Nutritional constraints including not only caloric restriction or protein deficiency, but also energy-dense diets affect metabolic health and frequently lead to obesity and insulin resistance, as ...well as glucose intolerance and type 2 diabetes. The effects of these environmental factors are often mediated via epigenetic modifiers that target the expression of metabolic genes. More recently, it was discovered that such parentally acquired metabolic changes can alter the metabolic health of the filial and grand-filial generations. In mammals, this epigenetic inheritance can either follow an intergenerational or transgenerational mode of inheritance. In the case of intergenerational inheritance, epimutations established in gametes persist through the first round of epigenetic reprogramming occurring during preimplantation development. For transgenerational inheritance, epimutations persist additionally throughout the reprogramming that occurs during germ cell development later in embryogenesis. Differentially expressed transcripts, genomic cytosine methylations, and several chemical modifications of histones are prime candidates for tangible marks which may serve as epimutations in inter- and transgenerational inheritance and which are currently being investigated experimentally. We review, here, the current literature in support of epigenetic inheritance of metabolic traits caused by nutritional constraints and potential mechanisms in man and in rodent model systems.
HDAC2 Facilitates Pancreatic Cancer Metastasis Krauß, Lukas; Urban, Bettina C; Hastreiter, Sieglinde ...
Cancer research (Chicago, Ill.),
02/2022, Letnik:
82, Številka:
4
Journal Article
Recenzirano
Odprti dostop
The mortality of patients with pancreatic ductal adenocarcinoma (PDAC) is strongly associated with metastasis, a multistep process that is incompletely understood in this disease. Although genetic ...drivers of PDAC metastasis have not been defined, transcriptional and epigenetic rewiring can contribute to the metastatic process. The epigenetic eraser histone deacetylase 2 (HDAC2) has been connected to less differentiated PDAC, but the function of HDAC2 in PDAC has not been comprehensively evaluated. Using genetically defined models, we show that HDAC2 is a cellular fitness factor that controls cell cycle in vitro and metastasis in vivo, particularly in undifferentiated, mesenchymal PDAC cells. Unbiased expression profiling detected a core set of HDAC2-regulated genes. HDAC2 controlled expression of several prosurvival receptor tyrosine kinases connected to mesenchymal PDAC, including PDGFRα, PDGFRβ, and EGFR. The HDAC2-maintained program disabled the tumor-suppressive arm of the TGFβ pathway, explaining impaired metastasis formation of HDAC2-deficient PDAC. These data identify HDAC2 as a tractable player in the PDAC metastatic cascade. The complexity of the function of epigenetic regulators like HDAC2 implicates that an increased understanding of these proteins is needed for implementation of effective epigenetic therapies.
HDAC2 has a context-specific role in undifferentiated PDAC and the capacity to disseminate systemically, implicating HDAC2 as targetable protein to prevent metastasis.
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