Biology subjects

Ajouaou, Y.

Publications and source records attributed to Ajouaou, Y..

3 recordsLinked to original sources

bioRxiv2026

Hepatocyte Embryonic Ectoderm Development (Eed) Deficiency Causes Liver Injury, Fibrosis and Impacts Liver Regeneration

Regeneration depends on tightly coordinated transcriptional programs governed by a dynamic epigenetic landscape to regulate cell identity, proliferation, and tissue remodelling following injury. The liver is highly regenerative due to its ability to rapidly upregulate genes that drive the cell cycle and other genes important for hepatocyte proliferation. In the uninjured liver, many of these genes are poised for activation based on promoter occupancy of trimethylated histone 3 lysine 27 (H3K27me3) and regenerative stimulus provided by partial hepatectomy leads to evacuation of this mark, suggesting this is a key component of proregenerative gene regulation in the liver. H3K27me3 is deposited by the polycomb repressive complex 2 (PRC2). Were we deplete H3K27me3 using hepatocyte specific deletion of key component of PRC2, Embryonic Ectoderm Development (EedHepKO). This results in reduced liver size, increased hepatocyte death, proliferation, and fibrosis associated with upregulation of cell cycle and fibrogenic genes. Though these mice are less likely to survive two-thirds partial hepatectomy than WT (WT) controls, those that do survive increase liver mass faster than WTs. Importantly, genes occupied by H3K27me3 in uninjured WT livers are upregulated in EEDHepKO livers, and become further induced following PH. This demonstrates that PRC2 loss induces liver injury and dysregulates pro-regenerative gene expression, highlighting that epigenetic modulation depends requires precise targeting to achieve enhanced regenerative

pathology↗

bioRxiv2021

The oxygen sensor Prolyl hydroxylase domain 2 regulates the in vivo suppressive capacity of regulatory T cells

The oxygen sensor PHD2 (prolyl hydroxylase domain 2) plays an important role in cell hypoxia adaptation by regulating the stability of HIF proteins (HIF1 and HIF2) in numerous cell types including T lymphocytes. The role of oxygen sensor on immune cells, in particular on regulatory T cell (Treg) function, has not been fully elucidated. The purpose of our study was to evaluate the role of PHD2 in the regulation of Treg phenotype and function. We demonstrate herein that selective ablation of PHD2 expression in Treg (PHD2{Delta}Treg mice) leads to a spontaneous systemic inflammatory syndrome, as evidenced by weight loss, development of a rectal prolapse, splenomegaly, shortening of the colon and elevated expression of IFN-{gamma} in the mesenteric lymph nodes, intestine and spleen. PHD2 deficiency in Tregs led to an increased number of activated CD4 conventional T cells expressing a Th1-like effector phenotype. Concomitantly, the expression of innate-type cytokines such as Il1b, Il12a, Il12b and Tnfa was found to be elevated in peripheral (gut) tissues and spleen. PHD2{Delta}Treg mice also displayed an enhanced sensitivity to DSS-induced colitis and to toxoplasmosis, suggesting that PHD2-deficient Tregs did not efficiently control inflammatory response in vivo, in particular those characterized by IFN-{gamma} production. Further analysis revealed that Treg dysregulation was largely prevented in PHD2-HIF2 (PHD2-HIF2{Delta}Treg mice), but not in PHD2-HIF1 (PHD2-HIF1{Delta}Treg mice) double KOs, suggesting an important and possibly selective role of the PHD2-HIF2 axis in the control of Treg function. Finally, the transcriptomic analysis of PHD2-deficient Tregs identified the STAT1 pathway as a target of the PHD2-HIF2 axis in regulatory T cell phenotype and in vivo function.

immunology↗

bioRxiv2019

Multiple environmental signaling pathways control the differentiation of RORγt-expressing regulatory T cells

ROR{gamma}t-expressing Tregs form a specialized subset of intestinal CD4+ Foxp3+ cells which is essential to maintain gut homeostasis and tolerance to commensal microbiota. Recently, c-Maf emerged as a critical factor in the regulation of ROR{gamma}t expression in Tregs. However, aside from c-Maf signaling, the signaling pathways involved in the differentiation of ROR{gamma}t+ Tregs and their possible interplay with c-Maf in this process are largely unknown. We show that ROR{gamma}t+ Treg development is controlled by positive as well as negative signals. Along with c-Maf signaling, signals derived from a complex microbiota, as well as IL-6/STAT3- and TGF-{beta}-derived signals act in favor of ROR{gamma}t+ Treg development. Ectopic expression of c-Maf did not rescue ROR{gamma}t expression in STAT3-deficient Tregs, indicating the presence of additional effectors downstream of STAT3. Moreover, we show that an inflammatory IFN-{gamma}/STAT1 signaling pathway acts as a negative regulator of ROR{gamma}t+ Treg differentiation in a c-Maf independent fashion.\n\nThese data thus argue for a complex integrative signaling network that finely tunes ROR{gamma}t expression in Tregs. The finding that type 1 inflammation impedes ROR{gamma}t+ Treg development even in the presence of an active IL-6/STAT3 pathway further suggests a dominant negative effect of STAT1 over STAT3 in this process.

immunology↗