Biology subjects

Tseng, H.-Y.

Publications and source records attributed to Tseng, H.-Y..

3 recordsLinked to original sources

bioRxiv2026

Transcription-Coupled Chromatin Reinforcement Maintains the Mature Cardiomyocyte State

Chromatin homeostasis is fundamental to maintaining transcriptional programs that stabilize cell states while permitting plasticity for timely state transitions. However, mechanisms that actively sustain mature cell states after their establishment remain poorly defined despite being essential for lifelong maintenance of specialized cellular functions. Here we demonstrate that the transcription-coupled chromatin regulator RNF20 is crucial for maintaining chromatin accessibility at identity-associated promoters that support mature cardiomyocyte transcriptional programs in adult murine cardiomyocytes. Depletion of RNF20 progressively erodes the transcriptional, structural, and functional integrity of adult cardiomyocytes and activates AP-1-associated stress-responsive enhancer elements without cell-cycle re-entry. Spatial transcriptomics further revealed a subendocardial localization of this stress-responsive state. Together, these findings support a model in which transcription-coupled chromatin reinforcement continuously stabilizes the mature cardiomyocyte attractor state while constraining transitions toward pathological cell states.

genetics↗

bioRxiv2021

Chromatin state transition underlies the temporal changes in gene expression during cardiomyocyte maturation

Congenital heart disease (CHD) is often rooted in gene expression anomalies that occur during heart development. As cells commit to a specific lineage, chromatin dynamics and developmental plasticity generally become more limited. However, it remains unclear how differentiated cardiomyocytes (CMs) undergo morphological and functional adaptations to the postnatal environment during their maturation. In this work, we sought to identify the regulatory mechanisms controlling postnatal cardiac gene networks. A time-series transcriptomic analysis of postnatal hearts revealed an integrated, time-ordered transcriptional network that regulates CM maturation. Remarkably, depletion of histone H2B ubiquitin ligase RNF20 after formation of the four-chamber heart disrupted these highly coordinated gene networks. Its ablation also caused early-onset cardiomyopathy, a phenotype reminiscent of CHD. Furthermore, we found that dynamic RNF20-mediated modulation of chromatin accessibility during CM maturation was necessary for the operative binding of cardiac transcription factors known to drive transcriptional gene networks. Together, our results reveal how epigenetic-mediated chromatin state transitions modulate time-ordered gene expression during CM maturation.

developmental biology↗

bioRxiv2021

Repurposing melanoma chemotherapy to activate inflammasomes in treatment of BRAF/MAPK inhibitor-resistant melanoma

The development of resistance to treatments of melanoma is commonly associated with upregulation of the MAPK pathway and development of an undifferentiated state. Prior studies have suggested that melanoma with these resistance characteristics may be susceptible to innate death mechanisms such as pyroptosis triggered by activation of inflammasomes. In the present studies we have taken cell lines from patients before and after development of resistance to BRAF V600 inhibitors and exposed the resistant melanoma to temozolomide (a commonly used chemotherapy) with and without chloroquine to inhibit autophagy. It was found that melanoma with an inflammatory undifferentiated state appeared susceptible to this combination when tested in vitro and in vivo against xenografts in NSG mice. Translation of the latter results into patients would promise durable responses in patients treated by the combination. The inflammasome and death mechanism involved appeared to vary between melanoma and involved either AIM2, NLRP3 or NLRC4 inflammasomes and gasdermin D or E. These preliminary studies have raised questions as to the selectivity for different inflammasomes in different melanoma and their selective targeting by chemotherapy. They also question whether the inflammatory state of melanoma may be used as biomarkers to select patients for inflammasome targeted therapy.

cancer biology↗