SFEBES2026 Oral Communications Metabolism, Obesity and Diabetes (6 abstracts)
A targeted epi-drug screen identifies HDAC6 inhibition as an enhancer of beta cell function and immune evasion
Maria Kalogeraki 1 , Tingyun Guan 1 , Kaiyven Afi Leslie 2 , Vicky Sham 1 , Matthew Johnson 2 , Adrien Osakwe 3 , Junyue Huang 4 , Remi Fiancette 4 , Wenchi Leu 1 , Ethan Xie 1 , Sayed Tabibi 1 , Caitlin Gray 2 , Guy Rutter 5,6,1 , Robert Sladek 3 , Jesus Gil 7,1 , Ildem Akerman 4 , Noel Morgan 2 , Mark Russell 2 & Steven Millership 1
1Imperial College London, London, United Kingdom; 2University of Exeter, Exeter, United Kingdom; 3McGill University, Montreal, Canada; 4University of Birmingham, Birmingham, United Kingdom; 5University of Montreal, Montreal, Canada; 6NTU, Singapore, Singapore; 7MRC LMS, London, United Kingdom
The destruction or dysfunction of pancreatic beta cells is central to the aetiology and pathogenesis of type 1 and type 2 diabetes (T1D/T2D), respectively. Human genetic approaches have indicated that the immune system is a key primary driver in T1D, and beta cells display inherent vulnerability to cytotoxic T lymphocytes vs other islet cells. We and others have demonstrated the importance of epigenetic pathways, including CpG methylation and modification to histone proteins, as drivers of beta cell functional maturation and/or function. We therefore screened for epigenetic molecules with potentially beneficial effects on beta cell adaptation using a library of ‘epi’-drugs. Our drug screen uncovered a novel role for a cytosolic histone deacetylase (HDAC) 6 whose inhibition increased insulin content and release in immature human beta cells, primary islets and stem cell-derived islet clusters. Meta-analysis of previously defined islet scRNA-seq datasets as well as pseudo-timing analysis also suggested that HDAC6 expression is aberrantly expressed at high levels in immature vs mature beta cells, consistent with an inverse relationship between HDAC6 expression and beta cell function. We have previously shown that HDAC6 inhibition mediates an anti-inflammatory response in beta cells via maintenance of STAT1 acetylation, thereby attenuating STAT1 phosphorylation. Consistent with these findings, RNA-seq analysis following HDAC6 inhibition in human beta cells revealed an enrichment for immune response pathways, increased expression of survival genes, as well as increased beta cell identity markers and diminished expression of beta cell ‘disallowed’ genes. HDAC6 inhibition also attenuated STAT3 activity and reduced beta cell surface expression of HLA class I proteins in response to pro-inflammatory cytokines, the latter a major hallmark of T1D. Overall, our findings demonstrate that HDAC6 inhibition in human beta cells may have therapeutic potential early in T1D to prevent/slow the autoimmune attack.
Volume 117
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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