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Results for “allelic expression switch”

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PubMed2026

Mammalian DNA methyltransferases in DNA methylation and imprinted gene expression in extraembryonic ectoderm of post-implantation embryos.

DNA methylation in mammals is mainly catalyzed by three DNA methyltransferases (DNMTs). Conventionally, DNMT1 is considered the primary DNMT protein for maintenance DNA methylation, whereas DNMT3A and DNMT3B function in de novo DNA methylation. In two previous studies, we demonstrated that DNMT3A and DNMT3B maintain genome-wide DNA methylation in embryonic stem (ES) cells and in the epiblast of post-implantation embryos. Interestingly, DNMT3A and DNMT3B also sustain genome-wide DNA methylation in the extraembryonic ectoderm (EXE) of post-implantation embryos, including repeats, genic and intergenic regions. Although DNMT1 plays a major role in maintaining DNA methylation at the imprinting control regions (ICRs) in the imprinted regions, DNMT3A and DNMT3B are required for preserving DNA methylation at the ICRs of a subset of imprinted regions in EXE, similar to the observations in ES cells and epiblast. Surprisingly, de novo DNA methylation mediated by DNMT3A and DNMT3B leads to increased DNA methylation at a large subset of imprinted regions. These results are consistent with what we previously elucidated in the epiblast of post-implantation embryos. Importantly, loss of DNA methylation at the ICR of an imprinted region, resulting from the absence of DNMT1 or two DNMT3 proteins, causes allelic expression switch of the corresponding imprinted genes in that imprinted region. This study provides further evidence that DNMT3A and DNMT3B exert both maintenance and de novo DNA methylation functions across the genome in post-implantation embryos. It also validates some previous findings for DNA methylation-dependent allelic expression switch of imprinted genes.

DNA methylation↗
PubMed1977

Differential control of the synthesis of two hemoglobin beta chains in normal mice.

A fetal-to-adult switch in the proportion of the mouse minor hemoglobin is described. Although mice have no fetal hemoglobin per se, the timing of this switch in the mouse suggests that the mechanism of its control may directly parallel that of the human switch from fetal to adult hemoglobin expression. The mouse minor hemoglobin is expressed only in strains with the "diffuse" allele for the beta chain complex locus. Fetal liver cells of these mice synthesize a much greater proportion of the betaminor globin chain that do adult hematopoietic cells. Consequently, circulating fetal erythrocytes carry a high level of the minor hemoglobin containing it. By the time of birth, a lowered proportion of betaminor is synthesized in the liver. This low proportion continues to be expressed during early erythroid maturation in the adult. The fetal-to-adult switch is the first indication that in normal mice, the two beta chain loci can be expressed noncoordinately. The similarity between the patterns of the decline of the minor hemoglobin in mice and of the disappearance of fetal hemoglobin in humans suggests that the minor hemoglobin in the "diffuse" mouse may function to some degree as a fetal hemoglobin in the period between the disappearance of the embryonic hemoglobins and the time of birth.

Animals↗
PubMed2016

17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells.

Asthma and autoimmune disease susceptibility has been strongly linked to genetic variants in the 17q21 haploblock that alter the expression of ORMDL3; however, the molecular mechanisms by which these variants perturb gene expression and the cell types in which this effect is most prominent are unclear. We found several 17q21 variants overlapped enhancers present mainly in primary immune cell types. CD4+ T cells showed the greatest increase (threefold) in ORMDL3 expression in individuals carrying the asthma-risk alleles, where ORMDL3 negatively regulated interleukin-2 production. The asthma-risk variants rs4065275 and rs12936231 switched CTCF-binding sites in the 17q21 locus, and 4C-Seq assays showed that several distal cis-regulatory elements upstream of the disrupted ZPBP2 CTCF-binding site interacted with the ORMDL3 promoter region in CD4+ T cells exclusively from subjects carrying asthma-risk alleles. Overall, our results suggested that T cells are one of the most prominent cell types affected by 17q21 variants.

Asthma↗
PubMed2025

Rapid Divergence of Visual Systems and Signaling Traits to Contrasting Light Regimes During Early Speciation of African Crater Lake Cichlid Fish.

Sensory adaptation is widely hypothesized to drive ecological speciation, yet empirical evidence from natural populations undergoing early stage divergence remains limited. In Lake Masoko, a young crater lake in East Africa, the haplochromine cichlid Astatotilapia calliptera is undergoing early stage sympatric speciation into shallow-water littoral and deep-water benthic ecotypes that experience contrasting light environments. Here, we integrate retinal transcriptomics, phenotypic analyses, and visual modeling to uncover rapid sensory divergence associated with this ecological transition. We find striking shifts in cone opsin expression, with the benthic ecotype exhibiting a switch from short-wavelength sensitive SWS2B to SWS2A and an overall narrowing of cone sensitivity toward the center of the light spectrum, consistent with changes in deep-water light environment. In contrast, coding sequence variation in opsin genes was limited and no significant differences in allele frequencies were detected across nine polymorphic sites, pointing to expression regulation as the primary axis of early divergence in visual systems. In parallel, we observed divergence in male signaling traits, with benthic males displaying deeper red egg-spots, aligning with predictions from visual modeling of signal efficiency in different light environments. These results demonstrate rapid transcriptomic and phenotypic divergence in associated signaling traits-within ∼1,000 years-supporting a potential role for regulatory evolution in sensory adaptation during early ecological speciation.

Animals↗
PubMed1979

Activation of mating type genes by transposition in Saccharomyces cerevisiae.

Yeast Saccharomyces cerevisiae may express an a or alpha mating type. These cells types may be interconverted as a consequence of heritable genetic alteractions at the mating type locus (MAT). According to the more general controlling element model [Oshima, U. & Takano, I. (1971) Genetics 67, 327--335] and the specific cassette model [Hicks, J., Strathern, J. & Herskowitz, I. (1977) in DNA Insertion Elements, Plasmids and Episomes, eds. Bukhari, A. I., Shapiro, J.A. & Adhya, S. L.(Cold Spring Harbor Laboratory, Cold Spring Harbor, NY), pp. 457--462], the regulatory information required for switching the MAT locus exists at two other loosely linked loci, HMa and HMalpha. Specifically, the HMa and HMalpha loci are proposed to carry silent alpha and silent a genes, respectively. According to these models, switching occurs when a replica of a silent gene replaces the resident information at the mating type locus and is thereby expressed. These models predict that mutations at the silent ("storage") loci would generate defective MAT loci subsequent to the switching process. Therefore, the behavior of HMalpha mutants during the mating type interconversion was investigated. The results demonstrate that defective MATa alleles are generated by switching the MATalpha locus in HMalpha mutants. Thus, the genetic information from HMalpha is transposed to the mating type locus. These results provide genetic evidence in support of these models.

Alleles↗
PubMed2026

Marked response to dabrafenib plus trametinib in a patient with BRAF V600E-mutant pancreatic hepatoid carcinoma: a case report and systematic analysis of 57 cases.

BACKGROUND: Pancreatic hepatoid carcinoma (PHC) is an extremely rare pancreatic malignancy characterized pathologically by hepatocellular-like differentiation. Some patients may present with elevated serum alpha-fetoprotein (AFP). Owing to the limited number of reported cases, the clinical features, molecular characteristics, and systemic treatment strategies for PHC remain poorly defined. BRAF V600E is an actionable alteration with established therapeutic value in several solid tumors; however, its clinical significance in PHC remains unclear. CASE PRESENTATION: We report the case of a 64-year-old man with advanced PHC who presented with painless jaundice, dark urine, and recent weight loss. Laboratory tests showed marked cholestatic liver injury and significantly elevated AFP. Imaging revealed a pancreatic head-neck mass with portal vein tumor thrombus and regional lymph node metastases, corresponding to cT4N1M1, stage IV disease. Percutaneous transhepatic biliary drainage was first performed to relieve obstructive jaundice. Biopsy of the pancreatic lesion showed poorly differentiated carcinoma. Based on hepatoid morphology, immunophenotype, elevated serum AFP, imaging findings, and exclusion of primary hepatocellular carcinoma, the patient was diagnosed with PHC. Comprehensive genomic profiling identified a BRAF V600E mutation with a variant allele frequency of 31.89%, together with MDM2 and MYC amplification. The molecular profile was characterized by microsatellite stability, low tumor mutational burden, MGMT promoter methylation, and low PD-L1 expression. After two cycles of pembrolizumab-based first-line therapy combined with paclitaxel, S-1, and lenvatinib, AFP continued to increase and imaging showed rapid tumor enlargement, consistent with immune checkpoint inhibitor-related hyperprogressive disease. The treatment was then switched to dabrafenib plus trametinib. AFP declined rapidly and returned to the normal range within approximately two months. Imaging showed marked regression of the pancreatic primary lesion, disappearance of the portal vein tumor thrombus and metastatic lymph nodes, and conversion of peripheral blood minimal residual disease to negative. The best response was partial response. After approximately six months of targeted therapy, occult disease progression emerged. Subsequent addition of cetuximab, replacement of the MEK inhibitor, and dose escalation of targeted therapy did not restore sustained systemic disease control, although local disease remained manageable with subsequent treatment adjustments. Proton radiotherapy was then delivered to the residual pancreatic lesion, followed by CyberKnife radiotherapy for a newly detected 2.3-cm metastasis in the caudate lobe of the liver. As of April 2026, the patient's AFP level remained close to normal at 14 ng/mL, local lesions were well controlled, peripheral blood minimal residual disease had turned positive, and the patient remained in a stable tumor-bearing state. SYSTEMATIC ANALYSIS: We further summarized 57 previously reported cases of PHC. The median age was 54 years, and 66.7% of patients were male. Tumors occurred at different pancreatic sites, including the pancreatic head in 21 cases, body in 8 cases, tail in 13 cases, and multifocal lesions in 15 cases. More than half of the patients had metastatic disease at initial diagnosis. The immunophenotype of PHC was highly heterogeneous. Regarding treatment, 47 patients underwent surgery, 20 received chemotherapy, and 6 received targeted therapy. The 1-year and 3-year overall survival rates were 70.7% and 43.1%, respectively, indicating an overall poor prognosis. CONCLUSION: This case suggests that BRAF V600E may represent a clinically actionable driver alteration in PHC. Dabrafenib plus trametinib induced a rapid and deep response in this patient with advanced BRAF V600E-mutant PHC. Microsatellite stability, low tumor mutational burden, low PD-L1 expression, and MDM2 amplification may be associated with limited benefit from immunotherapy and a risk of hyperprogression. After resistance to targeted therapy, local radiotherapy may serve as an important strategy for controlling oligoresidual and oligometastatic lesions. Together with the literature review, this case supports early comprehensive molecular profiling and individualized multidisciplinary management for advanced PHC.

BRAF V600E↗
PubMed2025

A novel regulation on the developmental checkpoint protein Sda that controls sporulation and biofilm formation in Bacillus subtilis.

UNLABELLED: Biofilm formation by Bacillus subtilis is triggered by an unusually simple environmental sensing mechanism. Certain serine codons, the four TCN codons (N for A, T, C, or G), in the gene for the biofilm repressor SinR caused lowered SinR translation and subsequent biofilm induction during transition from exponential to stationary growth. Global ribosome profiling showed that ribosomes pause when translating the four UCN (U for T on the mRNA) serine codons on mRNA, but not the two AGC/AGU serine codons. We proposed a serine codon hierarchy (AGC/AGT vs TCN) in that genes enriched in the TCN serine codons may experience reduced translation efficiency when serine is limited. In this study, we designed an algorithm to score all protein-coding genes in B. subtilis NCIB3610 based on the serine codon hierarchy. We generated a short list of 50 genes that could be subject to regulation by this novel mechanism. We further investigated one such gene from the list, sda, which encodes a developmental checkpoint protein regulating both sporulation and biofilm formation. We showed that synonymously switching the TCN serine codons to AGC in sda led to delayed biofilm formation and sporulation. This engineered strain also outgrew strains with other synonymously substituted sda alleles (TCN) in competition assays for biofilm formation and sporulation. Finally, we showed that the AGC serine codon substitutions in sda elevated the Sda protein levels. This serine codon hierarchy-based novel signaling mechanism could be exploited by bacteria in adapting to stationary phase and regulating important biological processes. IMPORTANCE: Genome-wide ribosome profiling in Bacillus subtilis shows that under serine limitation, ribosomes pause on the four TCN (N for A, C, G, and T), but not AGC/AGT serine codons, during translation at a global scale. This serine codon hierarchy (AGC/T vs TCN) differentially influences the translation efficiency of genes enriched in certain serine codons. In this study, we designed an algorithm to score all 4,000+ genes in the B. subtilis genome and generated a list of 50 genes that could be subject to this novel serine codon hierarchy-mediated regulation. We further investigated one such gene, sda, encoding a developmental checkpoint protein. We show that sda and cell developments controlled by Sda are also regulated by this novel mechanism.

Bacillus subtilis↗