Pharmacological HDAC Inhibition Impairs Pancreatic β-Cell Function Through an Epigenome-Wide Reprogramming

Oger, Frédérik; Moreno, Maeva; Derhourhi, Mehdi; Thiroux, Bryan; Berberian, Lionel; Bourouh, Cyril; Durand, Emmanuelle; Amanzougarene, Souhila; Badreddine, Alaa; Blanc, Étienne; Molendi-Coste, Olivier; Pineau, Laurent; Pasquetti, Gianni; Rolland, Laure; Carney, Charlène; Bornaque, Florine; Courty, Émilie; Gheeraert, Céline; Eeckhoute, Jérôme; Dombrowicz, David; Kerr–Conte, Julie; Pattou, François; Staels, Bart; Froguel, Philippe; Bonnefond, Amélie; Annicotte, Jean-Sébastien

doi:10.2139/ssrn.4347242

Cited by 2 publications

(3 citation statements)

References 36 publications

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“…Histone hyperacetylation by TSA reduced the partitioning between active and repressive targets. It decreased the co-enrichment of activation-associated targets and redistributed them to traditionally heterochromatic regions which is in agreement with prior studies demonstrating that TSA leads to both up-and downregulated gene expression 71,72 .…”

Section: Discussionsupporting

confidence: 92%

“…6B). This suggests that, in addition to reinforcing existing acetylated domains, TSA treatment leads to hyperacetylation throughout the nucleus [56][57][58] ; however, it may also lead to counterintuitive effects such as hypoacetylation of some gene regulatory elements, such as promoters 58,59 . Concordant with the increased histone acetylation, and in agreement with prior literature 43,60 , TSA treatment also decondensed DNA (Fig.…”

Section: Histone Hyperactylation Reduces Nuclear Compartmentalization...mentioning

confidence: 99%

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Mapping the nuclear landscape with multiplexed super-resolution fluorescence microscopy

Rahman,

Augoustides,

Tyler

et al. 2024

Preprint

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The nucleus coordinates many different processes. Visualizing how these are spatially organized requires imaging protein complexes, epigenetic marks, and DNA across scales from single molecules to the whole nucleus. To accomplish this, we developed a multiplexed imaging protocol to localize 13 different nuclear targets with nanometer precision in single cells. We show that nuclear specification into active and repressive states exists along a spectrum of length scales, emerging below one micron and becoming strengthened at the nanoscale with unique organizational principles in both heterochromatin and euchromatin. HP1-α was positively correlated with DNA at the microscale but uncorrelated at the nanoscale. RNA Polymerase II, p300, and CDK9 were positively correlated at the microscale but became partitioned below 300 nm. Perturbing histone acetylation or transcription disrupted nanoscale organization but had less effect at the microscale. We envision that our imaging and analysis pipeline will be useful to reveal the organizational principles not only of the cell nucleus but also other cellular compartments.

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Section: Discussionsupporting

confidence: 92%

Section: Histone Hyperactylation Reduces Nuclear Compartmentalization...mentioning

confidence: 99%

Mapping the nuclear landscape with multiplexed super-resolution fluorescence microscopy

Rahman,

Augoustides,

Tyler

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…However, mice carrying a constitutive b-cell-specific (Rip-Cre) deletion of HDAC3 caused an impairment of b-cell function 41 . This was consistent with a study that showed that the administration of HDAC inhibitors to the rodent b-cell line b-TC3 led to a loss of b-cell identity, with a concomitant elevation in a-cell marker expression within b-cells 42 , and a more recent study that reported HDAC inhibition using the pan-HDAC inhibitor, trichostatin A, appeared to impair pancreatic b-cell function through an epigenome wide reprogramming 43 . The discrepant results from all these studies suggest that the function of HDACs is more nuanced than appreciated, and a balance of the different HAT and HDAC activitiesperhaps in response to external conditionsmight function as a rheostat for sensing the metabolic condition of cells and translating it into an appropriate cellular response.…”

Section: Histone Acetylationsupporting

confidence: 89%

Glucose metabolism partially regulates β‐cell function through epigenomic changes

Kim,

Won,

Sussel

2024

J of Diabetes Invest

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The β‐cell relies predominantly on glucose utilization to generate adenosine triphosphate, which is crucial for both cell viability and insulin secretion. The β‐cell has evolved remarkable metabolic flexibility to productively respond to shifts in environmental conditions and changes in glucose availability. Although these adaptive responses are important for maintaining optimal cellular function, there is emerging evidence that the resulting changes in cellular metabolites can impact the epigenome, causing transient and lasting alterations in gene expression. This review explores the intricate interplay between metabolism and the epigenome, providing valuable insights into the molecular mechanisms leading to β‐cell dysfunction in diabetes. Understanding these mechanisms will be critical for developing targeted therapeutic strategies to preserve and enhance β‐cell function, offering potential avenues for interventions to improve glycemic control in individuals with diabetes.

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Pharmacological HDAC Inhibition Impairs Pancreatic β-Cell Function Through an Epigenome-Wide Reprogramming

Cited by 2 publications

References 36 publications

Mapping the nuclear landscape with multiplexed super-resolution fluorescence microscopy

Mapping the nuclear landscape with multiplexed super-resolution fluorescence microscopy

Glucose metabolism partially regulates β‐cell function through epigenomic changes

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