Biology subjects

Merino, J. M.

Publications and source records attributed to Merino, J. M..

2 recordsLinked to original sources

bioRxiv2021

ARYL HYDROCARBON RECEPTOR BLOCKS AGING-INDUCED SENESCENCE IN THE LIVER AND FIBROBLAST CELLS

Aging induces progressive organ degeneration and worsening of tissue homeostasis leading to multiple pathologies. Yet, little is known about the mechanisms and molecular intermediates involved. Here, we report that aged aryl hydrocarbon receptor-null mice (AhR-/-) had exacerbated senescence and larger numbers of liver progenitor cells. Senescence-associated markers {beta}-galactosidase (SA-{beta}-Gal), p16Ink4a and p21Cip1 and genes of the senescence-associated secretory phenotype (SASP) TNF and IL1 were overexpressed in aged AhR-/- livers. AhR binding to the promoter of those genes, as shown by chromatin immunoprecipitation, likely had a repressive effect maintaining their physiological levels in AhR+/+ livers. Furthermore, factors secreted by senescent cells MCP-2, MMP12 and FGF were also produced at higher levels in aged AhR-null livers. Supporting the linkage between senescence and stemness, liver progenitor cells were more abundant in AhR-/- mice, which could probably contribute to their increased hepatocarcinoma burden. These roles of AhR are not liver-specific since adult and embryonic AhR-null fibroblasts acquired cellular senescence upon culturing with overexpression of SA-{beta}-Gal, p16Ink4a and p21Cip1. Notably, depletion of senescent cells with the senolytic agent navitoclax restored basal expression of senescent markers in AhR-/- fibroblasts. Oppositely, senescence promoter palbociclib induced an AhR-null like phenotype in AhR+/+ fibroblasts. Moreover, doxycycline-induced senescence reduced AhR levels while depletion of p16Ink4a-expressing senescent cells restored basal AhR levels in mouse lungs. Thus, AhR is needed to restrict age-induced senescence, and such activity seems to correlate with a more differentiated phenotype and with increased resistance to liver tumorigenesis.

cancer biology↗

bioRxiv2020

The Aryl Hydrocarbon Receptor Promotes Differentiation During Mouse Preimplantational Embryo Development

Mammalian embryogenesis is a complex process controlled by transcription factors that dynamically regulate the balance between pluripotency and differentiation. Transcription factor AhR is known to regulate Oct4/Pou5f1 and Nanog, both essential genes in pluripotency, stemness and early embryo development. Yet, the molecular mechanisms controlling Oct4/Pou5f1 and Nanog during embryo development remain largely unidentified. Here, we show that AhR is required for proper embryo differentiation by regulating pluripotency factors and by maintaining adequate metabolic activity. AhR lacking embryos (AhR-/-) showed a more pluripotent phenotype characterized by a delayed expression of differentiation markers of the first and second cell divisions. Accordingly, central pluripotency factors OCT4/POU5F1, NANOG, and SOX2 were overexpressed in AhR-/- embryos at initial developmental stages. An altered intracellular localization of these factors was observed in absence of AhR and, importantly, OCT4 had an opposite expression pattern with respect to AhR from the 2-cell stage to blastocyst, suggesting a negative regulatory mechanism of OCT4/POU5F by AhR. Hippo signalling, rather than being repressed, was upregulated in very early AhR-/- embryos, possibly contributing to their undifferentiation at later stages. Consistently, AhR-null blastocysts overexpressed the early marker of inner cell mass (ICM) differentiation Sox17 whereas downregulated extraembryonic differentiation-driving genes Cdx2 and Gata3. Moreover, the persistent pluripotent phenotype of AhR-/- embryos was supported by an enhanced glycolytic metabolism and a reduction in mitochondrial activity. We propose that AhR is a regulator of pluripotency and differentiation in early mouse embryogenesis and that its deficiency may underline the reduced viability and increased resorptions of AhR-null mice.

developmental biology↗