Gene expression and epigenetic processes in several brain regions regulate physiological processes such as cognitive functions and social behavior. MacroH2A1.1 is a ubiquitous variant of histone H2A that regulates cell stemness and differentiation in various organs. Whether macroH2A1.1 has a modulatory role in emotional behavior is unknown. Here, we employed macroH2A1.1 knock-out (-/- ) mice to perform a comprehensive battery of behavioral tests, and an assessment of hippocampal synaptic plasticity (long-term potentiation) accompanied by whole hippocampus RNA sequencing. MacroH2A1.1-/- mice exhibit a stunningly enhancement both of sociability and of active stress-coping behavior, reflected by the increased social behavior in social activity tests and higher mobility time in the forced swim test, respectively. They also display an increased hippocampal synaptic plasticity, accompanied by significant neurotransmission transcriptional networks changes. These results suggest that systemic depletion of histone macroH2A1.1 supports an epigenetic control necessary for hippocampal function and social behavior.

• MeSH
• adaptace psychologická MeSH
• chování zvířat * MeSH
• hipokampus cytologie   MeSH
• histony klasifikace   genetika   metabolismus   MeSH
• myši knockoutované MeSH
• myši MeSH
• neuroplasticita fyziologie   MeSH
• psychický stres MeSH
• regulace genové exprese MeSH
• sociální chování MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Epigenetic regulation is important in hematopoiesis, but the involvement of histone variants is poorly understood. Myelodysplastic syndromes (MDS) are heterogeneous clonal hematopoietic stem cell (HSC) disorders characterized by ineffective hematopoiesis. MacroH2A1.1 is a histone H2A variant that negatively correlates with the self-renewal capacity of embryonic, adult, and cancer stem cells. MacroH2A1.1 is a target of the frequent U2AF1 S34F mutation in MDS. The role of macroH2A1.1 in hematopoiesis is unclear. RESULTS: MacroH2A1.1 mRNA levels are significantly decreased in patients with low-risk MDS presenting with chromosomal 5q deletion and myeloid cytopenias and tend to be decreased in MDS patients carrying the U2AF1 S34F mutation. Using an innovative mouse allele lacking the macroH2A1.1 alternatively spliced exon, we investigated whether macroH2A1.1 regulates HSC homeostasis and differentiation. The lack of macroH2A1.1 decreased while macroH2A1.1 haploinsufficiency increased HSC frequency upon irradiation. Moreover, bone marrow transplantation experiments showed that both deficiency and haploinsufficiency of macroH2A1.1 resulted in enhanced HSC differentiation along the myeloid lineage. Finally, RNA-sequencing analysis implicated macroH2A1.1-mediated regulation of ribosomal gene expression in HSC homeostasis. CONCLUSIONS: Together, our findings suggest a new epigenetic process contributing to hematopoiesis regulation. By combining clinical data with a discrete mutant mouse model and in vitro studies of human and mouse cells, we identify macroH2A1.1 as a key player in the cellular and molecular features of MDS. These data justify the exploration of macroH2A1.1 and associated proteins as therapeutic targets in hematological malignancies.

• MeSH
• buněčná diferenciace MeSH
• chromozomální delece MeSH
• down regulace * MeSH
• epigeneze genetická MeSH
• haploinsuficience MeSH
• hematopoetické kmenové buňky chemie   cytologie   MeSH
• histony genetika   MeSH
• lidé MeSH
• lidské chromozomy, pár 5 genetika   MeSH
• makrocytární anemie genetika   MeSH
• místa sestřihu RNA MeSH
• modely nemocí na zvířatech MeSH
• mutace MeSH
• myelodysplastické syndromy genetika   MeSH
• myši MeSH
• sekvenční analýza RNA MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Hepatocellular carcinoma (HCC) has one of the worst prognoses amongst all malignancies. It commonly arises in patients with established liver disease and the diagnosis often occurs at an advanced stage. Genetic variations, such as single nucleotide polymorphisms (SNPs), may alter disease risk and thus may have use as predictive markers of disease outcome. The aims of this study were (i) to assess the association of two SNPs, rs430397 in GRP78 and rs738409 in PNPLA3 with the risk of developing HCC in a Sicilian association cohort and, (ii) to use a machine learning technique to establish a predictive combinatorial phenotypic model for HCC including rs430397 and rs738409 genotypes and clinical and laboratory attributes. The controls comprised of 304 healthy subjects while the cases comprised of 170 HCC patients the majority of whom had hepatitis C (HCV)-related cirrhosis. Significant associations were identified between the risk of developing HCC and both rs430397 (p=0.0095) and rs738409 (p=0.0063). The association between rs738409 and HCC was significantly stronger in the HCV positive cases. In the best prediction model, represented graphically by a decision tree with an acceptable misclassification rate of 17.0%, the A/A and G/A genotypes of the rs430397 variant were fixed and combined with the three rs738409 genotypes; the attributes were age, sex and alcohol. These results demonstrate significant associations between both rs430397 and rs738409 and HCC development in a Sicilian cohort. The combinatorial predictive model developed to include these genetic variants may, if validated in independent cohorts, allow for earlier diagnosis of HCC.

• MeSH
• alely MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci genetika   MeSH
• genotyp MeSH
• hepatocelulární karcinom genetika   MeSH
• jednonukleotidový polymorfismus * MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• lipasa genetika   MeSH
• membránové proteiny genetika   MeSH
• nádory jater genetika   MeSH
• proteiny tepelného šoku genetika   MeSH
• rizikové faktory MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Sicilie MeSH