Biology subjects

Gamliel, A.

Publications and source records attributed to Gamliel, A..

3 recordsLinked to original sources

bioRxiv2025

Endogenous Real Time Imaging Reveals Dynamic Chromosomal Mobility During Ligand-Mediated Transcriptional Burst Events

Enhancers serve as the major genomic elements regulating mammalian signal-dependent transcriptional programs, characterized by alternating periods of target gene "bursting" and "non-busting" that require investigation of induced enhancer condensates and locus motility in real time to provide dynamic insights into signal/ligand-dependent regulatory events. Here, endogenous live cell imaging has revealed the altered chromosomal dynamics/condensate formation occurring during estrogen receptor (ER)-dependent target gene bursting/post-bursting and chronic activation events. Simultaneous DNA/RNA endogenous live imaging reveals that an increased mobility of acutely ER-stimulated loci observed during the bursting phase is, unexpectedly, further increased in the subsequent non-burst phase. Single molecule tracking (SMT) of ER shows that the relatively high-burst, lower-mobility acute state was indeed enriched for high-viscosity, 1,6-hexanediol-sensative ER molecules in a low sub-diffusive confined state with enhanced condensate formation during burst activation. Consistent with this, blocking transcription with flavopiridol shifts DNA tracks into a non-confined state. Differential DNA kinetics during burst vs non-burst has provided a strategy to assess altered condensate formation during gene activation events. (165)

molecular biology↗

bioRxiv2024

Recruitment of CTCF to the SIRT1 promoter after Oxidative Stress mediates Cardioprotective Transcription

Because most DNA-binding transcription factors (dbTFs), including the architectural regulator CTCF, bind RNA and exhibit di-/multimerization, a central conundrum is whether these distinct properties are regulated post-transcriptionally to modulate transcriptional programs. Here, investigating stress-dependent activation of SIRT1, encoding an evolutionarily-conserved protein deacetylase, we show that induced phosphorylation of CTCF acts as a rheostat to permit CTCF occupancy of low-affinity promoter DNA sites to precisely the levels necessary. This CTCF recruitment to the SIRT1 promoter is eliciting a cardioprotective cardiomyocyte transcriptional activation program and provides resilience against the stress of the beating heart in vivo. Mice harboring a mutation in the conserved low-affinity CTCF promoter binding site exhibit an altered, cardiomyocyte-specific transcriptional program and a systolic heart failure phenotype. This transcriptional role for CTCF reveals that a covalent dbTF modification regulating signal-dependent transcription serves as a previously unsuspected component of the oxidative stress response.

cell biology↗

bioRxiv2022

The regulatory landscapes of human ovarian ageing

Summary paragraphThe ovary is the first organ to age in the human body, affecting both fertility and overall health in women1-8. However, the biological mechanisms underlying human ovarian ageing remain poorly understood. Here we performed single-nuclei multi-omics analysis of young and reproductively aged human ovaries to understand the molecular and cellular basis of ovarian ageing in humans. Our analysis reveals coordinated changes in transcriptomic output and chromatin accessibility across cell types during ageing, including elevated mTOR and MAPK signaling, decreased activity of the oxidative phosphorylation and DNA damage repair pathways, and an increased signature of cellular senescence. By constructing cell type-specific regulatory networks, we uncover enhanced activity of the transcription factor CEBPD across cell types in the aged ovary, with a corresponding significant loss of activity of most cell identity-associated transcription factors. Moreover, by performing integrative analyses of our single-nuclei multi-omics data with common genetic variants associated with age at natural menopause (ANM) from genome-wide association studies, we demonstrate a global impact of functional variants on changes in gene regulatory networks across ovarian cell types. Finally, we nominate about a dozen of functional non-coding variants, their target genes and cell types and regulatory mechanisms that underlie genetic association with ANM. This work provides a comprehensive multimodal landscape of human ovarian ageing and mechanistic insights into inherited variation of ANM.

genomics↗