DNA methylation of the promoter region at the CREB1 binding site is a mechanism for the epigenetic regulation of brain-specific PKM zeta

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Pramio, Dimitrius Tansini ; Vieceli, Felipe Monteleone ; Varella-Branco, Elisa ; Goes, Carolina Purcell ; Kobayashi, Gerson Shigeru ; Pelegrina, Diogo Vieira da Silva ; Moraes, Beatriz Caroline de ; El Allam, Aicha ; De Kumar, Bony ; Jara, Gabriel ; Farfel, Jose Marcelo ; Bennett, David Alan ; Kundu, Somanath ; Viapiano, Mariano S. ; Reis, Eduardo Moraes ; Oliveira, Paulo Sergio Lopes de ; Passos-Bueno, Maria Rita dos Santos ; V. Rothlin, Carla ; Ghosh, Sourav ; Schechtman, Deborah

• Tipo de documento: Artigo Científico
• Fonte: BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS; v. 1866, n. 1, p. 13-pg., 2023-01-25.

Resumo

Protein kinase M zeta, PKM?, is a brain enriched kinase with a well characterized role in Long-Term Potentiation (LTP), the activity-dependent strengthening of synapses involved in long-term memory formation. However, little is known about the molecular mechanisms that maintain the tissue specificity of this kinase. Here, we characterized the epigenetic factors, mainly DNA methylation, regulating PKM?expression in the human brain. The PRKCZ gene has an upstream promoter regulating Protein kinase C ? (PKC?), and an internal promoter driving PKM?expression. A demethylated region, including a canonical CREB binding site, situated at the in-ternal promoter was only observed in human CNS tissues. The induction of site-specific hypermethylation of this region resulted in decreased CREB1 binding and downregulation of PKM?expression. Noteworthy, CREB binding sites were absent in the upstream promoter of PRKCZ locus, suggesting a specific mechanism for regulating PKM? expression. These observations were validated using a system of human neuronal differentiation from induced pluripotent stem cells (iPSCs). CREB1 binding at the internal promoter was detected only in differentiated neurons, where PKM?is expressed. The same epigenetic mechanism in the context of CREB binding site was identified in other genes involved in neuronal differentiation and LTP. Additionally, aberrant DNA hyper-methylation at the internal promoter was observed in cases of Alzheimer's disease, correlating with decreased expression of PKM?in patient brains. Altogether, we present a conserved epigenetic mechanism regulating PKM? expression and other genes enhanced in the CNS with possible implications in neuronal differentiation and Alzheimer's disease. (AU)

• Processo FAPESP: 19/06982-6 - Caracterização e desenvolvimento de novos moduladores das vias da TrkA e PKMzeta na dor inflamatória e crônica
• Beneficiário: Deborah Schechtman
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 15/24046-5 - Caracterizando substratos e proteínas parceiras das aPKCs no processo de polarização celular
• Beneficiário: Deborah Schechtman
• Modalidade de apoio: Bolsas no Exterior - Pesquisa
• Processo FAPESP: 20/13929-1 - Efeito de mutações em TrkA associadas à CIPA nas vias de sinalização da dor e no desenvolvimento dos neurônios nociceptivos
• Beneficiário: Felipe Monteleone Vieceli
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 20/16204-8 - Regulação transcricional da quinase PKM zeta e sua associação no estabelecimento da dor crônica
• Beneficiário: Carolina Purcell Goes
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 15/17812-3 - Mecanismos de regulação da expressão da proteína quinase C atípica PKMZ, e identificação do seu interactoma em contextos neurais específicos.
• Beneficiário: Dimitrius Tansini Pramio
• Modalidade de apoio: Bolsas no Brasil - Doutorado