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

• Document type: Journal article
• Source: BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS; v. 1866, n. 1, p. 13-pg., 2023-01-25.

Abstract

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)

• FAPESP's process: 19/06982-6 - Characterization and development of new modulators of the TrkA and PKMzeta pathways in inflammatory and chronic pain
• Grantee: Deborah Schechtman
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 15/24046-5 - Characterizing aPKC signaling substrates and binding partners in cell polarity
• Grantee: Deborah Schechtman
• Support Opportunities: Scholarships abroad - Research
• FAPESP's process: 20/13929-1 - Effects of CIPA-associated mutations in TrkA on the pain signaling pathways and development of nociceptive neurons
• Grantee: Felipe Monteleone Vieceli
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 20/16204-8 - Transcriptional regulation of PKM zeta kinase and its association in the establishment of chronic pain
• Grantee: Carolina Purcell Goes
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 15/17812-3 - Mecanisms of regulation of the expression of the atypical protein kinase C PKMz and identification of interacting proteins in a neuro specific context.
• Grantee: Dimitrius Tansini Pramio
• Support Opportunities: Scholarships in Brazil - Doctorate