Transdifferentiation of fibroblasts into induced neuronal cells (iNs) by the neuron-specific transcription factors Brn2, Myt1l, and Ascl1 is a paradigmatic example of inter-lineage conversion across epigenetically distant cells. Despite tremendous progress regarding the transcriptional hierarchy underlying transdifferentiation, the enablers of the concomitant epigenome resetting remain to be elucidated. Here, we investigated the role of KMT2A and KMT2B, two histone H3 lysine 4 methylases with cardinal roles in development, through individual and combined inactivation. We found that Kmt2b, whose human homolog's mutations cause dystonia, is selectively required for iN conversion through suppression of the alternative myocyte program and induction of neuronal maturation genes. The identification of KMT2B-vulnerable targets allowed us, in turn, to expose, in a cohort of 225 patients, 45 unique variants in 39 KMT2B targets, which represent promising candidates to dissect the molecular bases of dystonia.

• MeSH
• buněčná diferenciace genetika   MeSH
• dystonie genetika   MeSH
• embryo savčí cytologie   MeSH
• epigeneze genetická MeSH
• fibroblasty cytologie   MeSH
• genetické asociační studie * MeSH
• histonlysin-N-methyltransferasa metabolismus   MeSH
• histony metabolismus   MeSH
• lidé MeSH
• lysin metabolismus   MeSH
• metylace MeSH
• myši knockoutované MeSH
• neurony metabolismus   patologie   MeSH
• protoonkogenní protein MLL metabolismus   MeSH
• transdiferenciace buněk * genetika   MeSH
• transkriptom genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND INFORMATION: The in vitro co-culture models of communication between normal fibroblasts and epithelial cells, such as keratinocytes or squamous cell carcinoma cells of FaDu line representing wound healing or cancer development, were established by non-direct contact between the cells and utilised in this study to examine epithelia-induced changes in overall fibroblast proteome patterns. RESULTS: We were able to select the proteins co-regulated in both models in order to evaluate possible molecular commonalities between wound healing and tumour development. Amongst the most pronounced were the proteins implemented in contractile activity and formation of actin cytoskeleton such as caldesmon, calponin-2, myosin regulatory light-chain 12A and cofilin-1, which were expressed independently of the presence of α-smooth muscle actin. Additionally, proteins altered differently highlighted functional and cellular phenotypes during transition of fibroblasts towards myofibroblasts or cancer-associated fibroblasts. Results showed coordinated regulation of cytoskeleton proteins selective for wound healing which were lost in tumourigenesis model. Vimentin bridged this group of proteins with other regulated proteins in human fibroblasts involved in protein or RNA processing and metabolic regulation. CONCLUSIONS: The findings provide strong support for crucial role of stromal microenvironment in wound healing and tumourigenesis. In particular, epithelia-induced protein changes in fibroblasts offer new potential targets which may lead to novel tailored cancer therapeutic strategies.

• MeSH
• cytoskelet genetika   MeSH
• cytoskeletální proteiny * biosyntéza   genetika   MeSH
• fibroblasty * patologie   fyziologie   MeSH
• hojení ran * genetika   MeSH
• karcinogeneze * genetika   patologie   MeSH
• keratinocyty patologie   fyziologie   MeSH
• kokultivační techniky MeSH
• lidé MeSH
• mezibuněčná komunikace MeSH
• myofibroblasty patologie   fyziologie   MeSH
• nádorové buněčné linie MeSH
• regulace genové exprese MeSH
• spinocelulární karcinom genetika   patologie   MeSH
• transdiferenciace buněk genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• Alzheimerova nemoc etiologie   terapie   MeSH
• amyotrofická laterální skleróza etiologie   terapie   MeSH
• centrální nervový systém cytologie   imunologie   MeSH
• cévní mozková příhoda etiologie   terapie   MeSH
• hipokampus anatomie a histologie   cytologie   MeSH
• Huntingtonova nemoc etiologie   terapie   MeSH
• kmenové buňky * cytologie   klasifikace   MeSH
• lidé MeSH
• nervová tkáň * cytologie   fyziologie   imunologie   MeSH
• neurodegenerativní nemoci etiologie   genetika   MeSH
• neurogeneze * fyziologie   genetika   imunologie   MeSH
• neuroplasticita fyziologie   genetika   imunologie   MeSH
• Parkinsonova nemoc etiologie   terapie   MeSH
• poranění míchy diagnóza   etiologie   rehabilitace   MeSH
• reprodukční techniky využití   MeSH
• roztroušená skleróza etiologie   terapie   MeSH
• transdiferenciace buněk fyziologie   genetika   imunologie   MeSH
• Check Tag
• lidé MeSH