Biology subjects

Ng, Y. K.

Publications and source records attributed to Ng, Y. K..

5 recordsLinked to original sources

bioRxiv2026

The androgen receptor polyglutamine tract sets the transcriptional balance between muscle growth and atrophy

The androgen receptor (AR) mediates the potent anabolic effects of testosterone and other androgens on skeletal muscle, yet the transcriptional mechanisms coupling this hormonal signal to muscle growth remain unresolved. AR is a ligand-inducible transcription factor whose N-terminal transactivation domain (NTD) harbours a polymorphic polyglutamine (polyQ) tract that, when pathologically expanded, causes spinal and bulbar muscular atrophy (SBMA). To define how the NTD and its polyQ tract shape muscle transcription, we combined an engineered AR allelic series in human myogenic cells with super-resolution and single-molecule imaging, genome-wide binding and expression maps, and human population genetics. Under physiological conditions, androgen-activated AR assembles into dynamic transcriptional condensates and drives an anabolic programme in skeletal muscle through activation of the AP-1 pathway. Progressive expansion of the polyQ tract destabilises AR chromatin binding and shifts its occupancy from promoters to low-affinity distal enhancers, tracking with imaging signatures of muscle aging. In SBMA, this culminates in aberrant transactivation of ectodysplasin A2 receptor (EDA2R), a marker of senescence and inflammation, which engages non-canonical NF-{kappa}B signalling to drive muscle atrophy. Silencing Eda2r attenuated muscle wasting in SBMA mice, establishing this axis as therapeutically actionable. Together, these findings reveal a fundamental mechanism of skeletal-muscle homeostasis and open therapeutic avenues for the many conditions in which muscle atrophy is central.

molecular biology↗

bioRxiv2023

Endogenous Staphylococcus aureus CRISPR-cas system limits phage proliferation and efficiently excises from the genome as part of the SCCmec cassette

CRISPR-Cas is an adaptive immune system that allows bacteria to inactivate mobile genetic elements. Approximately 50% of bacteria harbor CRISPR-cas, however in the human pathogen Staphylococcus aureus, CRISPR-cas loci are less common and often studied in heterologous systems. We analyzed the prevalence of CRISPR-cas in genomes of methicillin resistant Staphylococcus aureus (MRSA) isolated in Denmark. Only 2.9 % of the strains carried CRISPR-cas systems, but for strains of sequence type ST630 over half were positive. All CRISPR-cas loci were type III-A and located within the staphylococcal chromosomal cassette (SCCmec) type V(5C2&5) conferring {beta}-lactam resistance. Curiously, only 23 different CRISPR spacers were identified in 69 CRISPR-positive strains and almost identical SCCmec cassettes, CRISPR arrays and cas genes, are present in staphylococcal species other than aureus, suggesting that these were transferred horizontally. For the ST630 strain 110900, we demonstrate that the SCCmec cassette containing CRISPR-cas excises from the chromosome at high frequency. However, the cassette was not transferable under the conditions investigated. One of the CRISPR spacers targets a late gene in the lytic bacteriophage (phage) virus philPLA-RODI, and we show that the system protects against phage infection by reducing phage burst size. However, CRISPR-Cas can be overloaded or bypassed by CRISPR escape mutants. Our results imply that the endogenous type III-A CRISPR-Cas system in S. aureus is active against targeted phages, albeit with low efficacy. This suggests native S. aureus CRISPR-Cas offers only partial immunity, and in nature may work in tandem with other defense systems. ImportanceCRISPR-Cas is an adaptive immune system enabling bacteria and archaea to protect themselves against mobile genetic elements such as phages. In strains of Staphylococcus aureus, CRISPR-cas is rare, but when present, it is located within the SCCmec element encoding resistance to methicillin and other {beta}-lactam antibiotics. We show that the entire module is excisable, with almost identical versions found in different species of non-aureus staphylococci suggesting that the system only rarely acquires new spacers in S. aureus. Additionally, we show that in its endogenous form, the S. aureus CRISPR-Cas is active but inefficient against lytic phages, with phages being able to form escape mutants or overload the system. This leads us to propose that CRISPR-Cas in S. aureus offers only partial immunity in native systems, and so may work together with other defense systems to prevent phage-mediated killing.

microbiology↗

bioRxiv2021

Both Simulation and Sequencing Data Reveal Multiple SARS-CoV-2 Variants Coinfection in COVID-19 Pandemic

SARS-CoV-2 is a single-stranded RNA betacoronavirus with a high mutation rate. The rapidly emerged SARS-CoV-2 variants could increase the transmissibility, aggravate the severity, and even fade the vaccine protection. Although the coinfections of SARS-CoV-2 with other respiratory pathogens have been reported, whether multiple SARS-CoV-2 variants coinfection exists remains controversial. This study collected 12,986 and 4,113 SARS-CoV-2 genomes from the GISAID database on May 11, 2020 (GISAID20May11) and April 1, 2021 (GISAID21Apr1), respectively. With the single-nucleotide variants (SNV) and network clique analysis, we constructed the single-nucleotide polymorphism (SNP) coexistence networks and noted the SNP number of the maximal clique as the coinfection index. The coinfection indices of GISAID20May11 and GISAID21Apr1 datasets were 16 and 34, respectively. Simulating the transmission routes and the mutation accumulations, we discovered the linear relationship between the coinfection index and the coinfected variant number. Based on the linear relationship, we deduced that the COVID-19 cases in the GISAID20May11 and GISAID21Apr1 datasets were coinfected with 2.20 and 3.42 SARS-CoV-2 variants on average. Additionally, we performed Nanopore sequencing on 42 COVID-19 patients to explore the virus mutational characteristics. We found the heterozygous SNPs in 41 COVID-19 cases, which support the coinfection of SARS-CoV-2 variants and challenge the accuracy of phylogenetic analysis. In conclusion, our findings reported the coinfection of SARS-CoV-2 variants in COVID-19 patients, demonstrated the increased coinfected variants number in the epidemic, and provided clues for the prolonged viral shedding and severe symptoms in some cases.

bioinformatics↗

bioRxiv2020

KIAA1841, a novel SANT and BTB domain-containing protein, inhibits class switch recombination

Class switch recombination (CSR) enables B cells to produce different immunoglobulin isotypes and mount an effective immune response against pathogens. Timely resolution of CSR prevents damage due to an uncontrolled and prolonged immune response. While many positive regulators of CSR have been described, negative regulators of CSR are relatively unknown. Using a shRNA library screen in a mouse B cell line, we have identified the novel protein KIAA1841 (NM_027860) as a negative regulator of CSR. KIAA1841 is an uncharacterized protein of 82kD containing SANT and BTB domains. The BTB domain of KIAA1841 exhibited characteristic properties such as self-dimerization and interaction with co-repressor proteins. Overexpression of KIAA1841 inhibited CSR in primary mouse splenic B cells, and inhibition of CSR is dependent on the BTB domain while the SANT domain is largely dispensable. Thus, we have identified a new member of the BTB family that serves as a negative regulator of CSR.

molecular biology↗

bioRxiv2019

On triangular inequalities of correlation-based distances for gene expression profiles

Various distance functions for evaluating the differences be- tween gene expression profiles have been proposed in the past. Such a function would output a low value if the profiles are strongly correlated--either negatively or positively--and vice versa. One popular distance function is the absolute correlation distance, da = 1 - |{rho}|, where{rho} is some similarity measures, such as Pearson or Spearman correlation. How- ever, absolute correlation distance fails to fulfill the triangular inequality, which would have guaranteed better performance at vector quantization, allowed fast data localization, as well as sped up data clustering. In this work, we propose [Formula] as an alternative. We prove that dr satisfies the triangular equality when{rho} represents Pearson correlation, Spearman correlation, or Cosine similarity. We empirically compared dr with da in gene clustering and sample clustering experiment, using real biological data. The two distances performed similarly in both gene cluster and sample cluster in hierarchical cluster and PAM cluster. However, dr demonstrated more robust clustering. According to bootstrap experiment, the number of times where dr generated more robust sample pair partition is significantly (p-value < 0.05) larger. This advantage in robustness is also supported by the class \"dissolved\" event.

bioinformatics↗