Biology subjects

Sin, Z.

Publications and source records attributed to Sin, Z..

3 recordsLinked to original sources

bioRxiv2026

Fasting disrupts the InsP6 HDAC3 axis to drive ER stress-mediated clearance of DNA-damaged cells and enforce tissue quality control.

Fasting drives metabolic adaptation but also elicits acute cellular stress. How this stress shapes tissue integrity is unknown. Here, we show that in the intestine, fasting depletes growth factor signaling, which triggers cellular stress. This response functions as a tissue quality-control checkpoint that selectively eliminates pre-existing DNA-damaged cells while sparing healthy counterparts. A short-term fast diminishes TGF-{beta} signaling and elicits endoplasmic reticulum (ER) stress, driving DNA-damaged intestinal cells beyond an apoptotic threshold, thereby reducing the inflammatory burden. Mechanistically, loss of TGF-{beta} signaling triggers FBXO22-Cullin1-mediated degradation of the inositol kinase IPMK, leading to depletion of inositol hexaphosphate (InsP). InsP loss attenuates HDAC3 activity and initiates coordinated epigenetic and post-translational reprogramming, thereby increasing CDK5RAP3 abundance. Elevated CDK5RAP3 inhibits ribosomal RPL26 UFMylation, thereby amplifying ER stress and selectively licensing apoptosis in DNA-damaged cells. Collectively, fasting disrupts a TGF-{beta}-InsP6-HDAC3 axis to drive ER stress-dependent clearance of DNA-damaged cells, enforcing tissue quality control.

cell biology↗

bioRxiv2024

Inositol Hexaphosphate (InsP6) Activates the HDAC1/3 Epigenetic Axis toMaintain Intestinal Barrier Function

While HDAC inhibition shows promise in cancer treatment, pan-HDAC inhibitors cause gastrointestinal issues in 48% of patients. Understanding HDAC activation mechanisms is crucial to treat diverse diseases beyond cancer. Our study reveals the essential role of inositol polyphosphate multikinase (IPMK) and inositol hexakisphosphate (InsP6 or phytic acid), enriched in vegan diets, in activating the HDAC3 epigenetic axis and maintaining intestinal barrier integrity. IPMK binds to HDAC3, driving InsP6 synthesis, which selectively activates HDAC3 at 10nM concentration by recruiting the DAD domain of its corepressor protein. IPMK deletion diminishes HDAC3 activation, leading to histone hyperacetylation and MMP gene transcription, compromising intestinal barrier integrity. InsP6 treatment is sufficient to rescue these effects. In inflammatory bowel disease, diminished IPMK levels exacerbated intestinal permeability, while oral InsP6 treatment mitigated gut permeability by restoring the HDAC3 epigenetic axis, indicating the clinical implications of the IPMK-HDAC3 epigenetic axis and therapeutic potential of phytic acid.

cell biology↗

bioRxiv2024

βA3/A1-crystallin is an epigenetic regulator of histone deacetylase 3 (HDAC3) in the retinal pigmented epithelial (RPE) cells

Introductory paragraphThe retinal pigmented epithelial (RPE) cells maintain retinal homeostasis, and alterations in their function contribute to non-exudative age-related macular degeneration (AMD)1,2. Here, we explore the intricate relationship between RPE cells, epigenetic modifications, and the development of AMD. Importantly, the study reveals a substantial decrease in histone deacetylase 3 (HDAC3) activity and elevated histone acetylation in the RPE of human AMD donor eyes. To investigate epigenetic mechanisms in AMD development, we used a mouse model with RPE-specific Cryba1 knockout3-5, revealing that the loss of {beta}A3/A1-crystallin selectively reduces HDAC3 activity, resulting in increased histone acetylation. {beta}A3/A1-crystallin activates HDAC3 by facilitating its interaction with the casein kinase II (CK2) and phosphorylating HDAC3, as well as by regulating intracellular InsP6 (phytic acid) levels, required for activating HDAC3. These findings highlight a novel function of {beta}A3/A1-crystallin as an epigenetic regulator of HDAC3 in the RPE cells and provide insights into potential therapeutic strategies in non-exudative AMD.

cell biology↗