| First Author | Kaur G | Year | 2023 |
| Journal | PLoS One | Volume | 18 |
| Issue | 8 | Pages | e0286109 |
| PubMed ID | 37624843 | Mgi Jnum | J:339369 |
| Mgi Id | MGI:7521472 | Doi | 10.1371/journal.pone.0286109 |
| Citation | Kaur G, et al. (2023) Helicase-like transcription factor (Hltf)-deletion activates Hmgb1-Rage axis and granzyme A-mediated killing of pancreatic beta cells resulting in neonatal lethality. PLoS One 18(8):e0286109 |
| abstractText | Epigenetic mechanisms are integral to pancreatic beta cell function. Promoter hypermethylation of the helicase like-transcription factor (HLTF) gene-a component of the cellular DNA damage response that contributes to genome stability-has been implicated in age-associated changes in beta cells. To study HLTF, we generated global and beta cell-specific (beta) Hltf knockout (KO) immune competent (IC) and immune deficient (ID) Rag2-/IL2- mice. IC global and beta Hltf KO mice were neonatal lethal whereas ID global and beta Hltf KO newborn mice had normal survival. This focused our investigation on the effects of Rag2 interruption with common gamma chain interruption on beta cell function/survival. Three-way transcriptomic (RNAseq) analyses of whole pancreata from IC and ID newborn beta Hltf KO and wild type (Hltf +/+) controls combined with spatially resolved transcriptomic analysis of formalin fixed paraffin embedded tissue, immunohistochemistry and laser scanning confocal microscopy showed DNA damage caused by beta Hltf KO in IC mice upregulated the Hmgb1-Rage axis and a gene signature for innate immune cells. Perforin-delivered granzyme A (GzmA) activation of DNase, Nme1, showed damaged nuclear single-stranded DNA (gammaH2AX immunostaining). This caspase-independent method of cell death was supported by transcriptional downregulation of Serpinc1 gene that encodes a serine protease inhibitor of GzmA. Increased transcriptional availability of complement receptors C3ar1 and C5ar1 likely invited crosstalk with Hmgb1 to amplify inflammation. This study explores the complex dialog between beta cells and immune cells during development. It has implications for the initiation of type I diabetes in utero when altered gene expression that compromises genome stability invokes a localized inflammatory response. |
