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GigaByte (Hong Kong, China) 2024The golden birdwing (Lepidoptera, Papilionidae), a significant species in Asia, faces habitat loss due to urbanization and human activities, necessitating its...
The golden birdwing (Lepidoptera, Papilionidae), a significant species in Asia, faces habitat loss due to urbanization and human activities, necessitating its protection. However, the lack of genomic resources hinders our understanding of their biology and diversity, and impedes our conservation efforts based on genetic information or markers. Here, we present the first chromosomal-level genome assembly of using PacBio SMRT and Omni-C scaffolding technologies. The assembled genome (351 Mb) contains 98.94% of the sequences anchored to 30 pseudo-molecules. The genome assembly has high sequence continuity with contig length N50 = 11.67 Mb and L50 = 14, and scaffold length N50 = 12.2 Mb and L50 = 13. A total of 24,946 protein-coding genes were predicted, with high BUSCO score completeness (98.8% and 94.7% of genome and proteome BUSCO, respectively. This genome offers a significant resource for understanding the swallowtail butterfly biology and carrying out its conservation.
PubMed: 38707630
DOI: 10.46471/gigabyte.122 -
MBio Aug 2023High-risk human papillomaviruses (PV) account for approximately 600,000 new cancers per year. The early protein E8^E2 is a conserved repressor of PV replication, whereas...
Mus musculus papillomavirus 1 E8^E2 represses expression of late protein E4 in basal-like keratinocytes via NCoR/SMRT-HDAC3 co-repressor complexes to enable wart formation .
High-risk human papillomaviruses (PV) account for approximately 600,000 new cancers per year. The early protein E8^E2 is a conserved repressor of PV replication, whereas E4 is a late protein that arrests cells in G2 and collapses keratin filaments to facilitate virion release. While inactivation of the Mus musculus PV1 (MmuPV1) start codon (E8-) increases viral gene expression, surprisingly, it prevents wart formation in FoxN1 mice. To understand this surprising phenotype, the impact of additional E8^E2 mutations was characterized in tissue culture and mice. MmuPV1 and HPV E8^E2 similarly interact with cellular NCoR/SMRT-HDAC3 co-repressor complexes. Disruption of the splice donor sequence used to generate the transcript or E8^E2 mutants (mt) with impaired binding to NCoR/SMRT-HDAC3 activates MmuPV1 transcription in murine keratinocytes. These MmuPV1 E8^E2 mt genomes also fail to induce warts in mice. The phenotype of E8^E2 mt genomes in undifferentiated cells resembles productive PV replication in differentiated keratinocytes. Consistent with this, E8^E2 mt genomes induced aberrant E4 expression in undifferentiated keratinocytes. In line with observations for HPV, MmuPV1 E4-positive cells displayed a shift to the G2 phase of the cell cycle. In summary, we propose that in order to enable both expansion of infected cells and wart formation , MmuPV1 E8^E2 inhibits E4 protein expression in the basal keratinocytes that would otherwise undergo E4-mediated cell cycle arrest. IMPORTANCE Human papillomaviruses (PVs) initiate productive replication, which is characterized by genome amplification and expression of E4 protein strictly within suprabasal, differentiated keratinocytes. Mus musculus PV1 mutants that disrupt splicing of the E8^E2 transcript or abolish the interaction of E8^E2 with cellular NCoR/SMRT-HDAC3 co-repressor complexes display increased gene expression in tissue culture but are unable to form warts . This confirms that the repressor activity of E8^E2 is required for tumor formation and genetically defines a conserved E8 interaction domain. E8^E2 prevents expression of E4 protein in basal-like, undifferentiated keratinocytes and thereby their arrest in G2 phase. Since binding of E8^E2 to NCoR/SMRT-HDAC3 co-repressor is required to enable expansion of infected cells in the basal layer and wart formation , this interaction represents a novel, conserved, and potentially druggable target.
PubMed: 37382436
DOI: 10.1128/mbio.00696-23 -
Nature Metabolism May 2024
Topics: Receptors, Glucocorticoid; Liver; Humans; Animals; Nuclear Receptor Co-Repressor 1; Nuclear Receptor Co-Repressor 2; Mice
PubMed: 38622412
DOI: 10.1038/s42255-024-01028-5 -
Leukemia Apr 2024Neutrophils are key component of the innate immune system in vertebrates. Diverse transcription factors and cofactors act in a well-coordinated manner to ensure proper...
Neutrophils are key component of the innate immune system in vertebrates. Diverse transcription factors and cofactors act in a well-coordinated manner to ensure proper neutrophil development. Dysregulation of the transcriptional program triggering neutrophil differentiation is associated with various human hematologic disorders such as neutropenia, neutrophilia, and leukemia. In the current study we show the zinc finger protein Znf687 is a lineage-preferential transcription factor, whose deficiency leads to an impaired neutrophil development in zebrafish. Mechanistically, Znf687 functions as a negative regulator of gfi1aa, a pivotal modulator in terminal granulopoiesis, to regulate neutrophil maturation. Moreover, we found BRD4, an important epigenetic regulator, directly interacts with ZNF687 in neutrophils. Deficiency of brd4 results in similar defective neutrophil development as observed in znf687 mutant zebrafish. Biochemical and genetic analyses further reveal that instead of serving as a canonical transcriptional coactivator, Brd4 directly interacts and bridges Znf687 and Smrt nuclear corepressor on gfi1aa gene's promoter to exert transcription repression. In addition, the ZNF687-BRD4-SMRT-GFI1 transcriptional regulatory network is evolutionary conserved in higher vertebrate. Overall, our work indicates Znf687 and Brd4 are two novel master regulators in promoting terminal granulopoiesis.
Topics: Animals; Bromodomain Containing Proteins; Cell Cycle Proteins; DNA-Binding Proteins; Neutrophils; Nuclear Proteins; Transcription Factors; Zebrafish
PubMed: 38326409
DOI: 10.1038/s41375-024-02165-2 -
European Thyroid Journal Oct 2023Transducin β-like 1 X-linked receptor 1 (TBL1XR1) is a WD40 repeat-containing protein and part of the corepressor complex SMRT/NCoR that binds to the thyroid hormone...
Transducin β-like 1 X-linked receptor 1 (TBL1XR1) is a WD40 repeat-containing protein and part of the corepressor complex SMRT/NCoR that binds to the thyroid hormone receptor (TR). We recently described a mutation in TBL1XR1 in patients with Pierpont syndrome. A mouse model bearing this Tbl1xr1 mutation (Tbl1xr1Y446C/Y446C ) displays several aspects of the Pierpont phenotype. Although serum thyroid hormone (TH) concentrations were unremarkable in these mice, tissue TH action might be affected due to the role of TBL1XR1 in the SMRT/NCoR corepressor complex. The aim of the present study was to evaluate tissue TH metabolism and action in a variety of tissues of Tbl1xr1Y446C/Y446C mice. We studied the expression of genes involved in TH metabolism and action in tissues of naïve Tbl1xr1Y446C/Y446C mice and wild type (WT) mice. In addition, we measured deiodinase activity in liver (Dio1 and Dio3), kidney (Dio1 and Dio3) and BAT (Dio2). No striking differences were observed in the liver, hypothalamus, muscle and BAT between Tbl1xr1Y446C/Y446C and WT mice. Pituitary TRα1 mRNA expression was lower in Tbl1xr1Y446C/Y446C mice compared to WT, while the mRNA expression of Tshβ and the positively T3-regulated gene Nmb were significantly increased in mutant mice. Interestingly, Mct8 expression was markedly higher in WAT and kidney of mutants, resulting in (subtle) changes in T3-regulated gene expression in both WAT and kidney. In conclusion, mice harboring a mutation in TBL1XR1 display minor changes in cellular TH metabolism and action. TH transport via MCT8 might be affected as the expression is increased in WAT and kidney. The mechanisms involved need to be clarified.
Topics: Animals; Mice; Co-Repressor Proteins; Receptors, Thyroid Hormone; RNA, Messenger; Thyroid Hormones; Transducin
PubMed: 37458724
DOI: 10.1530/ETJ-23-0077 -
Journal of Controlled Release :... Jun 2024Cardiovascular diseases (CVDs) are the leading cause of global mortality among non-communicable diseases. Current cardiac regeneration treatments have limitations and... (Review)
Review
Cardiovascular diseases (CVDs) are the leading cause of global mortality among non-communicable diseases. Current cardiac regeneration treatments have limitations and may lead to adverse reactions. Hence, innovative technologies are needed to address these shortcomings. Messenger RNA (mRNA) emerges as a promising therapeutic agent due to its versatility in encoding therapeutic proteins and targeting "undruggable" conditions. It offers low toxicity, high transfection efficiency, and controlled protein production without genome insertion or mutagenesis risk. However, mRNA faces challenges such as immunogenicity, instability, and difficulty in cellular entry and endosomal escape, hindering its clinical application. To overcome these hurdles, lipid nanoparticles (LNPs), notably used in COVID-19 vaccines, have a great potential to deliver mRNA therapeutics for CVDs. This review highlights recent progress in mRNA-LNP therapies for CVDs, including Myocardial Infarction (MI), Heart Failure (HF), and hypercholesterolemia. In addition, LNP-mediated mRNA delivery for CAR T-cell therapy and CRISPR/Cas genome editing in CVDs and the related clinical trials are explored. To enhance the efficiency, safety, and clinical translation of mRNA-LNPs, advanced technologies like artificial intelligence (AGILE platform) in RNA structure design, and optimization of LNP formulation could be integrated. We conclude that the strategies to facilitate the extra-hepatic delivery and targeted organ tropism of mRNA-LNPs (SORT, ASSET, SMRT, and barcoded LNPs) hold great prospects to accelerate the development and translation of mRNA-LNPs in CVD treatment.
PubMed: 38876358
DOI: 10.1016/j.jconrel.2024.06.023 -
BMC Genomics Apr 2024Cold hardiness is fundamental for amphibians to survive during the extremely cold winter on the Qinghai-Tibet plateau. Exploring the gene regulation mechanism of...
BACKGROUND
Cold hardiness is fundamental for amphibians to survive during the extremely cold winter on the Qinghai-Tibet plateau. Exploring the gene regulation mechanism of freezing-tolerant Rana kukunoris could help us to understand how the frogs survive in winter.
RESULTS
Transcriptome of liver and muscle of R. kukunoris collected in hibernation and spring were assisted by single molecule real-time (SMRT) sequencing technology. A total of 10,062 unigenes of R. kukunoris were obtained, and 9,924 coding sequences (CDS) were successfully annotated. Our examination of the mRNA response to whole body freezing and recover in the frogs revealed key genes concerning underlying antifreeze proteins and cryoprotectants (glucose and urea). Functional pathway analyses revealed differential regulated pathways of ribosome, energy supply, and protein metabolism which displayed a freeze-induced response and damage recover. Genes related to energy supply in the muscle of winter frogs were up-regulated compared with the muscle of spring frogs. The liver of hibernating frogs maintained modest levels of protein synthesis in the winter. In contrast, the liver underwent intensive high levels of protein synthesis and lipid catabolism to produce substantial quantity of fresh proteins and energy in spring. Differences between hibernation and spring were smaller than that between tissues, yet the physiological traits of hibernation were nevertheless passed down to active state in spring.
CONCLUSIONS
Based on our comparative transcriptomic analyses, we revealed the likely adaptive mechanisms of R. kukunoris. Ultimately, our study expands genetic resources for the freezing-tolerant frogs.
Topics: Animals; Transcriptome; Cold-Shock Response; Tibet; Gene Expression Profiling; Ranidae; Anura
PubMed: 38609871
DOI: 10.1186/s12864-024-10248-8 -
Frontiers in Plant Science 2023Potato ( L.) is one of the most important tuber food crops in the world; however, the cultivated potatoes are susceptible to high temperature, by which potato production...
Potato ( L.) is one of the most important tuber food crops in the world; however, the cultivated potatoes are susceptible to high temperature, by which potato production is adversely affected. Understanding the coping mechanism of potato to heat stress is essential to secure yield and expand adaptability under environmental conditions with rising temperature. However, the lack of heat-related information has significantly limited the identification and application of core genes. To gain deeper insights into heat tolerance genes, next-generation sequencing and single-molecule real-time sequencing were used to learn the transcriptional response of potato to heat stress and 13,159 differentially expressed genes (DEGs) were identified in this study. All DEGs were grouped into 12 clusters using the K-means clustering algorithm. Gene Ontology enrichment analysis revealed that they were involved in temperature signaling, phytohormone, and protein modification. Among them, there were 950 differentially expressed transcription factors (DETFs). According to the network analysis of DETFs at the sixth hour under heat stress, we found some genes that were previously reported to be associated with photoperiodic tuberization, (), tuber formation, (), and earliness in potato, () responding to temperature. Furthermore, we verified the relative expression levels using quantitative real-time polymerase chain reaction, and the results were consistent with the inferences from transcriptomes. In addition, there were 22,125 alternative splicing events and 2,048 long non-coding RNAs. The database and network established in this study will extend our understanding of potato response to heat stress. It ultimately provided valuable resources for molecular analysis of heat stress response in potato and cultivation of potato varieties with heat tolerance.
PubMed: 38023929
DOI: 10.3389/fpls.2023.1271084 -
Journal of Peptide Science : An... Apr 2024Histone deacetylase 4 (HDAC4) contributes to gene repression by complex formation with HDAC3 and the corepressor silencing mediator for retinoid or thyroid hormone...
Histone deacetylase 4 (HDAC4) contributes to gene repression by complex formation with HDAC3 and the corepressor silencing mediator for retinoid or thyroid hormone receptors (SMRT). We hypothesized that peptides derived from the class IIa specific binding site of SMRT would stabilize a specific conformation of its target protein and modulate its activity. Based on the SMRT-motif 1 (SM1) involved in the interaction of SMRT with HDAC4, we systematically developed cyclic peptides that exhibit K values that are 9 to 56 times lower than that of the linear SMRT peptide. The peptide macrocycles stabilize the wildtype of the catalytic domain of HDAC4 (cHDAC4) considerably better than its thermally more stable 'gain-of-function' (GOF) variant, cHDAC4-H976Y. Molecular docking and mutagenesis studies indicated that the cyclic peptides bind in a similar but not identical manner as the linear SMRT peptide to a discontinuous binding site. Ion mobility mass spectrometry showed no major changes in the protein fold upon peptide binding. Consistent with these results, preliminary hydrogen-deuterium exchange mass spectrometry measurements indicated only minor conformational changes. Taken together, the cyclic SMRT peptides most likely stabilize the apo form of cHDAC4.
PubMed: 38623824
DOI: 10.1002/psc.3603 -
Scientific Reports Feb 2024Baccaurea ramiflora Lour., an evergreen tree of the Baccaurea genus of the Phyllanthaceae family, is primarily distributed in South Asia, Southeast Asia, and southern...
Baccaurea ramiflora Lour., an evergreen tree of the Baccaurea genus of the Phyllanthaceae family, is primarily distributed in South Asia, Southeast Asia, and southern China, including southern Yunnan Province. It is a wild or semi-cultivated tree species with ornamental, edible, and medicinal value, exhibiting significant development potential. In this study, we present the whole-genome sequencing of B. ramiflora, employing a combination of PacBio SMRT and Illumina HiSeq 2500 sequencing techniques. The assembled genome size was 975.8 Mb, with a contig N50 of 509.33 kb and the longest contig measuring 7.74 Mb. The genome comprises approximately 73.47% highly repetitive sequences, of which 52.1% are long terminal repeat-retrotransposon sequences. A total of 29,172 protein-coding genes were predicted, of which 25,980 (89.06%) have been annotated, Additionally, 3452 non-coding RNAs were identified. Comparative genomic analysis revealed a close relationship between B. ramiflora and the Euphorbiaceae family, with both being sister groups that diverged approximately 59.9 million years ago. During the evolutionary process, B. ramiflora exhibited positive selection in 278 candidate genes. Synonymous substitution rate and collinearity analysis demonstrated that B. ramiflora underwent a single ancient genome-wide triploidization event, without recent genome-wide duplication events. This high-quality B. ramiflora genome provides a valuable resource for basic research and tree improvement programs focusing on the Phyllanthaceae family.
Topics: Genome, Plant; China; Repetitive Sequences, Nucleic Acid; Malpighiales; Evolution, Molecular; Phylogeny
PubMed: 38418841
DOI: 10.1038/s41598-024-55498-4