Biology subjects

Chong, S. Y.

Publications and source records attributed to Chong, S. Y..

4 recordsLinked to original sources

bioRxiv2026

Rpd3L Coordinates Chromatin State and Transcription-Replication Conflict Resolution through H3K4 Methylation-Dependent and Independent Mechanisms

Faithful genome duplication requires coordination between transcription and replication. Disruption of this coordination causes transcription-replication conflicts (TRCs), leading to replication stress and genome instability. How chromatin regulators modulate these processes remains unclear. Here, we show that the Rpd3L histone deacetylase complex dynamically modulates chromatin state to control replication fork progression and buffer TRCs in Saccharomyces cerevisiae. Rpd3L is targeted through both histone H3 lysine 4 methylation-dependent recruitment and methylation-independent mechanisms engaged under replication stress. Loss of H3K4 methylation or Rpd3L function promotes histone acetylation, accelerates fork progression through transcribed regions, and increases transcription-associated genome instability. Balanced acetylation at multiple histone lysines is required to stabilize replication forks under stress. While histone deacetylase complexes have been implicated in repairing damaged forks, our findings reveal that Rpd3L acts preemptively to modulate chromatin state and replication dynamics during TRCs, defining a chromatin-based mechanism that safeguards genome stability.

molecular biology↗

bioRxiv2022

Protection against doxorubicin-induced cardiotoxicity by ergothioneine

Anthracyclines such as doxorubicin remain the first line of treatment for haematological malignancies, and breast cancers. However, the potential risk of cardiac injury by anthracyclines, which may lead to severe myopathy or heart failure, severely limits their application, and remains a challenge to ensuring curative chemotherapy. While the complex interplay between pathological pathways of anthracycline cardiotoxicity is yet to be fully understood, oxidative damage, iron overload-mediated formation of reactive oxygen species (ROS), mitochondrial dysfunction, and inflammation are all believed to be involved. The unique dietary thione, ergothioneine, while not produced in animals and humans, can be avidly absorbed and accumulated in tissues including the heart. Amongst other cytoprotective properties ergothioneine has been shown to scavenge various ROS, decrease proinflammatory mediators, chelate metal cations such as Fe2+, preventing them from partaking in redox activities, and may protect against mitochondrial damage and dysfunction. Moreover, low plasma ergothioneine levels are also strongly correlated to risk of cardiovascular events in humans, suggestive of a cardioprotective role. Taken together this highlights the potential for ergothioneine to counteract anthracycline cardiotoxicity. Here we investigate the potential of ergothioneine supplementation to protect against cardiac dysfunction in mice models of doxorubicin-induced cardiotoxicity and found that it had significant protective effects. Moreover, ergothioneine administration in a mouse breast cancer model did not exacerbate the growth of the tumour and did not interfere with the chemotherapeutic efficacy of doxorubicin. These results suggest that ergothioneine could be a viable co-therapy to alleviate the cardiotoxic effects of anthracyclines in the treatment of cancers.

physiology↗

bioRxiv2018

In vivo generation of post-infarct mouse cardiac muscle by cardiomyocyte progenitors produced with a reproducible laminin-promoted human stem cell differentiation system

Regeneration of human heart muscle after injury is extremely limited and an unmet clinical need. Despite extensive research, there are no methods for the reproducible generation of clinical quality stem-cell-derived cardiovascular progenitors (CVPs). Here, we identified laminin-221 (LN-221) as the main cardiac laminin, which was produced here as human recombinant protein, and showed that LN-221 promotes differentiation of pluripotent hESCs towards cardiomyocyte lineage and downregulates genes associated with pluripotency and teratoma development. We developed a chemically defined, xeno-free laminin-based cardiomyocyte differentiation protocol to reproducibly generate CVPs that form human muscle in vivo. We assessed the reproducibility of the differentiation protocol using time-course bulk RNA sequencing developed from two different hESC lines. Single-cell RNA sequencing of CVPs derived from two hESC lines further showed high reproducibility and identified three main progenitor subpopulations. These CVPs were transplanted into myocardial infarction mice, where heart function was measured by echocardiogram and human heart muscle bundle formation was identified histologically. This method may provide clinical quality cells for use in regenerative cardiology.

cell biology↗

bioRxiv2018

The controlled direct effect of temperament at 2-3 years on cognitive and academic outcomes at 6-7 years

There is widespread interest in temperament and its impact upon cognitive and academic outcomes. Parents adjust their parenting according to their childs temperament, however, previous studies have not accounted for parenting while estimating the association between temperament and academic outcomes. We examined the controlled direct effect of temperament (2-3 years) on cognitive and academic outcomes (6-7 years) when mediation by parenting practices (4-5 years) was held constant. Participants were from the Longitudinal Study of Australian Children (n=5107). Cognitive abilities were measured by the Peabody Picture Vocabulary Test (verbal) and the Matrix Reasoning test (non-verbal). Literacy and numeracy were reported by teachers using the Academic Rating Scale. Mothers reported childrens temperament using the Short Temperament Scale for Toddlers (subscales: reactivity, approach, and persistence). Parenting practices included items about engagement in activities with children. Marginal structural models with inverse probability of treatment weights were used to estimate the controlled direct effect of temperament, when setting parenting to the mean. All temperament subscales were associated with cognitive abilities, with persistence showing the largest controlled direct effect on verbal ({beta}=0.58; 95%CI 0.27, 0.89) and non-verbal ({beta}=0.19; 0.02, 0.34) abilities. Higher persistence was associated with better literacy ({beta}=0.08; 0.03, 0.13) and numeracy ({beta}=0.08; 0.03, 0.13), and higher reactivity with lower literacy ({beta}=-0.08; -0.11, -0.05) and numeracy ({beta}=-0.07; -0.10, -0.04). There was little evidence that temperamental approach influenced literacy or numeracy. Overall, there was a small controlled direct effect of temperament on cognitive and academic outcomes after accounting for parenting and confounders.

epidemiology↗