, we show that the transcription factor HvMYB-1 regulate the expression of HvCOMT-1. Functional analysis in Arabidopsis shows that HvCOMT-1 increases stem diameter and lignin deposition. Further analysis reveals that the expression level of HvCOMT-1 is closely related to the barley lodging-related traits. Overall, our findings enhance the understanding of the genetic basis for phenolic acid variations in mature barley grains and provide valuable reference for genetic improvement of barley nutritional quality.

Strigolactones (SLs) are a group of phytohormones that enhance hyphal branching of arbuscular mycorrhizal fungi (AMF), promote seed germination of parasitic plants, and influence plant growth, development, and stress acclimation. SLs improve plant stress resilience by modulating shoot and root architecture, photosynthesis, nutrient homeostasis, and antioxidant defense. Under nutrient deficiency, SL accumulation enhances AMF colonization and triggers the expression of genes related to the nutrient starvation response. When subjected to drought, SLs mitigate water loss by modulating stomatal density and closure, cell membrane integrity, and anthocyanin biosynthesis. SLs also mitigate salinity and heavy metal stresses by maintaining ion homeostasis, while conferring thermotolerance and enhancing chilling tolerance. In this review, we highlight recent advances in SLs and their mechanisms in plant responses to environmental stresses, including nutrient deficiencies, drought, salinity, extreme temperatures, metal toxicity, herbivore attack, and pathogen infection. We further discuss how SLs interact with other phytohormones to coordinate the physiological, biochemical, and molecular regulatory events critical for plant acclimation to abiotic and biotic stresses.

Ethylene, a pivotal gaseous phytohormone, regulates diverse processes in plant growth, development, and stress adaptation. In Arabidopsis, ethylene perception by endoplasmic reticulum (ER)-localized receptors initiates a canonical signaling cascade involving CONSTITUTIVE TRIPLE RESPONSE 1 (AtCTR1) and ETHYLENE INSENSITIVE 2 (AtEIN2). This pathway culminates in nuclear translocation of AtEIN2-CEND and activation of the transcription factor AtEIN3/EIN3-LIKE1 (AtEIL1). Rice employs conserved (OsEIN2, OsCTR2, OsEIL1/2) and unique (Mao Huzi 3 [MHZ3], MHZ11, MHZ1) components for ethylene signaling, reflecting adaptations to semi-aquatic environments. Ethylene regulates developmental processes including seed germination, apical hook formation, root architecture, flowering, and senescence, often via intricate crosstalk with auxin, abscisic acid (ABA), jasmonic acid (JA), gibberellins (GA), and brassinosteroids (BR). Ethylene signaling also influences rice yield-related traits such as grain filling, grain size, and starch biosynthesis. Moreover, ethylene modulates responses to abiotic stresses (such as submergence, hypoxia, salinity, drought, and temperature fluctuations) and nutrient imbalances. This review synthesizes current understanding of ethylene signaling and its functions, focusing on the model dicot Arabidopsis thaliana and the monocot rice (Oryza sativa). It highlights conserved and diverged mechanisms, underscoring ethylene's potential as a target for enhancing crop resilience and productivity in changing environments.

Chromatin modifications, including histone acetylation, play essential roles in regulating flowering. The CBP/p300 family HISTONE ACETYLTRANSFERASE 1 (HAC1), which mediates histone acetylation, promotes the process of floral transition; however, the precise mechanism remains largely unclear. Specifically, how HAC1 is involved in the flowering regulatory network and which genes are the direct targets of HAC1 during flowering regulation are still unknown. In this study, we elucidate the critical function of HAC1 in promoting flowering via exerting active epigenetic markers at two key floral integrators, FLOWERING LOCUS T (FT) and SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1), thereby regulating their expression to trigger the flowering process. We show that HAC1 physically interacts with CONSTANS (CO) in vivo and in vitro. Chromatin immunoprecipitation results indicate that HAC1 directly binds to the FT and SOC1 loci. Loss of HAC1 impairs CO-mediated transcriptional activation of FT and SOC1 in promoting flowering. Moreover, CO mutation leads to the decreased enrichment of HAC1 at FT and SOC1, indicating that CO recruits HAC1 to FT and SOC1. Finally, HAC1, as well as CO, is required for the elevated histone acetylation level at FT and SOC1. Taken together, our finding reveals that HAC1-mediated histone acetylation boots flowering via a CO-dependent activation of FT and SOC1.

Multiple nucleotide variants (MNVs) are frequently misannotated as separate single-nucleotide variants (SNVs) by widely utilized variant-calling pipelines, presenting substantial challenges in genetic testing and research. The role of MNVs in genetic diagnosis remains inadequately characterized, particularly within large disease cohorts. In this study, we comprehensively investigate codon-level MNVs (cMNVs) across 157 hearing loss (HL)-related genes in 11,467 HL cases and 7258 controls from the Chinese Deafness Gene Consortium (CDGC) cohort. A total of 116 cMNVs are identified, occurring in 29.07% of HL cases. Among them, 56.03% of cMNVs exhibit functional consequences distinct from constituent SNVs. Moreover, amino acid substitutions exclusive to cMNVs cause more substantial physicochemical disruptions than those associated with SNVs. Notably, 51 cMNVs show pathogenicity classifications that diverge from at least one constituent SNV, impacting genetic interpretation in 145 cases. Pathogenicity interpretation of cMNV facilitates definitive genetic diagnoses in eight HL cases that would otherwise have been subject to misdiagnoses or missed diagnoses. These findings provide critical insights into the genomic characteristics, functional impacts, and diagnostic implications of cMNVs, underscoring their clinical significance in genetic diagnosis and emphasizing the necessity for comprehensive and accurate detection and interpretation of cMNVs in genetic testing and research.