HDAC3 is a protein that controls the activity of genes required to keep the lining of the intestine intact and functioning properly.
Mechanism
Synthesis from 3 studies
HDAC3 keeps the gut lining sealed by turning off genes that break down the connections between gut cells. It does this by removing a specific chemical tag from DNA packaging, which stops destructive enzymes from being made. Without these enzymes, the gut stays tightly sealed and doesn't leak.
Most probable mechanism
A specific protein called HDAC3 turns off genes that would otherwise break down the glue holding gut cells together. It does this by removing chemical tags from DNA packaging material, which silences genes that produce destructive enzymes. When these enzymes are turned off, the tight connections between gut cells stay intact, preventing leaks. If HDAC3 doesn't work, those enzymes get turned on, the connections break, and the gut becomes leaky.
HDAC3 is recruited to chromatin at promoter regions of matrix metalloproteinase (MMP) genes through interaction with a kinase that synthesizes inositol hexaphosphate (InsP6)
InsP6 binds directly to HDAC3 and induces conformational change that enables recruitment of the DAD domain of the NCoR1/2 corepressor complex, activating HDAC3's deacetylase function
Activated HDAC3 removes acetyl groups from histone H4 at lysine 16 at MMP gene promoters
Deacetylation of histone H4K16 represses transcription of MMP genes including MMP1, MMP3, MMP10, and MMP13
Reduced MMP enzyme production prevents degradation of tight junction proteins such as ZO-1, occludin, and claudin-1
Preservation of tight junction proteins maintains low paracellular permeability and structural integrity of the intestinal epithelial barrier
Evidence from Studies
Supporting (2)
Community contributions welcome
Phytic acid (InsP6) activates HDAC3 epigenetic axis to maintain intestinal barrier function
Phytic Acid (InsP6) Activates HDAC3 Epigenetic Axis to Maintain Intestinal Barrier Function
Contradicting (1)
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Butyrate suppresses mucosal inflammation in inflammatory bowel disease primarily through HDAC3 inhibition in monocytes and macrophages
Gold Standard Evidence Needed
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